IUBMB Life, 63(10): 881–895, October 2011
Critical Review
Signaling Epigenetics: Novel Insights on Cell Signaling and
Epigenetic Regulation
Rodrigo G. Arzate-Mejı́a, David Valle-Garcı́a and Félix Recillas-Targa
Instituto de Fisiologı´a Celular, Departamento de Gene´tica Molecular, Universidad Nacional Autónoma de Me´xico, Ciudad
Universitaria, Me´xico D.F., Me´xico
Summary
Cells must be able to respond rapidly and precisely not only
to changes in their external environment but also to developmen-
tal and differentiation cues to determine when to divide, die, or
acquire a particular cell fate. Signal transduction pathways are
responsible for the integration and interpretation of most of such
signals into specific transcriptional states. Those states are
achieved by the modulation of chromatin structure that activates
or represses transcription at particular loci. Although a large va-
riety of signal transduction pathways have already been
described, much less is known about the crosstalk between signal
transduction and its consequent changes in chromatin structure
and, therefore, gene expression. Here we present some examples
of the relationship between chromatin-associated proteins and
important signal transduction pathways during critical processes
like development, differentiation, and disease. There is a great
diversity of epigenetic mechanisms that have unexpected interac-
tions with signaling pathways to establish transcriptional pro-
grams. Moreover, there are also particular cases where signaling
pathways directly affect important components of the epigenetic
machinery. Based on such examples, we further propose future
research directions linking cell signaling and epigenetics. It is
foreseeable that analyzing the relationship between cell signaling
and epigenetics will be a huge area for future development that
will help us understand the complex process by which a cell is
able to induce transcriptional changes in response to external
and internal signals. Ó 2011 IUBMB
IUBMB Life, 63(10): 881–895, 2011
Keywords signal transduction; histone modifications; Polycomb;
chromatin..
Received 28 April 2011; accepted 12 July 2011
Address correspondence to: Félix Recillas-Targa; Instituto de Fisiolo-
gı́a Celular, Departamento de Genética Molecular, Universidad Nacio-
nal Autónoma de México, Apartado Postal 70-242, México D.F. 04510,
México. Tel: 152 55 56 22 56 74. Fax: 152 55 56 22 56 30.
E-mail: frecilla@ifc.unam.mx
ISSN 1521-6543 print/ISSN 1521-6551 online
DOI: 10.1002/iub.557
Abbreviations PcG, Polycomb; TrxG, Trithorax; bp, base pairs; AID,
activation-induced cytidine deaminase; ESC, embry-
onic stem cell; MLL, mixed-lineage leukemia factor;
MAPK, mitogen-activated protein kinase; CREB,
cAMP-response-element binding factor; NF-jB, nu-
clear factor jB; ERK, extracellular-signal-regulated
kinase; MEC, mammary epithelial cells; HMTs, his-
tone methyltransferases; HDACs, histone deacetylases;
NICD, Notch intracellular domain; PRC1, Polycomb
repressive complex 1; NURF, nucleosome remodeling
factor; GSC, germ stem cells; CPC, cyst progenitor
cells; PEV, position effect variegation; PKA, protein
kinase A; miRNAs, microRNAs; TEI, transgenera-
tional epigenetic inheritance
INTRODUCTION
Cell response to external stimuli requires the integration and
activation of a cascade of interdependent signals that travel
along the cytosol with the cell nuclei as the final destination.
Cell–cell interactions, differential kinetics of ligands, and thus
different signal transduction cascades converge in the transloca-
tion and integration of those fine-tuning signals for the activa-
tion or repression of gene expression. Such interplay of molecu-
lar signals will give the ability to the cell to start with exquisite
precision developmental and differentiation programs. An aspect
that has been less explored and that emerges as relevant is how
these signals contribute to the establishment of specific tran-
scriptional programs and, moreover, how these programs are
perpetuated through cell divisions. On the basis of such kind of
questions, and the expansion of epigenetics as a regulatory
driver of processes like signal transduction, cell cycle control,
and stress response, we are facing a totally new era that needs
to be analyzed from a distinct perspective (1–3). Here we focus
on some examples of the relationship between epigenetic proc-
esses and some signal transduction pathways with the aim to
extend our vision from external stimuli integration to gene
expression regulation through chromatin modifications.
882 ARZATE-MEJÍA ET AL.
THE CHROMATIN STRUCTURE AND EPIGENETIC
REGULATION
The genome is organized into a sophisticated set of DNA–
protein interactions known as chromatin. The chromatin struc-
ture represents the basal level of eukaryotic genome organiza-
tion. Such kind of organization has profound effects on several
nuclear processes such as DNA repair, DNA replication, recom-
bination, and gene transcription (4). Surprisingly, very little is
known concerning how extra- and intra-cellular signals are
transduced and translated into an epigenetic response. Epige-
netic regulation involves a set of processes that affect gene
expression without any change in DNA sequence that can be
segregated post-mitotically (5). Historically, the term epige-
netics was proposed by Conrad Waddington in the early 1940s
while trying to explain phenotypic changes without genetic var-
iations and, at the same time, comprehend how the environment
can yield a phenotype (6).
It is generally accepted that epigenetic regulation includes
histone post-translational modifications and DNA methylation.
But the epigenetic landscape is much more sophisticated than
these two important processes. Actually, we should incorporate
the ATP-dependent chromatin remodelers, the repressor and ac-
tivator group of proteins Polycomb (PcG) and Trithorax (TrxG),
and more recently, the noncoding RNAs and nuclear dynamics
as epigenetic components (7–12).
Briefly, we will discuss histone modifications, DNA methyla-
tion, and the groups of proteins PcG and TrxG to better under-
stand their roles in signal transduction cascades.
Histone Post-translational Modifications and Epigenetics
The basic component that allows the formation of the chro-
matin structure is the nucleosome which is composed by a his-
tone octamer and 146 base pairs (bp) of DNA (13). To a certain
point, it is expected that modulation of chromatin structure in
response to regulatory instructions requires direct histone post-
translational modifications with the concomitant relaxation or
compaction of the chromatin structure (14). Such covalent mod-
ifications mainly occur along the N-terminal domains of histo-
nes and include a combination of modifications like acetylation/
deacetylation, methylation, and more recently demethylation,
phosphorylation, ubiquitination, poly(ADP-ribosyl)ation, among
others (14). Notably, based on genome-wide scale studies, there
is a well-defined idea of the distribution of histone marks repre-
sentative of different areas of the genome. Such marks, with the
collaboration of transcription factors and co-factors, affect tran-
scription and many other processes like elongation or alterna-
tive splicing. For example, tri-methylation of lysine 4, 36, and
79 on histone H3 (H3K4me3, H3K36me3, and H3K79me3,
respectively), and differential acetylation of lysine residues of
histone H3 and H4 (H3ac and H4ac, respectively) are represen-
tative histone modifications constituting the so-called histone
code that result in gene activation (15). In contrast, di- and tri-
methylation of histone H3 lysine 9 (H3K9me2/3) and
H3K27me3 are well established repressive histone marks.
Importantly, the relative recent description of a family of his-
tone demethylases permits a versatile reversibility of either
active or repressive marks in a tightly regulated manner (16).
Finally, based on the action of transcription factors and co-fac-
tors and their ability to respond to highly specific signals, there
is the need for recruitment of enzymes that covalently modify
histones to specific regulatory locations, affecting the expression
of target genes.
Epigenetic Silencing Through DNA Methylation
Historically, DNA methylation has been considered as one of
the most relevant epigenetic processes. Based on the variety of
epigenetic processes and their interdependency, this assumption
can be hardly supported. In any case, DNA methylation is synon-
ymous of epigenetic silencing, and it is involved in organism de-
velopment, X-chromosome inactivation, imprinting, genome sta-
bility, and cell differentiation, among others (5). DNA methyla-
tion occurs at the 50 position of the cytosine ring mainly within
the CpG dinucleotides. The incorporation of the methyl (CH3)
group to the CpG is basically performed by two groups of DNA
methyltransferases. The Dnmt3a and Dnmt3b DNA methyltrans-
ferases, known as the de novo enzymes, act in the early stages of
development establishing genome-wide specific patterns of DNA
methylation and contributing to cell lineage commitment. The
second type of DNA methyltransferase is the Dnmt1, known as
the maintenance enzyme, which reads and segregates DNA meth-
ylation patterns during replication (5). In addition, the molecular
mechanisms responsible for epigenetic silencing by DNA meth-
ylation include a family of proteins with the capacity to bind
methylated DNA, like the methyl-CpG-binding proteins MeCP2,
MBD2, Kaiso, among others (17, 18). It is well known that aber-
rant DNA methylation participates in different pathologies
including cancer, through a not well understood combination of
hypo- and hyper-methylation of undesired regions of the genome
(17). Which molecules target abnormal DNA methylation is a
question that remains unanswered. Based on this question, it is
relevant to investigate if there are particular signaling pathways
linked to aberrant DNA methylation. Related to this, there is a
growing list of evidences describing alternative mechanisms for
DNA demethylation (19, 20). For years, it has been thought that
DNA methylation was the most stable epigenetic mark and that it
was almost erased during early stages of mammalian develop-
ment (21). The isolation of the enzymes and the elucidation of
the mechanisms for active DNA demethylation have been com-
plicated tasks. In the last years, it has been proposed that active
DNA demethylation involves the conversion of the 5-methylcyto-
sine (5mC) into 5-hydroxymethylcytosine (5hmC) by the Tet
group of proteins (22), deamination reactions by the activation-
induced cytidine deaminase (AID), and base excision repair
mechanisms (19, 23, 24). Moreover, one of the most exciting
findings of this topics is that active DNA demethylation is not re-
stricted just to early development (25, 26). Without no doubt,
 SIGNALING EPIGENETICS
this is a relevant topic and our prediction is that DNA demethyla-
tion should be a highly regulated process dependent on specific
signaling pathways.
The Repressive and Activating Group of Proteins
Polycomb and Trithorax
Another epigenetic component that has acquired a growing
relevance is the PcG and TrxG group of proteins (8, 11). The
PcG and TrxG group of proteins were initially discovered and
described in the fruit fly Drosophila melanogaster as negative
and positive regulators, respectively, of homeotic genes required
for specifying cell identity along the antero-posterior axis of
segmented animals. PcG and TrxG group of proteins are multi-
meric complexes that need to be attracted to their target loca-
tions by transcription factors, but more recently, such recruit-
ment has been documented through the intervention of short
and even, long noncoding RNAs (11, 27, 28). PcG and TrxG
coordinate critical function for cell homeostasis, like embryonic
stem cell (ESC) self-renewal capacity, epigenetic silencing of
defined genomic regions, inactivation of X-chromosome, cell
differentiation, regulation of cell signaling genes, among others.
(see later). The PcG and TrxG complexes’ subunits possess his-
tone methyltransferase activities, incorporating methyl groups to
specific lysine residues that are subsequently ‘‘read’’ by other
combination of PcG and TrxG proteins.
PcG-mediated epigenetic silencing requires the formation of
two interrelated repressive complexes named PRC2 and PRC1
(11). In the PRC2 complex, the histone methyltransferase EZH2
is responsible for the di- and tri-methylation of the histone H3
at lysine 27 (H3K27me2/3) in the context of a complex formed
by SUZ12, EED, and RbAp46/48 proteins. The H3K27me3 rep-
resents the signal for the incorporation of the PRC1 complex
formed by BMI1, RING1A, RING1B, MEL18, or NSOC1,
complementing the formation of repressive chromatin configura-
tion. This is reinforced by the action of RING1A/1B which
ubiquitinates the lysine 119 of histone H2A (H2AK119ub1).
Importantly, both complexes, PRC1 and PRC2, are formed with
an additional combination of peptides that are proposed to in-
crement its specificity and facilitate higher levels of activity
(11). How the PRC2 complex is recruited to the PcG-regulated
regions of the genome is an aspect that still remains unsolved
in mammals. It is worth mentioning that none of the PRC2/
PRC1 complexes possess DNA-binding domains’ subunits.
Thus, two main proposals have been recently suggested on the
literature: (1) the action of specific transcription factors, like
YY1, which have been involved in the regulation of genes
through PcG of proteins and (2) an attractive and novel strategy
has been documented on the basis of the action of noncoding
RNAs, like in the case of the Kcnq1 imprinted domain or the
action in trans of HOTAIR in the HOX genes loci, among others
(29, 30).
The activation group of protein TrxG counteracts the repres-
sive function of PcG as ‘‘anti-silencers,’’ not only of the home-
883
otic genes but also of many others (31). TrxG forms multisubu-
nit complexes with variable compositions. Such complexes are
then able to mediate their activities through histone modifica-
tions and ATP-dependent chromatin remodelers. The histone
modifications are dictated by a SET domain histone methyl-
transferase known in humans as the mixed lineage leukemia
factor (MLL) which tri-methylates the lysine 4 of the histone
H3 to establish an active chromatin configuration (32). As men-
tioned, the TrxG group of proteins contain ATP-dependent
chromatin remodeling proteins with the capacity for reposition-
ing nucleosomes. Among them we found subunits of the SWI/
SNF complex, like BRM, BAF250, BAF170, and BAF47, and
components of the NURF complex like SNF2L, RpAp46, and
RpAp48 (8, 31). Furthermore, histone acetylation has also been
associated to TrxG activity. Co-purified with MLL-containing
complexes it has been identified the MYTS1/MOF histone ace-
tyltransferase which specifically acetylates histone H4K16
which is a histone mark of actively transcribed genes (33). This
histone mark favors an open chromatin structure that in addition
prevents the incorporation of the repressive histone mark
H3K27me3. Therefore, the interplay between PcG and TrxG
complexes’ activities associated with different covalent histone
modifications and ATP-dependent chromatin remodeling com-
plexes modulates different chromatin configurations and gene
expression. An outstanding aspect of such complexes is their
varied composition that has been suggested, in terms of their
ability to respond to discrete signals in a cell-specific manner or
during organism development probably through the activation
of different signal transduction pathways.
In conclusion, today the PcG and TrxG proteins symbolize
one of the most important epigenetic regulators. In the context
of the present review, it is critical to mention that there are no
substantial evidences of the connection between signal transduc-
tion pathways and regulated recruitment of PcG and TrxG com-
plexes. Consequently, this is a topic that clearly deserves partic-
ular attention and should be investigated in the next future.
With this brief background in mind about some epigenetic
regulatory processes, we address different signal pathways that
are relevant in cell differentiation and organism development
from the epigenetic perspective. Despite the intense research
that has been done in both cell signaling and epigenetics, link-
ing epigenetics and signaling pathways remains as a vast
unstudied field. Although scarce, pioneer studies have begun to
uncover some aspects of this signaling–epigenetic crosstalk.
In particular, we present an overview of the MAPK, Wnt,
Notch, JAK-STAT, JNK , NF-jB, and PKA signaling pathways.
Based on such overview, we further propose future research
directions linking cell signaling and epigenetics.
THE MITOGEN-ACTIVATED PROTEIN KINASE (MAPK)
PATHWAY TARGETING CHROMATIN
Mitogen-activated protein kinase (MAPK) pathways regulate
eukaryotic gene expression at multiple levels in response to
884 ARZATE-MEJÍA ET AL.

Figure 1. A, Mammalian mitogen-activated protein kinase (MAPK) pathways and some of the downstream targets converging to
transcription factors and chromatin components. B, Scheme of the MSK1 and histone H3 Ser28-acK27 marks antagonize PcG re-
pressive function. This histone post-translational combinatorial should further facilitate the incorporation of chromatin modifiers
that favor transcriptional activation of the targeted genes.

diverse extracellular signals. This occurs not only by regulating
the activity of transcription factors but also by modulating the
chromatin structure of regulatory elements among other cellular
processes (34). MAPKs mediate their effects through specific
phosphorylation, activating or inactivating a large range of pro-
tein substrates including MAPK-activated protein kinases and
other types of kinases (Fig. 1A; 35). Among the downstream
MAPKs pathway targets, the mitogen- and stress-activated pro-
tein kinases 1 and 2 (MSK1/2) and the p38 MAPK show partic-
ular interest since they are able to directly target several types
of transcription factors, including the cAMP-response-element
binding factor (CREB), the nuclear factor jB (NF-jB), and
they can also induce phosphorylation of the histone H3 and the
HMG-14 chromatin-associated protein (34, 36–38). In particu-
lar, MSK1/2 possesses at their C-terminal domain a docking
configuration that is responsive to activating extracellular-sig-
nal-regulated kinase (ERK) and p38 MAPK (Fig. 1A).
As mentioned earlier, the induction of multiple transcrip-
tional activation or repression programs by signal transduction
cascades do not only have transcription factors as targets, inte-
gral components of the chromatin structure are also responsive
to those signals. The differential phosphorylation of Ser10 and
Ser28 of the histone H3 is a clear example. Historically, it has
been assumed that histone H3 Ser10 phosphorylation is the
major modification that has a vital role in maintaining con-
densed mitotic chromosomes allowing successful chromosome
segregation (39). The activation of ERK and p38 MAPK allows
an efficient phosphorylation of the histone H3 (36). Interest-
ingly, there is a differential phosphorylation of histone H3
Ser10 and Ser28 (36, 37). Based on immunofluorescence and
sequential immunoprecipitation experiments using phospho-
Ser10- and phospho-Ser28-specific antibodies, it has been dem-
onstrated that each type of covalent modification occurs in dis-
tinct subsets of histone H3, for example, that each modification
 SIGNALING EPIGENETICS
is associated in vivo to chromatin distributed in different
genomic regions.
But, it is until recently, that the histone H3-Ser28 phospho-
rylation functional meaning has been elucidated (40). Based on
the targeting of MSK1 to the a-globin gene promoter and the
consequently induced phosphorylation of the histone H3-Ser28,
Lau and Cheung demonstrated that Ser28 phosphorylation dis-
places the binding of the PcG repressive complex causing a sig-
nificant reduction in the incorporation of the histone H3K27me3
repressive histone mark (40). Furthermore, this modification
induces a dual code associated to gene activation through the
phosphorylation of Ser28 and the acetylation of the Lys 27
(Fig. 1B). Thus, it has been suggested that in response to
MSK1 pathway, histone H3 Ser28-acK27 marks antagonize
PcG repressive function, facilitating the subsequent recruitment
of the other chromatin modifier enzymes and/or specific tran-
scription factors allowing gene expression activation.
We conclude that histone H3 phosphorylation through ERK
and p38 MAPK activation of MSK kinases represents a critical
step that with no doubt couples signal transduction pathways
that are responsive to external stimuli to regulate gene expres-
sion in particular cell-types.
The p38 MAPK pathway participates in numerous biological
processes like response to stress and inflammation, cell prolifer-
ation, differentiation, and survival of particular cell types (41).
The p38 MAPK family members are approximately 60% identi-
cal in their amino acid composition and are known as p38a,
p38b, p38c, and p38d. The p38a MAPK presents a constitutive
expression in most cell types, in contrast to others which show
a more tissue-specific expression profiles (41). As mentioned,
for their activation MAPK pathways require phosphorylation of
target proteins by MAPK kinases which induce conformational
changes facilitating substrate recognition.
Myogenesis represent one of the most studied cell lineage
differentiation system in which epigenetics and cell signaling
give us a nice example of cross talk during this critical process.
Myoblasts can be differentiated in multinucleated myotubes,
mainly using the C2C12 murine cells as an in vitro differentia-
tion system simply based on serum withdrawal. This system has
provided a very useful way to study signaling pathways and
chromatin associated events allowing myoblast cells to differen-
tiate. MyoD is a transcription factor which has been referred to
a master regulator of myogenesis. It is able to recognize
E-boxes in the genome and can initiate the myogenic program
in differentiating myoblasts (42). At the chromatin level, MyoD
is associated with histone acetylation of its target regulatory ele-
ments associated with key myogenic genes (42). Interestingly,
many of these genes are repressed by the PcG proteins. In myo-
blast, the histone methyltransferase EZH2 and PRC2 compo-
nents are recruited to target genes by the transcription factor
YY1 with the concomitant enrichment of the histone repressive
mark H3K27me3 (43). During myoblast differentiation, several
chromatin-modifying enzymes are coordinately recruited
through transduction of external signals. First, the repressive
885
histone mark H3K27me3 needs to be erased. Thus, in MyoD
target genes the homeobox transcription factor Six4 recruits the
histone demethylase specific of the H3K27me3, UTX, and
removes this histone repressive mark at promoter regions of
genes involved in myogenic differentiation (44). Once the chro-
matin structure of regulatory elements is more permissive, the
MADS-box transcription factor Mef2d and MyoD can now start
to positively regulate transcription of myogenic genes (45). p38
MAPK is activated upon cell-to-cell contact and Medf2d is
phosphorylated. Then, the phosphorylated form of Mef2d can
recruit the TrxG histone methyltransferase Ash2L/MLL2 which
is able to incorporate the chromatin ‘‘open’’ histone mark,
H3K4me3 to target genes and induce transcription initiation
(45). The activation mechanism is then complemented by the
pTEF-b-mediated phosphorylation of the RNA polymerase II
which is recruited by MyoD (46). Interestingly, and as part of
the myogenic differentiation program, EZH2 and YY1 are post-
transcriptionally inhibited by specific microRNAs (47, 48).
In summary, myogenesis responds to an interdependent cas-
cade of events that initiates with the reversal of the repressive
chromatin context imposed by PcG proteins, the recruitment of
myogenic transcription factors, and, importantly, the activation
of the p38 MAPK pathway in response to extra-cellular signals,
which further enhances the recruitment of chromatin modifying
proteins that change chromatin structure to activate transcrip-
tion.
WNT CELL SIGNALING PATHWAY AND ITS
CROSSTALK WITH EPIGENETICS
Cell differentiation can be summarized as the process in
which a pluripotent cell becomes a more specialized cell
through the controlled establishment of specific gene expression
patterns. This complex process is guided by both, intra- and
extra-cellular signals that establish those patterns. It has been
widely recognized that cell signaling plays a crucial role during
the differentiation process. On one hand, a cell must be able to
respond to the external stimuli that drives the differentiation
process. On the other hand, the transcriptional changes guided
by external stimuli must be inherited to the daughter cells after
mitosis to maintain their lineage.
The epigenetic features of mammalian stem cells have been
extensively studied, although the interplay between external
stimuli and epigenetic effectors during self-renewal and differ-
entiation processes is poorly understood. A recent publication
by Gu et al. (49) described that Pygo2 is essential for mammary
stem/progenitor cells self-renewal. Pygo2 contains a PHD do-
main, a common domain in epigenetic regulators (50). Deficient
Pygo2 mice show a reduced proliferation of mammary epithelial
cells (MEC). Moreover, Pygo2 deficiency rescues b-catenin-
induced mammary overgrowth thus implying an interaction
between Pygo2 and Wnt/b-catenin signaling pathway. Further-
more, it was proved that Pygo2 promotes the trimethylation of
H3K4 in the promoter regions of Wnt/b-catenin target genes, a
886 ARZATE-MEJÍA ET AL.
typical mark of transcriptional active chromatin, through the
recruitment of histone methyltransferases (HMTs). Taken to-
gether, this evidence shows a clear interaction between the
Wnt/b-catenin pathway, the PHD finger protein Pygo2, and
HMTs during the maintenance of MEC self-renewal (49, 51).
Several interesting issues remain to be studied regarding the
Pygo2-Wnt/b-catenin crosstalk. It is not clear if b-catenin and
Pygo2 interact directly or if there are other factor involved in
the recruitment of Pygo2 to the Wnt/b-catenin target gene pro-
moters. It would also be interesting to determine if other epige-
netic factors, such as histone demethylases, guided by Wnt or
other signaling pathways influence the transcription of the Wnt/
b-catenin target genes during MEC differentiation. Also, there
is an interesting link between Pygo2 and breast cancer. Abnor-
mal over-expression of Pygo2, caused by genetic or epigenetic
or both processes, may induce uncontrolled proliferation. In this
sense, it has been observed that Pygo2 is upregulated in cancer
cell lines and breast cancer (49, 52). This example opens the
possibility of a completely new field of study for therapeutic
targets in cancer regarding the epigenetic–cell signaling cross-
talk.
Histone deacetylases (HDACs) are involved in epigenetic
silencing, a fundamental process for cell function, both during
differentiation and in differentiated cells (for review, see ref.
53). In an interesting example, Ye et al. (54) proved recently
that HDAC1 and HDAC2 are involved in oligodendrocyte de-
velopment and interact with the Wnt/b-catenin signaling path-
way (Fig. 2). To assess the role of HDAC during oligodendro-
cyte formation, these authors generated oligodendrocyte-specific
HDAC1/2 double knock-out mice. HDAC1/2 mice are not able
to generate mature oligodendrocytes. Furthermore, they showed
that b-catenin is abnormally stabilized and translocated to the
nucleus of oligodendrocyte precursor cells in HDAC1/2 mice,
then inhibiting the expression of Olig2, an essential gene for
oligodendrocyte differentiation. This evidence indicates that
HDAC1/2 are essential for oligodendrocyte maturation and that
they antagonize the Wnt/b-catenin pathway. b-catenin activates
canonical Wnt signaling by forming a biparite transcriptional
factor with a member of the TCF/LEF transcription factor fam-
ily (55). They also found that TCF7L2 is the oligodendrocyte
specific effector of the Wnt/b-catenin signaling pathway. They
further proved that HDAC1/2 is able to interact with TCF7L2,
and that this interaction is disrupted by b-catenin over-expres-
sion. Based on all their evidence, they finally propose that while
b-catenin/TCF7L2 dimer act as a repressor of oligodendrocyte
differentiation, HDAC1/2 competes with b-catenin for the bind-
ing to TCF7L2, promoting the function of TCF7L2 as an acti-
vator of oligodendrocyte differentiation. Together, these findings
show an unexpected role for HDACs: not only they act as epi-
genetic repressors, but they can also inhibit Wnt signaling
through directly disrupting b-catenin/TCF7L2 interaction (Fig.
2; 54). It remains to be solved if the HDAC/TCF7L2 dimer is
involved directly in the transcriptional regulation of genes or if
its only function is disrupting b-catenin/TCF7L2. Also, it will
Figure 2. HDAC1/2 regulates Wnt/b-catenin signaling during
oligodendrocyte differentiation. In oligodendrocyte precursors,
the bipartite transcription factor conformed by b-catenin and the
Wnt effector TCF7L2 act as a repressor for genes involved in
oligodendrocyte differentiation such as Olig2. As differentiation
goes on, HDAC1/2 competes with b-catenin for the binding to
TCF7L2, disrupting the repressive bipartite transcription factor
and allowing the expression of oligodendrocyte-specific genes.
be interesting to explore if this kind of mechanism, in which
epigenetic factors interact and modify directly the effector pro-
teins of signaling pathways is a rule rather than an exception.
Finding new functions for canonical epigenetic factors and their
contribution in co-regulating signaling transduction pathways,
besides their direct role in chromatin modification, will be an
exciting area of research in the near future that remains unex-
plored.
NOTCH SIGNALING PATHWAY AND ITS EPIGENETIC
REGULATION
Notch signaling is a highly conserved developmental pathway
that is present in all metazoans and controls different processes
like cell fate specification, self-renewal, differentiation, prolifer-
ation, and apoptosis throughout development and regeneration
(56). Notch receptors are single-pass transmembrane receptors
comprising one extracellular and one transmembrane segment
(57), which are activated by transmembrane ligands of the DSL
family on neighboring cells. Whereas Drosophila has only one
Notch receptor that is bound by two different ligands (Delta and
Serrate), there are four Notch receptors (1–4) and five ligands
(Jagged 1 and 2, and Delta-like 1,3,4) in mammals (56).
Activation of Notch pathway results in the proteolytic cleav-
age of the Notch receptor and the subsequent release of the
Notch Intracellular Domain (NICD), which then translocates
into the nucleus to activate specific gene targets via the CSL
family (CBF1/RB-Jk, Su(H), and Lag1) of sequence-specific
DNA-binding proteins (56, 58). Once activated, the NICD asso-
ciates with CSL and other complexes inducing expression of
genes that are members of the E(spl) class in Drosophila or the
 SIGNALING EPIGENETICS 887

Hes class in mammals. These genes are transcription factors,

the so-called Notch-effector genes (57, 59, 60). In the absence
of NICD, CSL recruits transcriptional co-repressor complexes to
actively inhibit expression of most Notch target genes (56, 58,
61–66).
Different chromatin modifying proteins, like histone deacety-
lases, H3K9 methyltransferases, CtBP, NcoR/SMRT, Groucho,
and, more recently, histone chaperones and histone H3K4 deme-
thylases have been reported to associate with Notch repressor
complexes to silence target genes (58, 61–64). Despite the exis-
tence of different co-repressor complexes, all appear to recruit
HDACs (65) and histone H3K4 demethylases (58, 61, 66).
Recent reports suggest an important role for histone chaper-
ones during gene silencing of Notch-regulated genes (58). His-
tone chaperones bind specific histones and include the highly
conserved H3/H4 chaperones ASF1, CAF1, HIRA, and SPT6
and the H2A/H2B chaperones NAP1, nucleoplasmin, and FACT
(67, 68). A proteomics survey of the protein interaction net-
works of the histone chaperones ASF1, CAF1, HIRA, and
NAP1 in Drosophila embryos revealed that ASF1 and NAP1
interact with two related repressor complexes. ASF1 interacts
with LAF (including the H3K4 demethylase LID/KDM5)
Figure 3. Notch signaling and its epigenetic regulation. A, In
whereas NAP1 interacts with RLAF, comprising LAF 1 RPD3
Drosophila, PRC1 represses gene expression of Notch, Serrate,
(histone deacetylase, 69). These two repressor complexes inter-
and other important genes of this pathway. B, Different co-
act with Notch target genes via Su(H) and mediate gene selec-
repressor complexes can represses expression of Notch target
tive silencing (58). Depletion of ASF1 or NAP1 resulted in de-
genes by increasing nucleosome density at regulatory regions
repression of the E(spl) genes. Importantly, depletion of other
and inducing loss of H3K16 acetylation and H3K4 tri-methyla-
histone chaperones (i.e., HIRA) had no effect on Notch target
tion, marks associated with a permissive chromatin structure for
gene expression, suggesting a specific role for these histone
transcription. Red circles represent methyl groups associated
chaperones in Notch gene silencing (58).
with the histone residue H3K27.
Both ASF1 and NAP1 are necessary for the specific removal
of H3K4me3 by facilitating LID/KDM5 recruitment to chroma-
tin. Further, depletion of NAP1, but not ASF1, caused a strong
loss of nucleosomes at the E(spl) promoters and enhancers indi- In Drosophila, imaginal eye discs are groups of epithelial
cating that NAP1 mediates higher nucleosome density at regula- cells present in larvae that will differentiate into specific parts
tory elements of Notch target genes (Fig. 3B). Finally NAP1 of the adult fly. The Notch signaling pathway can control
cooperates with RLAF stimulating histone deacetylation by growth of eye imaginal discs (71, 72). Eye imaginal discs bear-
RPD3 (58). ing cells with mutations in ph (polihomeotic), a member of the
Other HDACs have been reported to affect Notch target Polycomb Repressive Complex 1 (PRC1), have defects in pro-
gene expression. For example, SIRT1, a H4K16 deacetylase liferation and differentiation. Moreover, mutant cells with Ras
(70), interacts with LSD1/KDM1A a histone H3K4 demethylase over-expression invade other tissues and trigger the formation
and CtBP1 a repressor adaptor protein making a complex that of metastases. When ph mutant cells are transplanted into the
acts selectively as a co-repressor of the CSL/Notch target genes abdomen of wild-type adult flies, they over-proliferate, killing
in the absence of Notch signaling via the establishment of re- the host, resembling the phenotype of mammalian epithelial
pressive chromatin. In particular, SIRT1 is necessary for deace- cancers. Finally, mutations in ph induced loss of Notch, Ser and
tylation of H4K16 during repression of target genes in absence eyg repression, indicating that PRC1 is controlling gene expres-
of Notch signaling (Fig. 3B). Upon induction of Notch signal- sion of key genes along the entire pathway (Fig. 3A) (i.e., is
ing, H4K16 is acetylated and H3K4 is methylated, inducing a affecting the expression of the receptor, ligand, and target
chromatin state permissive for transcription (61). genes) (71).
Even that so much work has been done to identify those pro- In summary, the Notch signaling pathway is regulated at all
teins that interact with CLS DNA-binding proteins to regulate levels by important chromatin modifying proteins. Different
Notch target gene expression, less is known about which chro- co-repressor complexes associate specifically with certain his-
matin-modifying proteins could be regulating Notch receptors tone demethylases, histone deacetylases, and histone chaperones
and ligands. that collectively repress target gene expression. Moreover, the
888 ARZATE-MEJÍA ET AL.

Figure 4. JAK-STAT signaling and its epigenetic regulation. A, In Drosophila, PRC1 represses gene expression of Upd genes. B,
NURF complex positively regulates expression of STAT92E gene, although it is not known if the regulation is direct or by inhibi-
tion of an inhibitor of JAK-STAT pathway. C, JAK-STAT pathway can regulate heterochromatin formation. If the pathway is acti-
vated, HP1 is realized from heterochromatin foci inducing a generalized loss of repressive chromatin configuration.

receptors and ligands are regulated at the epigenetic level by
PcG proteins. Most of these proteins are highly conserved among
different organisms from Drosophila to humans, suggesting that
the mechanisms of regulation may also be conserved.
JAK-STAT SIGNALING PATHWAY AND ITS
EPIGENETIC REGULATION
JAK-STAT signaling is a highly conserved pathway that has
been implicated in different processes like regulation of differ-
entiation, apoptosis, proliferation and disease like cancer. (73).
JAK-STAT signaling activation involves the binding of one of
the Upd ligands to the hop receptor, which activates the Jak ki-
nase resulting in the phosphorylation of STAT92E and its trans-
location to the nucleus, where it functions as a transcriptional
activator, inducing expression of target genes (74). Different
lines of evidence suggest that JAK-STAT signaling pathway
can be regulated at the epigenetic level (74–77). Most of this
work has been done using D. melanogaster as a model system,
in part because the components of this pathway are encode by a
single gene copy and also because of its powerful genetics.
In Drosophila, mutations in components of the PRC1 com-
plex can reactivate JAK/STAT signaling in eye imaginal discs
producing an enlarged eye phenotype in adults, characterized by
an increase in cell number. It was demonstrated that all Upd
ligands (Upd1, Upd2, and Upd3) are direct targets of PRC1-
mediated repression (Fig. 4A) (76). This contrasts with Notch
signaling, where just one of the two ligands are affected by
PRC1 (71). Moreover, the Notch signaling pathway seems to be
regulated by PRC1 at all levels (receptor, ligand, target genes).
Recently, the ATP-dependent chromatin remodeler complex,
nucleosome remodeling factor (NURF) was implicated in the
regulation of JAK-STAT signaling in Drosophila testis (75).
The NURF complex is composed by different subunits (ISWI,
Nurf55, Nurf30) being Nurf301 the only component that is not
shared by other ATP-dependent chromatin remodeler complexes
(78). The JAK-STAT signaling pathways are responsible for the
maintenance of the germ stem cells (GSC) and cyst progenitor
cells (CPC) in Drosophila testis (79, 80). The Upd ligand is
secreted by a group of somatic post mitotic cells called the
niche that are adjacent to the GSC and the CPC, thus activating
the JAK-STAT signaling and preventing differentiation. By
using different genetic approaches it was demonstrated that
Nurf301 promotes expression of STAT92E and prevents the
expression of the differentiating factor Bam. Flies in which
STAT92E was overexpressed in a mutant loss-of-function
 SIGNALING EPIGENETICS
background for Nurf301 recover CPC cells; also, Nurf301 inter-
acts genetically with SOCS36E (repressor of the pathway) in a
manner consistent as NURF acting as a positive regulator (Fig.
4B). This finding is surprising because during hematopoiesis,
NURF represses STAT target genes through interaction with the
transcriptional repressors Ken and Barbie (81, 82). At this point,
it is unknown if NURF promotes JAK-STAT signaling by tran-
scriptional activation or indirectly by repression of JAK-STAT
inhibitors (75).
So far, we have described some examples of epigenetic regu-
lation of JAK-STAT pathway in eye imaginal disc and also in
Drosophila testis during spermatogenesis. Recent findings in
Drosophila have identified a noncanonical mode of JAK-STAT
signaling which controls heterochromatin stability (77). An
hyperactivated form of Jak kinase is associated with a high inci-
dence of hematopoietic tumors, a leukemia-like phenotype.
Loss-of-function mutations in the heterochromatin components,
HP1 and Su(var)3-9, enhance tumor formation under hyperac-
tive Jak kinase background. It was demonstrated that hyperacti-
vation of Jak kinase induces loss of heterochromatin gene
silencing. This disruption allows derepression of genes that are
not direct targets of STAT92E as evidenced by loss of hetero-
chromatin-mediated position effect variegation (PEV) silencing
of white gene (Fig. 4C). Jak loss of function enhances hetero-
chromatin silencing, while HP1 overexpression suppresses the
tumorigenic phenotype associated with Jak kinase hyperactiva-
tion. This phenomena demonstrates a global effect of JAK-
STAT signaling activation that can affect many genes irrespec-
tive of STAT93E binding to their regulatory regions.
In conclusion, in Drosophila, PRC1 controls JAK-STAT sig-
naling through direct inhibition of expression of Upd genes,
thus blocking activation of the pathway, even that the neighbor-
ing cells are expressing hop ligand. Moreover, the NURF com-
plex seems to positively regulate JAK-STAT signaling in Dro-
sophila testis, through positive regulation of STAT92E in GSC
and CPC cells. Finally, this pathway can affect global hetero-
chromatin conformation through disruption of HP1 binding. It
could be possible that in spermatogenesis, JAK-STAT signaling
maintains the stem cell phenotype not just by repression of Bam
gene, but also through induction of an open chromatin configu-
ration affecting genes that are not direct targets of STAT92E
but are important for stem cell maintenance. During differentia-
tion, those genes could be silenced because of heterochromatin
formation as a consequence of silencing of JAK-STAT path-
way.
We have given some examples about how signaling path-
ways use the epigenetic machinery to regulate gene expression,
and also we have discussed some examples in which important
chromatin modifying proteins affect critical components of the
signaling pathways. However, it is extremely important to
emphasize those cases in which signaling pathways can affect
chromatin-modifying proteins. From this part, we present exam-
ples of direct regulation of critical epigenetic components by
signaling pathways.
889
JNK SIGNALING PATHWAY AND THE REGULATION
OF POLYCOMB GROUP OF PROTEINS
During regeneration of Drosophila imaginal discs, cells can
change their identity during a process known as transdetermina-
tion. In 2005, it was reported that some components of PcG are
downregulated during transdetermination (83). In particular, it
was shown that the frequency of transdetermination from leg to
wing is enhanced in PcG mutant flies. This downregulation is
directly controlled by the JNK signaling pathway, which is acti-
vated in cells undergoing regeneration, repressing the expression
of PcG genes like Pc, ph-h, and E(Pc), thereby losing the
repression of target genes and allowing cell plasticity. Finally,
they carried out the analogous experiment in mammalian cells,
using mouse embryonic fibroblast in which JNK signaling was
activated by exposition to UV light. They found that upon
induction of JNK signaling, Mph2 (mouse polihomeotic) was
also downregulated (83), suggesting that JNK signaling can
control expression of PcG genes across species.
NF-KB SIGNALING PATHWAY AND THE
REGULATION OF HISTONE DEMETHYLASES
Cells can recognize external harassment like microbial infec-
tion, tissue injury, and many others through a large variety of
sensing mechanisms that mainly involve trans-membrane recep-
tors activating different signaling transduction pathways (84).
Thus, through a cascade of biochemical signals the stimuli is
translated and transmitted to the cell nucleus with the aim to
activate or repress the transcription of genes encoding a broad
range of regulatory and effectors proteins. A less explored as-
pect of such response to external stimuli is the contribution of
the chromatin structure and its modification enzymes to such
variety of signals. In other words, even though signal transduc-
tion remains a major player, it is now relevant to understand
how chromatin structure is targeted in a regulated manner to
allow differential gene expression in response to an inflamma-
tory stimulus.
An attractive example is shown by the regulated alteration of
PcG-mediated silencing of genes involved in inflammation
response, in particular, through the action of specific histone
demethylating enzymes (1). Natoli et al. hypothesized that
demethylation of specific histone repressive residues, in
response to external stimuli, may regulate inflammatory
response. Therefore, they assessed the expression profile of 30
genes containing the JumonjiC domain which is known to
mainly catalyze site-specific histone demethylation of mono-,
di-, and tri-methylated lysine residues (16, 85). Interestingly,
they found that the Jmjd3 histone demethylase expression (spe-
cific for H3K27me3) is robustly induced in macrophage
exposed to bacterial products and inflammatory cytokines. Fur-
thermore, they demonstrated that Jmjd3 induction depends on
direct binding of NF-jB to a set of three jB-binding sites in
the Jmjd3 gene promoter (1). NF-jB was the first transcription
factor described whose DNA-binding activity could be induced
890 ARZATE-MEJÍA ET AL.
by an extracellular stimulus (86). NF-jB family of nuclear fac-
tors consists of five members: p56, p52, RelA, c-Rel, and Relb
(87). A variety of dimeric and multimeric NF-jB-IjB com-
plexes have been described in the cytoplasm of unstimulated
cells (88). One of the most common activation pathways
involves phosphorylation of the associated IjB, which leads to
its ubiquitylation and proteasome-mediated degradation, thereby
releasing the NF-jB dimer allowing it to translocate to the nu-
cleus (87, 89). Then, among several mechanisms by which the
NF-jB pathway can activate subsets of target genes in response
to a particular stimulus, the activation of a specific histone de-
methylase is one of them, pointing out the relevance of chroma-
tin structure in this particular pathway.
It has been documented that the Jmjd3 histone demethylase
gene is highly expressed in differentiating bone marrow cells
and downregulated in differentiated macrophages. In contrast,
the Utx histone demethylase, which belongs to the Jmjd3 sub-
family, that is also able to demethylate the histone H3K27me3,
is expressed in constant levels and is considered a housekeeping
gene (1). This implies that the Jmjd3 histone methylase is
expressed in an inducible and cell-type restricted fashion and
that is responsive to the NF-jB signal transduction pathway.
Furthermore, a novel series of evidences show that acetyla-
tion of NF-jB has an effect on the specificity, strength, and dura-
tion of the NF-jB-dependent signal pathway (90). It is actually
known that in addition to histones, HATs and HDACs have other
targets in particular, transcription factors favoring or decreasing
their affinity to their DNA-binding sites with regulatory conse-
quences. Serine and threonine acetylation of NF-jB residues has
been shown to positively regulate NF-jB signaling cascade. This
is further supported by the demonstration of the direct acetylation
of NF-jB subunits like p52 and p65 (90). These findings have
contributed to propose that acetylation of NF-jB subunits and the
recruitment of HATs and HDACs by members of the same path-
way are responsible of an intricate crosstalk between NF-jB sig-
nal pathway and the trans-activation or repression of genes that
are associated to this signal transduction cascade.
Those are examples of mechanisms by which chromatin struc-
ture and specific transcription factors contribute to the selective
regulation in response to external signals and outline the versatile
relevance of histone demethylases, HATs and HDACs.
PKA SIGNALING-DEPENDENT REGULATION OF
HISTONE DEMETHYTLASE PHF2.
The glucagon–PKA signaling pathway regulates glucose ho-
meostasis by controlling glycogenesis and glycogenolysis (91,
92). After glucagon binds to its receptor in the cell surface, the
protein kinase A (PKA) becomes activated and phosphorylates
the glycogen phosphorylase kinase which activates other
enzymes, resulting in an increased glycogen breakdown (glyco-
genolysis) and production of glucose, for hepatic output (92).
The PKA can phosphorylate other proteins, like histone deme-
thylases (91). PHF2 is a jmjC H3K9me2 demethylase that is a
target of PKA. Inactive in its unphosphorylated form, this his-
tone demethylase is catalytically activated after phosphorylation
by PKA (91). Once PHF2 has been phosphorylated, it can bind
and demethylate ARID5B, a DNA-binding protein, making a
complex that associates with target promoters of genes like
Pepck and G6Pase where it removes the H3K9me2 mark (91).
This is the first example of a jmjC histone demethylase that in
order to be active needs a post-transcriptional modification, like
phosphorylation, mediated by a protein that is active only if a
signaling pathway is induced.
These remarkable findings indicate that some signaling path-
ways can control directly the expression of PcG and histone
demethylases genes during critical processes like development
or regeneration. So far, just a couple of examples exist that link
signaling pathways to regulation of critical components of the
epigenetic machinery (93).
FUTURE DIRECTIONS ON CELL SIGNALING AND
EPIGENETICS
Signal Transduction and MicroRNAs: The Epigenetic
Connection
The crosstalk between the epigenetic machinery and cell signal-
ing pathways may not be always direct. Diverse mechanisms could
affect this relationship and have a great impact in the way that cell
signaling and epigenetics interact. An attractive prediction of such
mechanisms are noncoding RNAs. In particular, microRNAs could
participate as an intermediary between cell signaling pathways and
the epigenetic machinery. Briefly, microRNAs (miRNAs) are small
RNAs of about 21 bases that recognize its target mRNAs by
sequence complementarity and trigger their degradation or inhibit
their translation. The sequence that miRNAs recognize, typically
known as seed sequence, is composed by 7–8 bases and is critical
for the miRNAs specificity (94). It has been widely recognized that
miRNAs are fundamental post-transcriptional regulators and have
been implicated in several cellular processes such as cell cycle con-
trol and progression, differentiation, apoptosis, and stress response,
among others (94–96).
There are several examples in which it is clear that miRNAs
are key players in the regulation of cell signaling pathways (for
review, see ref. 97). Moreover, miRNAs are also involved in the
regulation of several epigenetic factors, and are regulated by epi-
genetic mechanisms as well (98). Therefore, miRNAs are excel-
lent candidates for a functional interphase between cell signaling
pathways and epigenetic mechanisms. For example, it has been
reported that miR-145 is essential for stem cell differentiation
and participates in a complex regulatory feedback loop: it is neg-
atively regulated by the pluripotency factor OCT4 while it tar-
gets the post-transcriptional inhibition of OCT4, SOX2, and
KLF4, all essential factors for pluripotency maintenance (99).
Interestingly, it has been shown that BMP signaling pathway can
trigger human stem cell differentiation by inhibiting OCT4,
therefore allowing miR-145 expression which in turn silences
OCT4, SOX2, and KLF4 (97, 99–101). Furthermore, it has
 SIGNALING EPIGENETICS
recently been shown that miR-145 can be epigenetically silenced
by DNA hypermethylation in prostate cancer (102). Moreover, it
has also been demonstrated that OCT4 transcription is downre-
gulated through differentiation by DNA methylation (103).
Taken together, the previous findings can show us a complex
regulatory mechanism that links cell signaling, epigenetics, and
miRNAs. During stem cell maintenance, OCT4 promoter
remains hypomethylated (103), and we may speculate that miR-
145 is hypermethylated. During differentiation, BMP pathway
inhibits OCT4 expression, maybe by recruiting DNA methylases
and histone deacetylases to OCT4 promoter/enhancer region.
On the other hand, miR-145 transcription is upregulated,
although it remains to be studied which mechanisms are
involved in such process. One attractive possibility is that BMP
or other related pathway is also involved in miR-145 upregula-
tion. Thereafter, miR-145 post-transcriptionally inhibits OCT4,
SOX2, and KLF4 and finally, as differentiation goes on, their
gene promoters are epigenetically silenced. It should also be
interesting to study if signaling pathways, miRNAs, or a combi-
nation of both regulates such silencing.
Other interesting example is miR-7 in Drosophila. miR-7
has been implicated in the regulation of important signaling
pathways, like Notch (104) and EGF (105) signaling pathways.
Its function has been elucidated during eye development (Fig.
5). In early photoreceptors, miR-7 transcription is repressed by
Yan, a transcription factor involved in the differentiation of reti-
nal progenitor cells, by direct interaction with miR-7 cis-regula-
tory sequences. As photoreceptor differentiation goes on, EGF
signaling is transiently induced and breaks this equilibrium by
upregulating miR-7, while inhibiting Yan transcription. During
EGF transient stimulation, miR-7 avoids Yan repression and in
turn is able to inhibit Yan protein synthesis. After the stimuli
are over, in mature photoreceptors, miR-7 transcription is sus-
tained, and Yan is permanently inhibited by miR-7 (105). This
example is illustrative of a noncanonical epigenetic process
guided by a signaling pathway: a double-negative-feedback loop
in which two negative regulators that are mutually exclusive
change their expression patterns in response to a signal (Fig. 5).
Before, and after the signal, the cell has a steady transcriptional
memory that is maintained until it is perturbed by the signal.
Such regulatory loops are common during processes that require
robust and fine-tuned changes in expression patterns such as de-
velopment (106). It is quite probable that classic epigenetic
mechanisms, for example, DNA methylation, histone post-tran-
scriptional modifications, are also important for the transcrip-
tional switch between miR-7 and Yan expression, and for the
memory maintenance once the change was done. It will be
interesting to determine if such epigenetic processes are guided
by signaling pathways and involved other miRNAs.
There is a vast and unexplored field of study regarding the
interaction between miRNAs, epigenetic processes, and cell sig-
naling pathways. However, we hypothesize that miRNAs as
well as other noncoding RNAs are fundamental players in the
crosstalk between epigenetics and cell signaling.
891
Figure 5. miR-7 and YAN form a double-negative-feedback
loop sensitive to EGF signaling with epigenetic memory proper-
ties during photoreceptor differentiation. In photoreceptor pre-
cursor cells, miR-7 is downregulated by YAN, thus maintaining
an undifferentiated state. As differentiation goes on, PNTP1, an
effector of EGF signaling pathway, promotes the upregulation
of miR-7 while it downregulates YAN, switching its transcrip-
tion patterns. When the EGF stimuli are over, miR-7 is perma-
nently upregulated and act as a YAN repressor allowing the
photoreceptor differentiation program termination. The double-
negative-feedback loop has the property of epigenetic memory,
as the changes in the transcriptional patterns of YAN and miR-
7 are stably maintained in the absence of the EGF signal.
Transgenerational Epigenetic Inheritance: Integrating
Information to the Epigenome
Epigenetic information as well as DNA have to be replicated
during mitosis and been inherited to the next cell generations to
maintain cell fate. During gametogenesis, germ cells have the
capacity of erasing this epigenetic memory thus enabling
reprogramming of epigenetic information. However, certain
regions of the genome maintain this information, bypassing the
reprogramming events and allowing the transmission of this in-
formation to the offspring (21). The transmission of epigenetic
information through generations, that is, from F0 to F1 to
F2. . .Fn, is defined as transgenerational epigenetic inheritance
(TEI) (107). True gametic transmission requires that the epige-
netic changes can be inherited during the generations independ-
ent of the environmental conditions that induced these modifica-
tions in the parental generation (107).
Transgenerational epigenetic inheritance can occur through
the maternal and the paternal germ line (108). For a long time, it
was believed that the paternal genome had almost no contribu-
tion to the epigenetic constitution of the new organism, because
most of the histones were replaced during spermatogenesis by
protamines. Recently, it has been reported that not all histones
are replaced by protamines during spermatogenesis and that
some histones with specific marks are retained specially within
892 ARZATE-MEJÍA ET AL.
the regulatory regions of important developmental genes, poten-
tially affecting the early development of the embryo (109, 110).
Some very interesting examples have come out during the past
years about TEI. The most important example supporting TEI
comes from studying the agouti (A) locus in mice that controls
coat color. Those mice carrying an IAP transposon inserted
upstream of the agouti locus (Avy allele) have ectopic expres-
sion of the Agouti protein (111). The methylation status of IAP
transposon can affect the transcription of the agouti locus; the
methylated state of this transposon was shown to be inherited
through the female germ line (111) and bypass the epigenetic
reprogramming events during early development (112); however,
the mechanism of protection toward the erasing of epigenetic
marks is not fully understood. Other studies suggest that paternal
diet can affect lipid gene expression in the offspring and that
epigenetic information in the sperm respond to this environmen-
tal influence (113) affecting the expression of Ppara possibly by
affecting the methylation status of a putative enhancer for this
gene. In the offspring of male parents that were fed with a low-
protein diet, the putative enhancer of Ppara shows higher meth-
ylation when compared with control offspring. This suggests that
the change in methylation could happen during spermatogenesis
and it can be potentially inherited to the next generations. How-
ever, no change in methylation for the Ppara enhancer could be
detected when sperm of the parental generation where analyzed,
suggesting that these change could possible arise because of
other modification that may have happened during spermatogen-
esis. In fact, diet affected the RNA content and chromatin pack-
aging of sperm, thus making histone marks and noncoding
RNAs as potential candidates for transmission of epigenetic in-
formation to the next generation (113).
Several questions arise from these works. First, which signal-
ing pathways the cells use to integrate specific environmental
information and induce changes in gene expression that can be
potentially inherited? Second, are all the cells capable of
responding to the environmental influences? and finally, how do
the germ cells integrate this environmental information? Is this
information transduced to the cells during the early process of
gametogenesis? Do they use different signaling pathways that
those that control gametogenesis? Which are the target genes
that these pathways could affect to potentially change the epige-
nome of the next generation? And which molecular mechanisms
make possible to bypass the reprogramming events of early de-
velopment to maintain specific epigenetic changes?
We must remember that epigenetic information is reversible
and dynamic. This dynamic nature allows the epigenome to
respond or to be affected by more environmental influences
than the more stable DNA sequence (21). Owing to their
dynamic nature, epigenetic marks seem an ideal way to ensure
a short-term adaptation to environmental changes (107). Identi-
fying the molecular mechanisms and the signaling pathways
that can control this dynamic nature is an exciting and promis-
ing area of research that should be addressed and certainty will
give us amazing answers and also will open up new challenges
to our understanding of the relationship between the epigenome
and cell signaling.
CONCLUDING REMARKS
As we can appreciate from these examples, the ways in
which cell signaling pathways can interact with epigenetic ele-
ments appear to be varied and complex. We are just beginning
to understand such interactions, and is very likely that in the
future, more and more examples like those presented earlier
will show unexpected links between cell signaling networks and
epigenetic mechanisms. Integrating both networks, cell signaling
and epigenetics, is the next necessary step for the comprehen-
sion of complex processes such as development, cell differentia-
tion, and cell plasticity. We can no longer see cell signaling
and epigenetics phenomenon as separated issues. There is
increasing evidence that shows they are not only complemen-
tary networks, but in most cases, they are just two sides of the
same coin. We cannot understand differentiation without epige-
netics, but we neither can explain the epigenetic processes with-
out the input and specificity given by cell signaling pathways.
The relationship between signal transduction pathways and
their target effects over diverse epigenetic processes is forming
part of a new era for epigenetic regulation. Until recently, it is our
opinion that epigenetics was situated in a more descriptive con-
text. The accumulated epigenetic evidences are currently allowing
the incorporation of novel processes like signal transduction. For
example, microRNAs could be considered as candidates to better
understand the relationships between signal transduction and epi-
genetics. Furthermore, attractive fields like cell differentiation and
reprogramming, trans-differentiation or even the heritable aspects
of epigenetics, like transgenerational phenomena, are emerging.
Studying both mechanisms will be complex and may require
the development of new technologies, but integrative research
will be the only way to understand, and eventually manipulate
complex processes such as development, both in health and in
disease.
ACKNOWLEDGEMENTS
We thank Ricardo Saldaña-Meyer and Alejandro Athie-Cuervo
for critical reading of the manuscript. This work was supported
by the Dirección General de Asuntos del Personal Académico-
Universidad Nacional Autónoma de México (IN209403,
IN214407, and IN203811) and Consejo Nacional de Ciencia y
Tecnologı́a (CONACyT: 42653-Q, 58767, and 128464). RGA-M
and DV-G are supported by a Ph.D. fellowship from CONACyT
(255707, 239663).
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