Editing Cellular differentiation (section)

===Role of signaling in epigenetic control===

A final question to ask concerns the role of cell signaling in influencing the epigenetic processes governing differentiation. Such a role should exist, as it would be reasonable to think that extrinsic signaling can lead to epigenetic remodeling, just as it can lead to changes in gene expression through the activation or repression of different transcription factors. Little direct data is available concerning the specific signals that influence the [[epigenome]], and the majority of current knowledge about the subject consists of speculations on plausible candidate regulators of epigenetic remodeling.<ref name = "Mohammad">{{cite journal | vauthors = Mohammad HP, Baylin SB | title = Linking cell signaling and the epigenetic machinery | journal = Nature Biotechnology | volume = 28 | issue = 10 | pages = 1033–1038 | date = October 2010 | pmid = 20944593 | doi = 10.1038/nbt1010-1033 | s2cid = 6911946 }}</ref> We will first discuss several major candidates thought to be involved in the induction and maintenance of both embryonic stem cells and their differentiated progeny, and then turn to one example of specific signaling pathways in which more direct evidence exists for its role in epigenetic change.

The first major candidate is [[Wnt signaling pathway]]. The Wnt pathway is involved in all stages of differentiation, and the ligand Wnt3a can substitute for the overexpression of c-Myc in the generation of induced pluripotent stem cells.<ref name = "Mohammad"/> On the other hand, disruption of [[Beta-catenin|β-catenin]], a component of the Wnt signaling pathway, leads to decreased proliferation of neural progenitors.

[[Growth factors]] comprise the second major set of candidates of epigenetic regulators of cellular differentiation. These morphogens are crucial for development, and include [[bone morphogenetic proteins]], [[transforming growth factors]] (TGFs), and [[fibroblast growth factors]] (FGFs). TGFs and FGFs have been shown to sustain expression of OCT4, SOX2, and NANOG by downstream signaling to [[SMAD (protein)|Smad]] proteins.<ref name = "Mohammad"/> Depletion of growth factors promotes the differentiation of ESCs, while genes with bivalent chromatin can become either more restrictive or permissive in their transcription.<ref name = "Mohammad"/>

Several other signaling pathways are also considered to be primary candidates. Cytokine [[leukemia inhibitory factor]]s are associated with the maintenance of mouse ESCs in an undifferentiated state. This is achieved through its activation of the Jak-STAT3 pathway, which has been shown to be necessary and sufficient towards maintaining mouse ESC pluripotency.<ref name = "Niwa">{{cite journal | vauthors = Niwa H, Burdon T, Chambers I, Smith A | title = Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3 | journal = Genes & Development | volume = 12 | issue = 13 | pages = 2048–2060 | date = July 1998 | pmid = 9649508 | pmc = 316954 | doi = 10.1101/gad.12.13.2048 }}</ref> [[Retinoic acid]] can induce differentiation of human and mouse ESCs,<ref name = "Mohammad"/> and [[Notch signaling]] is involved in the proliferation and self-renewal of stem cells. Finally, [[Sonic hedgehog]], in addition to its role as a morphogen, promotes embryonic stem cell differentiation and the self-renewal of somatic stem cells.<ref name = "Mohammad"/>

The problem, of course, is that the candidacy of these signaling pathways was inferred primarily on the basis of their role in development and cellular differentiation. While epigenetic regulation is necessary for driving cellular differentiation, they are certainly not sufficient for this process. Direct modulation of gene expression through modification of transcription factors plays a key role that must be distinguished from heritable epigenetic changes that can persist even in the absence of the original environmental signals. Only a few examples of signaling pathways leading to epigenetic changes that alter cell fate currently exist, and we will focus on one of them.

Expression of Shh (Sonic hedgehog) upregulates the production of [[BMI1]], a component of the PcG complex that recognizes [[H3K27me3]]. This occurs in a Gli-dependent manner, as [[Gli1]] and [[Gli2]] are downstream effectors of the [[Hedgehog signaling pathway]]. In culture, Bmi1 mediates the Hedgehog pathway's ability to promote human mammary stem cell self-renewal.<ref name = "Liu">{{cite journal | vauthors = Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS | title = Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells | journal = Cancer Research | volume = 66 | issue = 12 | pages = 6063–6071 | date = June 2006 | pmid = 16778178 | pmc = 4386278 | doi = 10.1158/0008-5472.CAN-06-0054 }}</ref> In both humans and mice, researchers showed Bmi1 to be highly expressed in proliferating immature cerebellar granule cell precursors. When Bmi1 was knocked out in mice, impaired cerebellar development resulted, leading to significant reductions in postnatal brain mass along with abnormalities in motor control and behavior.<ref name = "Leung">{{cite journal | vauthors = Leung C, Lingbeek M, Shakhova O, Liu J, Tanger E, Saremaslani P, Van Lohuizen M, Marino S | title = Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas | journal = Nature | volume = 428 | issue = 6980 | pages = 337–341 | date = March 2004 | pmid = 15029199 | doi = 10.1038/nature02385 | s2cid = 29965488 | bibcode = 2004Natur.428..337L }}</ref> A separate study showed a significant decrease in neural stem cell proliferation along with increased astrocyte proliferation in Bmi null mice.<ref name = "Zencak">{{cite journal | vauthors = Zencak D, Lingbeek M, Kostic C, Tekaya M, Tanger E, Hornfeld D, Jaquet M, Munier FL, Schorderet DF, van Lohuizen M, Arsenijevic Y | title = Bmi1 loss produces an increase in astroglial cells and a decrease in neural stem cell population and proliferation | journal = The Journal of Neuroscience | volume = 25 | issue = 24 | pages = 5774–5783 | date = June 2005 | pmid = 15958744 | pmc = 6724881 | doi = 10.1523/JNEUROSCI.3452-04.2005 }}</ref>

An alternative model of cellular differentiation during embryogenesis is that positional information is based on mechanical signalling by the cytoskeleton using [[Embryonic differentiation waves]]. The mechanical signal is then epigenetically transduced via signal transduction systems (of which specific molecules such as Wnt are part) to result in differential gene expression.

In summary, the role of signaling in the epigenetic control of cell fate in mammals is largely unknown, but distinct examples exist that indicate the likely existence of further such mechanisms.