Cell Stem Cell
Epigenetic Mechanisms that Regulate Cell Identity
Stephanie Boue´ ,
and Juan Carlos Izpisu´ a Belmonte
Center of Regenerative Medicine in Barcelona, Dr. Aiguader, 88, 08003 Barcelona, Spain
Individualcellfatedecisionscanvaryaccordingtochangesingeneexpressioninresponsetoenvironmental,developmental, or metabolic cues. This plasticity is tightly regulated during embryonic development andmediated by the exquisitely coordinated activation and repression of groups of genes. Genes that becomerepressed are immersed in a condensed chromatin environment that renders them refractory to stimulation.Thismechanismisresponsibleforboththelossofcellplasticityduringdifferentiationandthepreservationof cell identity. Understanding the molecular events involved in the establishment and maintenance of theserestrictivedomainswillbeneﬁtthedesignofstrategiesforcellularreprogramming,differentiation,andcancer treatment.
Despite sharing the same genome, different cell types froma given organism respond differently to environmental, develop-mental, or metabolic cues. This variable property, or plasticity of responsiveness, is a deﬁning aspect of a cell’s identity and ismainly interpreted at the level of gene expression. Stem andprogenitor cells are a special case, given that their potential forplasticity is, by deﬁnition, more pronounced than for othertissue-speciﬁc cells. During differentiation, stem cells lose theirplasticityandnarrowdowntheiridentityintoaparticulardifferen-tiated cell type. For many years this differentiated state wasthought to be irreversible but recent ﬁndings indicate that it ispossible to manipulate cells in order to change cell identity orto regain plasticity. Understanding how fate decisions are regu-lated and maintained by different cell types, both during devel-opment and under pathological or experimental conditions,represents an important step toward the successful manipula-tion of cell plasticity in clinical settings.We have known for a long time that genetic material associ-ateswithstructuralproteinstoconstitutechromatin,whichplaysimportant roles structurally and functionally. Hence, genesimmersed in highly packed areas of chromatin remain largelyinaccessible, fail to recruit the RNA polymerase to their pro-moters, and thus remain silent and refractory to stimulation.However, genes having a more open and accessible chromatinstructure are more likely to recruit and engage the RNA poly-merase into productive rounds of transcription and their expres-sion is more prone to be modulated by signaling events. Impor-tantly, the chromatin environment in which a particular gene isembedded can differ from one cell type to another, contributingto cell diversity and identity.Thefundamentalunitofchromatinisthenucleosome,whichiscomposed of two copies each of four core histones, H2A, H2B,H3,andH4,andwrappedby146bpofDNA.TheN-terminaltailsof histones are relatively accessible to enzymatic modiﬁcationssuch as acetylation, methylation, phosphorylation, ubiquitina-tion, and sumoylation. Of all the known histone modiﬁcations,acetylation is the only modiﬁcation that directly causes a struc-tural relaxation of chromatin by introducing a negative charge.Other modiﬁcations seem to act as docking sites that promotethe recruitment and stabilization of effector protein complexesrather than altering the chromatin structure per se. In a similarfashion, DNA methylation, which takes place at cytosine resi-dues within CpG dinuclotides at gene promoters, is usuallycorrelated with transcriptional repression and mediates itseffect by blocking the binding of transcription factors and/orfacilitating the assembly of repressor complexes at the methyl-ated regions. In general, the presence of histone modiﬁcationsinvolved in gene activation, such as trimethylation of histoneH3 at lysine 4 (H3K4me3), promotes the recruitment andstabilization of effector complexes with histone acetyltransfer-ase (HAT) and ATP-dependent remodeling activities. Thesecomplexes mediate the acetylation of histones and stimulatethe mobility of the nucleosomes, or even their eviction, to facili-tate the relaxation of chromatin. Ultimately, this change rendersDNA more accessible and facilitates the recruitment of DNA-binding transcription factors to target genes, which in turncontribute to the recruitment of RNA polymerase and the stabi-lization of the preinitiation complex (PIC). Modiﬁcations involvedin gene repression, such as DNA methylation and trimethylationofhistoneH3atlysine9(H3K9me3)andatlysine27(H3K27me3),serve as docking sites for repressor complexes that containhistone deacetylase (HDAC) and ATP-dependent remodelingactivities. The action of these complexes, together with therecruitmentofstructuralnonhistoneproteins,leadstochromatincompaction and reduced DNA accessibility.
Molecular Basis of Pluripotency in EmbryonicStem Cells
The chromatin in pluripotent embryonic stem cells (ESCs) dis-plays distinctive features when compared to differentiated cells.In ESCs the chromatin structural proteins display hyperdynamicinteractions with chromatin ( Meshorer et al., 2006 ) and the over-all transcriptional activity is hyperactive compared to differenti-ated cells ( Efroni et al., 2008 ). ESCs also express high levels of chromatin-remodeling factors involved in maintaining the openchromatin status. Moreover, variations in the expression levelsof speciﬁc subunits of remodeling complexes, such as the BAFcomplex, in ESCs relative to differentiated cells leads to theformation of unique remodeling complexes that differ in subunitcomposition and potentially in function ( Ho et al., 2009 ). These
Cell Stem Cell
, November 5, 2010
2010 Elsevier Inc.