ATP dependent chromatin remodeling enzymes in embryonic stem cells

Abstract

Embryonic stem (ES) cells are pluripotent cells that can self renew or be induced to differentiate into multiple cell lineages, and thus have the potential to be utilized in regenerative medicine. Key pluripotency specific factors (Oct 4/Sox2/Nanog/Klf4) maintain the pluripotent state by activating expression of pluripotency specific genes and by inhibiting the expression of developmental regulators. Pluripotent ES cells are distinguished from differentiated cells by a specialized chromatin state that is required to epigenetically regulate the ES cell phenotype. Recent studies show that in addition to pluripotency specific factors, chromatin remodeling enzymes play an important role in regulating ES cell chromatin and the capacity to self-renew and to differentiate. Here we review recent studies that delineate the role of ATP dependent chromatin remodeling enzymes in regulating ES cell chromatin structure.

Fig. 1

Embryonic Stem Cell Chromatin. The specialized state of chromatin structure in ES cells is promoted by incorporation of histone variants and by specific histone modifications and is dramatically remodeled upon differentiation. a In pluripotent ES cells, incorporation of the histone variant H2AZ is associated with the repressive covalent modification, H3K27me3 (red triangles) and is required to repress developmentally regulated promoters. Upon differentiation, H2AZ is redistributed to active promoters. b The chromatin structure at developmentally regulated sites is characterized by bivalent domains that have both repressive, H3K27me3 (red triangles) and activating, H3K4me3 (green triangles) covalent modifications. Upon differentiation, these bivalent modifications are resolved depending on transcriptional activity. c ES cell chromatin is characterized by hyperdynamic binding and rapid exchange of heterochromatin protein 1 (HP1) and histone H1. Upon differentiation, HP1 and H1 association with chromatin is stabilized and contributes to heterochromatin formation. There is also an increase in the repressive histone modifications, H3K9me2 (purple triangles) and incorporation of macroH2A at heterochromatin foci

Fig. 2

Three ATP Dependent Chromatin Remodeling Families are distinguished by signature motifs that recognize specific histone modifications. The different ATP dependent chromatin remodeling enzymes have a conserved ATPase domain and additional motifs that confer functional specificity. a The SWI/SNF ATPases contain a bromodomain that has high affinity for acetylated histones. b The ISWI ATPases contain a SANT domain that has high affinity for unmodified histones. c The CHD ATPases have chromodomains that have high affinity for methylated histones

Fig. 3

SWI/SNF complexes regulate ES cell pluripotency. a Brg1 interacts with pluripotency factors to down-modulate pluripotency specific gene expression and to inhibit expression of developmental regulators. BRG1 is significantly enriched at loci that have bivalent domains with H3K27me3 (red triangles) and H3K4me3 (green triangles). b Baf155 is required to compact chromatin and promote increased H3K27me3 (red triangles) at the Nanog promoter during differentiation. These modifications lead to repression of Nanog expression

Fig. 4

BPTF is required for endoderm differentiation. The BPTF subunit of the NURF complex interacts with H3K4me3 (green triangles) and with SMAD transcription factors to activate genes important for distal visceral endoderm differentiation

Fig. 5

The CHD chromatin remodelers regulate chromatin structure in ES cells. a CHD1 is associated with the activating histone mark, H3K4me3 (green triangles) required to maintain permissive chromatin structure in pluripotent ES cells, possibly by promoting the incorporation of H3.3. Down-regulation of CHD1 results in formation of heterochromatin foci. b The ES cell specific complex called NODE interacts with Nanog and Oct4 to repress expression of developmentally regulated genes. C. CHD7 is enriched at distal regulatory elements at actively expressed loci and co-localizes with H3K4me2 (light green triangles). CHD7 binding at distal regions may promote enhancer-promoter interactions

Fig. 6

The Tip60-p400 complex represses gene expression in pluripotent ES cells. In ES cells, down-regulation of Tip60-p400 has a de-repressive effect on the expression of many genes. This introduces the possibility that Tip60-p400 mediated histone acetylation can be associated with gene repression rather than activation depending on the chromatin context