Dynamic chromatin states in human ES cells reveal potential regulatory sequences and genes involved in pluripotency

Abstract

Pluripotency, the ability of a cell to differentiate and give rise to all embryonic lineages, defines a small number of mammalian cell types such as embryonic stem (ES) cells. While it has been generally held that pluripotency is the product of a transcriptional regulatory network that activates and maintains the expression of key stem cell genes, accumulating evidence is pointing to a critical role for epigenetic processes in establishing and safeguarding the pluripotency of ES cells, as well as maintaining the identity of differentiated cell types. In order to better understand the role of epigenetic mechanisms in pluripotency, we have examined the dynamics of chromatin modifications genomewide in human ES cells (hESCs) undergoing differentiation into a mesendodermal lineage. We found that chromatin modifications at promoters remain largely invariant during differentiation, except at a small number of promoters where a dynamic switch between acetylation and methylation at H3K27 marks the transition between activation and silencing of gene expression, suggesting a hierarchy in cell fate commitment over most differentially expressed genes. We also mapped over 50 000 potential enhancers, and observed much greater dynamics in chromatin modifications, especially H3K4me1 and H3K27ac, which correlate with expression of their potential target genes. Further analysis of these enhancers revealed potentially key transcriptional regulators of pluripotency and a chromatin signature indicative of a poised state that may confer developmental competence in hESCs. Our results provide new evidence supporting the role of chromatin modifications in defining enhancers and pluripotency.

NOTCH1–RBPJ complexes drive target gene expression through dynamic interactions with superenhancers

“…One factor that is hypothesized to influence pairing of distal regulatory elements with promoters is their spatial relationship to constitutive CTCF-binding sites, which appear to organize the mammalian genome into functional chromatin domains (25)(26)(27). Using constitutive CTCF binding data from the ENCODE consortium, we identified a strong bias toward colocalization of dynamic NOTCH1 sites and high-confidence direct Notch target genes within the same CTCF domain.…”

“…In mammalian genomes, functional chromatin domains are hypothesized to be delineated by constitutive CCCTC-binding factor (CTCF) sites (25)(26)(27). We partitioned the genome using constitutive CTCF-binding sites derived from Encyclopedia of DNA elements (ENCODE) data and asked if CTCF domains restrict the regulatory activity of dynamic NOTCH1 sites.…”

Genetics of complex traits: prediction of phenotype, identification of causal polymorphisms and genetic architecture

“…Sites in the genome that would affect gene expression if mutated can also be identified by genomic features such as histone marks and transcription factor binding sites, which are indicative of enhancers [36], transcription start sites [36] or promoters [37], any of which could be involved in gene regulation, and which therefore might affect phenotype if mutated. A consortium called Functional Annotation of ANimal Genomes (FAANG [38]) is now planning to annotate livestock genomes for such histone marks as well as other markers of open chromatin in a similar fashion to that in humans (the ENCODE consortium).…”

Mark the transition: chromatin modifications and cell fate decision

“…In this issue of Cell Research, Hawkins et al addressed many aspects of this question [5]. The authors first induced hES cells to differentiate into a mixture of mesendodermal and trophectodermal cells (denoted as DFC).…”