Chd1 regulates open chromatin and pluripotency of embryonic stem cells

Abstract

Summary An open chromatin largely devoid of heterochromatin is a hallmark of stem cells, from Planarians to Mammals. It remains unknown whether an open chromatin is necessary for the differentiation potential of stem cells, and what are the molecules that maintain open chromatin in stem cells. Here we show that the chromatin remodeling factor Chd1 is required to maintain the open chromatin state of pluripotent mouse Embryonic Stem (ES) cells. Chd1 is a euchromatin protein that associates with the promoters of active genes, and down-regulation of Chd1 leads to accumulation of heterochromatin in ES cells. Chd1-deficient ES cells are no longer pluripotent, because they are incapable of giving rise to primitive endoderm and have a high propensity for neural differentiation. Furthermore, Chd1 is required for efficient reprogramming of fibroblasts to the pluripotent stem cell state. Our results indicate that Chd1 is essential for open chromatin and pluripotency of ES cells, and for somatic cell reprogramming to the pluripotent state. The data suggest that pluripotent stem cells exist in a dynamic state of opposing epigenetic influences of euchromatin and heterochromatin.

Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective

“…Chd1 helps maintain the open chromatin in ESCs, as depletion of Chd1 leads to accumulation of heterochromatin and interferes with proper differentiation. Consistently, Chd1 deficiency reduces reprogramming efficiency [36], indicating that establishing the ESC chromatin state is crucial for acquiring pluripotency.…”

“…The CHD class remodeling factor, Chd1, preferentially binds to euchromatin and colocalizes with RNA polymerase II (Pol II) [36]. Chd1 helps maintain the open chromatin in ESCs, as depletion of Chd1 leads to accumulation of heterochromatin and interferes with proper differentiation.…”

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

“…One of these was chromodomain‐helicase‐DNA‐binding protein 1 ( Chd1 ), which is involved in maintaining the promoters of differentiation‐associated genes silenced in pluripotent stem cell cells (Gaspar‐Maia et al ., 2009). The cell‐type‐weighed transcript lists were submitted to a GO term enrichment analysis.…”

Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape

“…The absence of DNA synthesis-independent nucleosome assembly factor, HirA, largely elevates the level of soluble core histones in ES cells, and leads to accelerated embryoid body differentiation [122]. This unique chromatin structure of ES cells appears to be actively maintained as the downregulation of the chromatin remodeler Chd1 in ES cells leads to an accumulation of heterochromatin and loss of pluripotency [123]. Perhaps not surprisingly, manipulation at this level of chromatin organization has effects on cellular reprogaming as Chd1 is essential for iPS cell generation and overexpression of ES cell-specific components of the ATP-dependent chromatin remodeling complex (named ES-BAF) enhances reprogramming [123,124].…”

“…This unique chromatin structure of ES cells appears to be actively maintained as the downregulation of the chromatin remodeler Chd1 in ES cells leads to an accumulation of heterochromatin and loss of pluripotency [123]. Perhaps not surprisingly, manipulation at this level of chromatin organization has effects on cellular reprogaming as Chd1 is essential for iPS cell generation and overexpression of ES cell-specific components of the ATP-dependent chromatin remodeling complex (named ES-BAF) enhances reprogramming [123,124]. Electron spectroscopy imaging also showed that the epiblast progenitor cells of the mouse blastocyst and mouse ES cells have highly dispersed global chromatin architecture, which is distinct from the more compact chromatin state of differentiated cells, with specialized silencing compartments formed [125].…”