A Novel Human Polycomb Binding Site Acts As a Functional Polycomb Response Element in Drosophila

Polycomb group (PcG) proteins are key chromatin regulators implicated in multiple processes including embryonic development, tissue homeostasis, genomic imprinting, X-chromosome inactivation, and germ cell differentiation. The PcG proteins recognize target genomic loci through cis DNA sequences known as Polycomb Response Elements (PREs), which are well characterized in Drosophila. However, mammalian PREs have been elusive until two groups reported putative mammalian PREs recently. Consistent with the existence of mammalian PREs, here we report the identification and characterization of a potential PRE from human T cells. The putative human PRE has enriched binding of PcG proteins, and such binding is dependent on a key PcG component SUZ12. We demonstrate that the putative human PRE carries both genetic and molecular features of Drosophila PRE in transgenic flies, implying that not only the trans PcG proteins but also certain features of the cis PREs are conserved between mammals and Drosophila

Acute depletion of Tet1-dependent 5-hydroxymethylcytosine levels impairs LIF/Stat3 signaling and results in loss of embryonic stem cell identity

The TET family of FE(II) and 2-oxoglutarate-dependent enzymes (Tet1/2/3) promote DNA demethylation by converting 5-methylcytosine to 5-hydroxymethylcytosine (5hmC), which they further oxidize into 5-formylcytosine and 5-carboxylcytosine. Tet1 is robustly expressed in mouse embryonic stem cells (mESCs) and has been implicated in mESC maintenance. Here we demonstrate that, unlike genetic deletion, RNAi-mediated depletion of Tet1 in mESCs led to a significant reduction in 5hmC and loss of mESC identity. The differentiation phenotype due to Tet1 depletion positively correlated with the extent of 5hmC loss. Meta-analyses of genomic data sets suggested interaction between Tet1 and leukemia inhibitory factor (LIF) signaling. LIF signaling is known to promote self-renewal and pluripotency in mESCs partly by opposing MAPK/ERK-mediated differentiation. Withdrawal of LIF leads to differentiation of mESCs. We discovered that Tet1 depletion impaired LIF-dependent Stat3-mediated gene activation by affecting Stat3's ability to bind to its target sites on chromatin. Nanog overexpression or inhibition of MAPK/ERK signaling, both known to maintain mESCs in the absence of LIF, rescued Tet1 depletion, further supporting the dependence of LIF/Stat3 signaling on Tet1. These data support the conclusion that analysis of mESCs in the hours/days immediately following efficient Tet1 depletion reveals Tet1's normal physiological role in maintaining the pluripotent state that may be subject to homeostatic compensation in genetic models

Transcriptional enhancer factor 1 (TEF-1/TEAD1) mediates activation of IFITM3 gene by BRGl

AbstractThe interferon inducible transmembrane (IFITM) proteins mediate several cellular processes such as homotypic cell adhesion functions of interferons (IFNs) and cellular anti-proliferative activities. We show that the BAF complex-mediated induction of IFITM3 is dependent on binding of the transcriptional enhancer factor 1 (TEF-1/TEAD1) to the M-CAT like elements of its promoter. TEF-1 knock-down reduced the BAF complex-mediated activation of IFITM3 promoter. In the absence of the BAF complex, TEF-1 is repressive to IFITM3 expression. The regulation of IFITM3 by TEF-1 demonstrates that TEF-1 dependent regulation is more widespread than its previously established role in the expression of muscle specific genes

Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping

The identity and developmental potential of a human cell is specified by its epigenome that is largely defined by patterns of chromatin modifications including histone acetylation. Here we report high-resolution genome-wide mapping of diacetylation of histone H3 at Lys 9 and Lys 14 in resting and activated human T cells by genome-wide mapping technique (GMAT). Our data show that high levels of the H3 acetylation are detected in gene-rich regions. The chromatin accessibility and gene expression of a genetic domain is correlated with hyperacetylation of promoters and other regulatory elements but not with generally elevated acetylation of the entire domain. Islands of acetylation are identified in the intergenic and transcribed regions. The locations of the 46,813 acetylation islands identified in this study are significantly correlated with conserved noncoding sequences (CNSs) and many of them are colocalized with known regulatory elements in T cells. TCR signaling induces 4045 new acetylation loci that may mediate the global chromatin remodeling and gene activation. We propose that the acetylation islands are epigenetic marks that allow prediction of functional regulatory elements

Epigenetic toxicity of heavy metals − implications for embryonic stem cells

Exposure to heavy metals, such as cadmium, nickel, mercury, arsenic, lead, and hexavalent chromium has been linked to dysregulated developmental processes, such as impaired stem cell differentiation. Heavy metals are well-known modifiers of the epigenome. Stem and progenitor cells are particularly vulnerable to exposure to potentially toxic metals since these cells rely on epigenetic reprogramming for their proper functioning. Therefore, exposure to metals can impair stem and progenitor cell proliferation, pluripotency, stemness, and differentiation. In this review, we provide a comprehensive summary of current evidence on the epigenetic effects of heavy metals on stem cells, focusing particularly on DNA methylation and histone modifications. Moreover, we explore the underlying mechanisms responsible for these epigenetic changes. By providing an overview of heavy metal exposure-induced alterations to the epigenome, the underlying mechanisms, and the consequences of those alterations on stem cell function, this review provides a foundation for further research in this critical area of overlap between toxicology and developmental biology