Coassembly of REST and its cofactors at sites of gene repression in embryonic stem cells

Yu, Hongbing; Johnson, Rory; Kunarso, Galih; Stanton, Lawrence W.

doi:10.1101/gr.114488.110

Cited by 48 publications

(61 citation statements)

References 42 publications

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“…The enrichment or depletion of DNA-binding proteins at a given promoter site depends not only on the cellular or nuclear abundance, but also on binding affinity of the regulatory element for the binding protein (Bruce et al, 2009;Yu et al, 2011). An additional and nontrivial point to account for the increased REST affinity is that of multivalency, the situation in which two or more DNA-binding proteins or epigenetic marks bound at the same promoter act synergistically to promote repression (or activation) and alter the affinity/ capacity for a given DNA-binding protein, relative to the affinity observed in the absence of the marks (Ruthenburg et al, 2007).…”

Section: Transcriptional Regulation By Rest During Strokementioning

confidence: 99%

Epigenetic Mechanisms in Stroke and Epilepsy

Hwang

Aromolaran

Zukin

2012

Neuropsychopharmacol

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Epigenetic remodeling and modifications of chromatin structure by DNA methylation and histone modifications represent central mechanisms for the regulation of neuronal gene expression during brain development, higher-order processing, and memory formation. Emerging evidence implicates epigenetic modifications not only in normal brain function, but also in neuropsychiatric disorders. This review focuses on recent findings that disruption of chromatin modifications have a major role in the neurodegeneration associated with ischemic stroke and epilepsy. Although these disorders differ in their underlying causes and pathophysiology, they share a common feature, in that each disorder activates the gene silencing transcription factor REST (repressor element 1 silencing transcription factor), which orchestrates epigenetic remodeling of a subset of 'transcriptionally responsive targets' implicated in neuronal death. Although ischemic insults activate REST in selectively vulnerable neurons in the hippocampal CA1, seizures activate REST in CA3 neurons destined to die. Profiling the array of genes that are epigenetically dysregulated in response to neuronal insults is likely to advance our understanding of the mechanisms underlying the pathophysiology of these disorders and may lead to the identification of novel therapeutic strategies for the amelioration of these serious human conditions.

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Section: Transcriptional Regulation By Rest During Strokementioning

confidence: 99%

Epigenetic Mechanisms in Stroke and Epilepsy

Hwang

Aromolaran

Zukin

2012

Neuropsychopharmacol

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“…Nevertheless, the more highly bound genomic regions include most known and probable functional targets, whereas the lowest-occupancy DNA binding events generally do not appear to be involved in the cis-regulation of transcription (1,3,7,8). For example, in studies of Drosophila blastoderm patterning transcription factors we determined that genomic regions only bound at low occupancy have some of the following characteristics: proximity to genes whose biological functions are not associated with the bound transcription factors; proximity to genes that are not spatially regulated or not transcribed in early embryos; and mapping to poorly conserved sequences or protein coding sequences (6,9).…”

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confidence: 99%

DNA regions bound at low occupancy by transcription factors do not drive patterned reporter gene expression in Drosophila

Fisher¹,

Li²,

Hammonds³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

147

139

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In animals, each sequence-specific transcription factor typically binds to thousands of genomic regions in vivo. Our previous studies of 20 transcription factors show that most genomic regions bound at high levels in Drosophila blastoderm embryos are known or probable functional targets, but genomic regions occupied only at low levels have characteristics suggesting that most are not involved in the cis-regulation of transcription. Here we use transgenic reporter gene assays to directly test the transcriptional activity of 104 genomic regions bound at different levels by the 20 transcription factors. Fifteen genomic regions were selected based solely on the DNA occupancy level of the transcription factor Kruppel. Five of the six most highly bound regions drive blastoderm patterns of reporter transcription. In contrast, only one of the nine lowly bound regions drives transcription at this stage and four of them are not detectably active at any stage of embryogenesis. A larger set of 89 genomic regions chosen using criteria designed to identify functional cis-regulatory regions supports the same trend: genomic regions occupied at high levels by transcription factors in vivo drive patterned gene expression, whereas those occupied only at lower levels mostly do not. These results support studies that indicate that the high cellular concentrations of sequence-specific transcription factors drive extensive, low-occupancy, nonfunctional interactions within the accessible portions of the genome.

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“…It has been mostly studied as a suppressor of important neural genes in embryonic stem cells (ESCs), neural progenitors, and other non-neural systems. Its function in neuronal cells, however, seems to be more complex and dependent on contexts [8][9][10][11][12][13][14] To better understand the roles of REST in regulating neural programs and how its cistrome has evolved, Rockowitz and Zheng recently compared genome-wide REST occupancy in human and mouse ESCs, using data from chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq). They identified significant expansion of REST binding in human ESCs (hESCs) compared with its binding in mouse ESCs (mESCs) (8,199 occurrences in human versus 4,107 in mice).…”

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confidence: 99%

Divergence and rewiring of regulatory networks for neural development between human and other species

et al. 2016

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Neural and brain development in human and other mammalian species are largely similar, but distinct features exist at the levels of macrostructure and underlying genetic control. Comparative studies of epigenetic regulation and transcription factor (TF) binding in humans, chimpanzees, rodents, and other species have found large differences in gene regulatory networks. A recent analysis of the cistromes of REST/NRSF, a critical transcriptional regulator for the nervous system, demonstrated that REST binding to syntenic genomic regions (i.e., conserved binding) represents only a small percentage of the total binding events in human and mouse embryonic stem cells. While conserved binding is significantly associated with functional features (e.g., co-factor recruitment) and enriched at genes important for neural development and function, >3000 genes, including many related to brain and neural functions, either contain extra REST-bound sites (e.g., NRXN1) or are targeted by REST only (e.g. PSEN2) in humans. Surprisingly, several genes known to have critical roles in learning and memory, or brain disorders (e.g., APP and HTT) exhibit characteristics of human specific REST regulation. These findings indicate that more systematic studies are needed to better understand the divergent wiring of regulatory networks in humans, mice, and other mammals and their functional implications.

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Coassembly of REST and its cofactors at sites of gene repression in embryonic stem cells

Cited by 48 publications

References 42 publications

Epigenetic Mechanisms in Stroke and Epilepsy

Epigenetic Mechanisms in Stroke and Epilepsy

DNA regions bound at low occupancy by transcription factors do not drive patterned reporter gene expression in Drosophila

Divergence and rewiring of regulatory networks for neural development between human and other species

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