title: Significant expansion of the REST/NRSF cistrome in human versus mouse embryonic stem cells: potential implications for neural development.
abstract: Recent studies have employed cross-species comparisons of transcription factor binding, reporting significant regulatory network 'rewiring' between species. Here, we address how a transcriptional repressor targets and regulates neural genes differentially between human and mouse embryonic stem cells (ESCs). We find that the transcription factor, Repressor Element 1 Silencing Transcription factor (REST; also called neuron restrictive silencer factor) binds to a core group of ∼1200 syntenic genomic regions in both species, with these conserved sites highly enriched with co-factors, selective histone modifications and DNA hypomethylation. Genes with conserved REST binding are enriched with neural functions and more likely to be upregulated upon REST depletion. Interestingly, we identified twice as many REST peaks in human ESCs compared to mouse ESCs. Human REST cistrome expansion involves additional peaks in genes targeted by REST in both species and human-specific gene targets. Genes with expanded REST occupancy in humans are enriched for learning or memory functions. Analysis of neurological disorder associated genes reveals that Amyotrophic Lateral Sclerosis and oxidative stress genes are particularly enriched with human-specific REST binding. Overall, our results demonstrate that there is substantial rewiring of human and mouse REST cistromes, and that REST may have human-specific roles in brain development and functions.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Shira
authors.initials: S
authors.lastname: Rockowitz
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA deyou.zheng@einstein.yu.edu.
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D053263:Gene Regulatory Networks; D016678:Genome; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D055495:Neurogenesis / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D006657:Histones; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor