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PLoS Comput Biol. 2014 Jun 12;10(6):e1003671. doi: 10.1371/journal.pcbi.1003671. eCollection 2014 Jun.

Comparison of REST cistromes across human cell types reveals common and context-specific functions.

Author information

1
Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.
2
Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology & Development, The Rockefeller University, New York, New York, United States of America.
3
Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.
4
Systems Biology Center, National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, Maryland, United States of America.
5
Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America; Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America; Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.
6
Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America; Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.

Abstract

Recent studies have shown that the transcriptional functions of REST are much broader than repressing neuronal genes in non-neuronal systems. Whether REST occupies similar chromatin regions in different cell types and how it interacts with other transcriptional regulators to execute its functions in a context-dependent manner has not been adequately investigated. We have applied ChIP-seq analysis to identify the REST cistrome in human CD4+ T cells and compared it with published data from 15 other cell types. We found that REST cistromes were distinct among cell types, with REST binding to several tumor suppressors specifically in cancer cells, whereas 7% of the REST peaks in non-neuronal cells were ubiquitously called and <25% were identified for ≥ 5 cell types. Nevertheless, using a quantitative metric directly comparing raw ChIP-seq signals, we found the majority (∼80%) was shared by ≥ 2 cell types. Integration with RNA-seq data showed that REST binding was generally correlated with low gene expression. Close examination revealed that multiple contexts were correlated with reduced expression of REST targets, e.g., the presence of a cognate RE1 motif and cellular specificity of REST binding. These contexts were shown to play a role in differential corepressor recruitment. Furthermore, transcriptional outcome was highly influenced by REST cofactors, e.g., SIN3 and EZH2 co-occupancy marked higher and lower expression of REST targets, respectively. Unexpectedly, the REST cistrome in differentiated neurons exhibited unique features not observed in non-neuronal cells, e.g., the lack of RE1 motifs and an association with active gene expression. Finally, our analysis demonstrated how REST could differentially regulate a transcription network constituted of miRNAs, REST complex and neuronal factors. Overall, our findings of contexts playing critical roles in REST occupancy and regulatory outcome provide insights into the molecular interactions underlying REST's diverse functions, and point to novel roles of REST in differentiated neurons.

PMID:
24922058
PMCID:
PMC4055426
DOI:
10.1371/journal.pcbi.1003671
[Indexed for MEDLINE]
Free PMC Article

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