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.
| Original language | English (US) |
|---|---|
| Article number | e1003671 |
| Journal | PLoS Computational Biology |
| Volume | 10 |
| Issue number | 6 |
| DOIs | |
| State | Published - 2014 |
Fingerprint
ASJC Scopus subject areas
- Computational Theory and Mathematics
- Modeling and Simulation
- Ecology, Evolution, Behavior and Systematics
- Genetics
- Molecular Biology
- Ecology
- Cellular and Molecular Neuroscience
Cite this
Comparison of REST Cistromes across Human Cell Types Reveals Common and Context-Specific Functions. / Rockowitz, Shira; Lien, Wen Hui; Pedrosa, Erika; Wei, Gang; Lin, Mingyan; Zhao, Keji; Lachman, Herbert M.; Fuchs, Elaine; Zheng, Deyou.
In: PLoS Computational Biology, Vol. 10, No. 6, e1003671, 2014.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Comparison of REST Cistromes across Human Cell Types Reveals Common and Context-Specific Functions
AU - Rockowitz, Shira
AU - Lien, Wen Hui
AU - Pedrosa, Erika
AU - Wei, Gang
AU - Lin, Mingyan
AU - Zhao, Keji
AU - Lachman, Herbert M.
AU - Fuchs, Elaine
AU - Zheng, Deyou
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84903384828&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84903384828&partnerID=8YFLogxK
U2 - 10.1371/journal.pcbi.1003671
DO - 10.1371/journal.pcbi.1003671
M3 - Article
VL - 10
JO - PLoS Computational Biology
JF - PLoS Computational Biology
SN - 1553-734X
IS - 6
M1 - e1003671
ER -