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Systematic mapping of occluded genes by cell fusion reveals prevalence and stability of cis-mediated silencing in somatic cells.

ABSTRACT: Both diffusible factors acting in trans and chromatin components acting in cis are implicated in gene regulation, but the extent to which either process causally determines a cell's transcriptional identity is unclear. We recently used cell fusion to define a class of silent genes termed "cis-silenced" (or "occluded") genes, which remain silent even in the presence of trans-acting transcriptional activators. We further showed that occlusion of lineage-inappropriate genes plays a critical role in maintaining the transcriptional identities of somatic cells. Here, we present, for the first time, a comprehensive map of occluded genes in somatic cells. Specifically, we mapped occluded genes in mouse fibroblasts via fusion to a dozen different rat cell types followed by whole-transcriptome profiling. We found that occluded genes are highly prevalent and stable in somatic cells, representing a sizeable fraction of silent genes. Occluded genes are also highly enriched for important developmental regulators of alternative lineages, consistent with the role of occlusion in safeguarding cell identities. Alongside this map, we also present whole-genome maps of DNA methylation and eight other chromatin marks. These maps uncover a complex relationship between chromatin state and occlusion. Furthermore, we found that DNA methylation functions as the memory of occlusion in a subset of occluded genes, while histone deacetylation contributes to the implementation but not memory of occlusion. Our data suggest that the identities of individual cell types are defined largely by the occlusion status of their genomes. The comprehensive reference maps reported here provide the foundation for future studies aimed at understanding the role of occlusion in development and disease.

SUBMITTER: Looney TJ

PROVIDER: S-EPMC3912417 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Systematic mapping of occluded genes by cell fusion reveals prevalence and stability of cis-mediated silencing in somatic cells.

Looney Timothy J TJ Zhang Li L Chen Chih-Hsin CH Lee Jae Hyun JH Chari Sheila S Mao Frank Fuxiang FF Pelizzola Mattia M Zhang Lu L Lister Ryan R Baker Samuel W SW Fernandes Croydon J CJ Gaetz Jedidiah J Foshay Kara M KM Clift Kayla L KL Zhang Zhenyu Z Li Wei-Qiang WQ Vallender Eric J EJ Wagner Ulrich U Qin Jane Yuxia JY Michelini Katelyn J KJ Bugarija Branimir B Park Donghyun D Aryee Emmanuel E Stricker Thomas T Zhou Jie J White Kevin P KP Ren Bing B Schroth Gary P GP Ecker Joseph R JR Xiang Andy Peng AP Lahn Bruce T BT

Genome research 20131205 2

Both diffusible factors acting in trans and chromatin components acting in cis are implicated in gene regulation, but the extent to which either process causally determines a cell's transcriptional identity is unclear. We recently used cell fusion to define a class of silent genes termed "cis-silenced" (or "occluded") genes, which remain silent even in the presence of trans-acting transcriptional activators. We further showed that occlusion of lineage-inappropriate genes plays a critical role in ...[more]

PMID: 24310002

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Systematic mapping of occluded genes by cell fusion reveals prevalence and stability of cis-mediated silencing in somatic cells.

Publications

Systematic mapping of occluded genes by cell fusion reveals prevalence and stability of cis-mediated silencing in somatic cells.

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