title: 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.
authors: Department of Human Genetics, University of Chicago, Howard Hughes Medical Institute, Chicago, Illinois 60637, USA;
authors: Timothy J
authors: TJ
authors: Looney
authors: Li
authors: L
authors: Zhang
authors: Chih-Hsin
authors: CH
authors: Chen
authors: Jae Hyun
authors: JH
authors: Lee
authors: Sheila
authors: S
authors: Chari
authors: Frank Fuxiang
authors: FF
authors: Mao
authors: Mattia
authors: M
authors: Pelizzola
authors: Lu
authors: L
authors: Zhang
authors: Ryan
authors: R
authors: Lister
authors: Samuel W
authors: SW
authors: Baker
authors: Croydon J
authors: CJ
authors: Fernandes
authors: Jedidiah
authors: J
authors: Gaetz
authors: Kara M
authors: KM
authors: Foshay
authors: Kayla L
authors: KL
authors: Clift
authors: Zhenyu
authors: Z
authors: Zhang
authors: Wei-Qiang
authors: WQ
authors: Li
authors: Eric J
authors: EJ
authors: Vallender
authors: Ulrich
authors: U
authors: Wagner
authors: Jane Yuxia
authors: JY
authors: Qin
authors: Katelyn J
authors: KJ
authors: Michelini
authors: Branimir
authors: B
authors: Bugarija
authors: Donghyun
authors: D
authors: Park
authors: Emmanuel
authors: E
authors: Aryee
authors: Thomas
authors: T
authors: Stricker
authors: Jie
authors: J
authors: Zhou
authors: Kevin P
authors: KP
authors: White
authors: Bing
authors: B
authors: Ren
authors: Gary P
authors: GP
authors: Schroth
authors: Joseph R
authors: JR
authors: Ecker
authors: Andy Peng
authors: AP
authors: Xiang
authors: Bruce T
authors: BT
authors: Lahn
mesh_terms: D000818:Animals; D002459:Cell Fusion; D002460:Cell Line; D002843:Chromatin / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D005786:Gene Expression Regulation; D020868:Gene Silencing; D016678:Genome; D006657:Histones / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D006657:Histones; D015534:Trans-Activators