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Bcl11b sets pro-T cell fate by site-specific cofactor recruitment and by repressing Id2 and Zbtb16

Hosokawa, Hiroyuki ; Romero-Wolf, Maile ; Yui, Mary A. ; Ungerbäck, Jonas LU ; Quiloan, Maria L.G. ; Matsumoto, Masaki ; Nakayama, Keiichi I. ; Tanaka, Tomoaki and Rothenberg, Ellen V. (2018) In Nature Immunology 19(12). p.1427-1440
Abstract

Multipotent progenitor cells confirm their T cell–lineage identity in the CD4CD8 double-negative (DN) pro-T cell DN2 stages, when expression of the essential transcription factor Bcl11b begins. In vivo and in vitro stage-specific deletions globally identified Bcl11b-controlled target genes in pro-T cells. Proteomics analysis revealed that Bcl11b associated with multiple cofactors and that its direct action was needed to recruit those cofactors to selective target sites. Regions near functionally regulated target genes showed enrichment for those sites of Bcl11b-dependent recruitment of cofactors, and deletion of individual cofactors relieved the repression of many genes normally repressed by Bcl11b. Runx1... (More)

Multipotent progenitor cells confirm their T cell–lineage identity in the CD4CD8 double-negative (DN) pro-T cell DN2 stages, when expression of the essential transcription factor Bcl11b begins. In vivo and in vitro stage-specific deletions globally identified Bcl11b-controlled target genes in pro-T cells. Proteomics analysis revealed that Bcl11b associated with multiple cofactors and that its direct action was needed to recruit those cofactors to selective target sites. Regions near functionally regulated target genes showed enrichment for those sites of Bcl11b-dependent recruitment of cofactors, and deletion of individual cofactors relieved the repression of many genes normally repressed by Bcl11b. Runx1 collaborated with Bcl11b most frequently for both activation and repression. In parallel, Bcl11b indirectly regulated a subset of target genes by a gene network circuit via the transcription inhibitor Id2 (encoded by Id2) and transcription factor PLZF (encoded by Zbtb16); Id2 and Zbtb16 were directly repressed by Bcl11b, and Id2 and PLZF controlled distinct alternative programs. Thus, our study defines the molecular basis of direct and indirect Bcl11b actions that promote T cell identity and block alternative potentials.

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published
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Nature Immunology
volume
19
issue
12
pages
14 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85055711430
  • pmid:30374131
ISSN
1529-2908
DOI
10.1038/s41590-018-0238-4
language
English
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yes
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5ad02330-4993-4451-a8e8-91dbf72ec482
date added to LUP
2018-12-07 12:09:38
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2020-10-07 06:11:53
@article{5ad02330-4993-4451-a8e8-91dbf72ec482,
  abstract     = {<p>Multipotent progenitor cells confirm their T cell–lineage identity in the CD4<sup>–</sup>CD8<sup>–</sup> double-negative (DN) pro-T cell DN2 stages, when expression of the essential transcription factor Bcl11b begins. In vivo and in vitro stage-specific deletions globally identified Bcl11b-controlled target genes in pro-T cells. Proteomics analysis revealed that Bcl11b associated with multiple cofactors and that its direct action was needed to recruit those cofactors to selective target sites. Regions near functionally regulated target genes showed enrichment for those sites of Bcl11b-dependent recruitment of cofactors, and deletion of individual cofactors relieved the repression of many genes normally repressed by Bcl11b. Runx1 collaborated with Bcl11b most frequently for both activation and repression. In parallel, Bcl11b indirectly regulated a subset of target genes by a gene network circuit via the transcription inhibitor Id2 (encoded by Id2) and transcription factor PLZF (encoded by Zbtb16); Id2 and Zbtb16 were directly repressed by Bcl11b, and Id2 and PLZF controlled distinct alternative programs. Thus, our study defines the molecular basis of direct and indirect Bcl11b actions that promote T cell identity and block alternative potentials.</p>},
  author       = {Hosokawa, Hiroyuki and Romero-Wolf, Maile and Yui, Mary A. and Ungerbäck, Jonas and Quiloan, Maria L.G. and Matsumoto, Masaki and Nakayama, Keiichi I. and Tanaka, Tomoaki and Rothenberg, Ellen V.},
  issn         = {1529-2908},
  language     = {eng},
  number       = {12},
  pages        = {1427--1440},
  publisher    = {Nature Publishing Group},
  series       = {Nature Immunology},
  title        = {Bcl11b sets pro-T cell fate by site-specific cofactor recruitment and by repressing Id2 and Zbtb16},
  url          = {http://dx.doi.org/10.1038/s41590-018-0238-4},
  doi          = {10.1038/s41590-018-0238-4},
  volume       = {19},
  year         = {2018},
}