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

Hiroyuki Hosokawa, Maile Romero-Wolf, Mary A. Yui, Jonas Ungerbäck, Maria L.G. Quiloan, Masaki Matsumoto, Keiichi Nakayama, Tomoaki Tanaka, Ellen V. Rothenberg

Research output: Contribution to journalArticle

Abstract

Multipotent progenitor cells confirm their T cell–lineage identity in the CD4 CD8 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.

Original languageEnglish
Pages (from-to)1427-1440
Number of pages14
JournalNature Immunology
Volume19
Issue number12
DOIs
Publication statusPublished - Dec 1 2018

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T-Lymphocytes
Gene Regulatory Networks
Genes
Transcription Factors
Proteomics
Stem Cells
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Hosokawa, H., Romero-Wolf, M., Yui, M. A., Ungerbäck, J., Quiloan, M. L. G., Matsumoto, M., ... Rothenberg, E. V. (2018). Bcl11b sets pro-T cell fate by site-specific cofactor recruitment and by repressing Id2 and Zbtb16. Nature Immunology, 19(12), 1427-1440. https://doi.org/10.1038/s41590-018-0238-4

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; Quiloan, Maria L.G.; Matsumoto, Masaki; Nakayama, Keiichi; Tanaka, Tomoaki; Rothenberg, Ellen V.

In: Nature Immunology, Vol. 19, No. 12, 01.12.2018, p. 1427-1440.

Research output: Contribution to journalArticle

Hosokawa, H, Romero-Wolf, M, Yui, MA, Ungerbäck, J, Quiloan, MLG, Matsumoto, M, Nakayama, K, Tanaka, T & Rothenberg, EV 2018, 'Bcl11b sets pro-T cell fate by site-specific cofactor recruitment and by repressing Id2 and Zbtb16' Nature Immunology, vol. 19, no. 12, pp. 1427-1440. https://doi.org/10.1038/s41590-018-0238-4
Hosokawa, Hiroyuki ; Romero-Wolf, Maile ; Yui, Mary A. ; Ungerbäck, Jonas ; Quiloan, Maria L.G. ; Matsumoto, Masaki ; Nakayama, Keiichi ; Tanaka, Tomoaki ; Rothenberg, Ellen V. / Bcl11b sets pro-T cell fate by site-specific cofactor recruitment and by repressing Id2 and Zbtb16. In: Nature Immunology. 2018 ; Vol. 19, No. 12. pp. 1427-1440.
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