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

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. (2018) Bcl11b sets pro-T cell fate by site-specific cofactor recruitment and by repressing Id2 and Zbtb16. Nature Immunology, 19 (12). pp. 1427-1440. ISSN 1529-2908. PMCID PMC6240390. https://resolver.caltech.edu/CaltechAUTHORS:20180830-074139017

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41590-018-0238-4DOIArticle
https://rdcu.be/bak4MPublisherFree ReadCube access
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240390PubMed CentralArticle
ORCID:
AuthorORCID
Hosokawa, Hiroyuki0000-0002-9592-2889
Romero-Wolf, Maile0000-0002-8024-7198
Yui, Mary A.0000-0002-3136-2181
Tanaka, Tomoaki0000-0002-9761-1750
Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2018 Springer Nature Limited. Received 15 March 2018; Accepted 05 September 2018; Published 30 October 2018. Data availability: Additional data that support the findings of this study are available from the corresponding author upon request. In addition to the complete description and explanation of the methods presented here, reagent lists and some general methods are also repeated, along with statistical checklists, in the Nature Research Reporting Summary that accompanies this paper. The GEO accession codes for all the deep-sequencing data reported in this paper are GSE110305, GSE110882 and GSE115744. We thank D. Perez, J. Tijerina, and R. Diamond for cell sorting and advice; I. Soto for mouse colony care; V. Kumar for library preparation and sequencing; H. Amrhein and D. Trout for computational assistance; I. Antoshechkin for sequencing management; X.Wang for related exploratory experiments; and members of the Rothenberg group for discussions and reagents. Supported by the Manpei Suzuki Diabetes Foundation (H.H.), the US Public Health Service (R01AI083514 and R01HD076915 to E.V.R.), Grants-in-Aid for Advanced Research and Development Programs for Medical Innovation (T.T.), the Takeda Science Foundation (T.T.), the SENSHINE Medical Research Foundation (T.T.), the Swedish Research Council (J.U.), the California Institute of Regenerative Medicine Bridges to Stem Cell Research Program (Pasadena City College and Caltech; M.R.-W.), the L. A. Garfinkle Memorial Laboratory Fund and the Al Sherman Foundation, special project funds from the Provost and Division of Biology & Biological Engineering of Caltech, and the Albert Billings Ruddock Professorship (E.V.R.). This work was performed in part in the Collaborative Research Project Program of the Medical Institute of Bioregulation, Kyushu University. Author Contributions: H.H. designed the study, performed experiments, analyzed data and wrote the manuscript; M.R.-W. performed experiments, analyzed data and wrote the manuscript; M.A.Y., J.U., M.L.G.Q., M.M., K.I.N., T.T. performed experiments, analyzed data and provided discussions; and E.V.R. designed and supervised the study, analyzed data and wrote the manuscript. The authors declare no competing interests.
Funders:
Funding AgencyGrant Number
Manpei Suzuki Diabetes FoundationUNSPECIFIED
NIHR01AI083514
NIHR01HD076915
Advanced Research and Development Programs for Medical InnovationUNSPECIFIED
Takeda Science FoundationUNSPECIFIED
SENSHINE Medical Research FoundationUNSPECIFIED
Swedish Research CouncilUNSPECIFIED
California Institute for Regenerative Medicine (CIRM)UNSPECIFIED
Louis A. Garfinkle Memorial Laboratory FundUNSPECIFIED
Al Sherman FoundationUNSPECIFIED
Caltech Division of Biology and Biological EngineeringUNSPECIFIED
Albert Billings Ruddock ProfessorshipUNSPECIFIED
Issue or Number:12
PubMed Central ID:PMC6240390
Record Number:CaltechAUTHORS:20180830-074139017
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180830-074139017
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:89293
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:30 Oct 2018 00:03
Last Modified:09 Mar 2020 13:19

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