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Cell type–specific actions of Bcl11b in early T-lineage and group 2 innate lymphoid cells

Hosokawa, Hiroyuki and Romero-Wolf, Maile and Yang, Qi and Motomura, Yasutaka and Levanon, Ditsa and Groner, Yoram and Moro, Kazuyo and Tanaka, Tomoaki and Rothenberg, Ellen V. (2020) Cell type–specific actions of Bcl11b in early T-lineage and group 2 innate lymphoid cells. Journal of Experimental Medicine, 217 (1). Art. No. e20190972. ISSN 0022-1007. PMCID PMC7037248 . https://resolver.caltech.edu/CaltechAUTHORS:20191105-110746748

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Abstract

The zinc finger transcription factor, Bcl11b, is expressed in T cells and group 2 innate lymphoid cells (ILC2s) among hematopoietic cells. In early T-lineage cells, Bcl11b directly binds and represses the gene encoding the E protein antagonist, Id2, preventing pro-T cells from adopting innate-like fates. In contrast, ILC2s co-express both Bcl11b and Id2. To address this contradiction, we have directly compared Bcl11b action mechanisms in pro-T cells and ILC2s. We found that Bcl11b binding to regions across the genome shows distinct cell type–specific motif preferences. Bcl11b occupies functionally different sites in lineage-specific patterns and controls totally different sets of target genes in these cell types. In addition, Bcl11b bears cell type–specific post-translational modifications and organizes different cell type–specific protein complexes. However, both cell types use the same distal enhancer region to control timing of Bcl11b activation. Therefore, although pro-T cells and ILC2s both need Bcl11b for optimal development and function, Bcl11b works substantially differently in these two cell types.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1084/jem.20190972DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7037248/PubMed CentralArticle
ORCID:
AuthorORCID
Hosokawa, Hiroyuki0000-0002-9592-2889
Romero-Wolf, Maile0000-0002-8024-7198
Yang, Qi0000-0002-8365-0986
Moro, Kazuyo0000-0003-3218-7255
Tanaka, Tomoaki0000-0002-9761-1750
Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2019 Hosokawa et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). Submitted: 31 May 2019; Revision received 16 August 2019; Accepted: 27 September 2019; Published October 25, 2019. We thank A. Bhandoola (National Cancer Institute, National Institutes of Health) for helpful discussions; 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; and members of the Rothenberg group for valuable discussion and reagents. This work was supported by grants from the US Public Health Service to E.V. Rothenberg (R01 AI135200, R01AI083514, and R01HD076915); the Japan Society for the Promotion of Science KAKENHI grant number JP19H03692, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Takeda Science Foundation (to H. Hosokawa); and the Japan Society for the Promotion of Science KAKENHI grant numbers JP19H03708, JP18K08464, JP19K07635, and JP18K07439, the Takeda Science Foundation, the Naito Foundation, the SENSHIN Medical Research Foundation, and the Novartis Research Foundation (to T. Tanaka). This work was partly performed in the Cooperative Research Project Program of the Medical Institute of Bioregulation at Kyushu University and was supported by the Donated Fund of Next Generation Hormone Academy for Human Health & Longevity. This work was partly supported by the California Institute of Regenerative Medicine Bridges to Stem Cell Research Program (Pasadena City College and California Institute of Technology, to M. Romero-Wolf), 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 the California Institute of Technology, and the California Institute of Technology Albert Billings Ruddock Professorship (to E.V. Rothenberg). The authors declare no competing financial interests. Author contributions: H. Hosokawa designed the study, performed experiments, analyzed data, and wrote the manuscript. M. Romero-Wolf performed experiments and analyzed data. Q. Yang provided the ILC2 cell line (ILC2/b6) and helpful discussions and edited the manuscript. D. Levanon and Y. Groner provided unique biological reagents and valuable criticism and edited the manuscript. Y. Motomura, K. Moro, and T. Tanaka performed experiments, analyzed data, and provided helpful discussions and comments on the manuscript. E.V. Rothenberg designed and supervised the study, analyzed data, and wrote the manuscript.
Funders:
Funding AgencyGrant Number
NIHR01AI135200
NIHR01AI083514
NIHR01HD076915
Japan Society for the Promotion of Science (JSPS)JP19H03692
Mochida Memorial Foundation for Medical and Pharmaceutical ResearchUNSPECIFIED
Takeda Science FoundationUNSPECIFIED
Japan Society for the Promotion of Science (JSPS)JP19H03708
Japan Society for the Promotion of Science (JSPS)JP18K08464
Japan Society for the Promotion of Science (JSPS)JP19K07635
Japan Society for the Promotion of Science (JSPS)JP18K07439
Takeda Science FoundationUNSPECIFIED
Naito FoundationUNSPECIFIED
SENSHIN Medical Research FoundationUNSPECIFIED
Novartis Research FoundationUNSPECIFIED
Next Generation Hormone Academy for Human Health & LongevityUNSPECIFIED
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:1
PubMed Central ID:PMC7037248
Record Number:CaltechAUTHORS:20191105-110746748
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191105-110746748
Official Citation:Hiroyuki Hosokawa, Maile Romero-Wolf, Qi Yang, Yasutaka Motomura, Ditsa Levanon, Yoram Groner, Kazuyo Moro, Tomoaki Tanaka, Ellen V. Rothenberg; Cell type–specific actions of Bcl11b in early T-lineage and group 2 innate lymphoid cells. J Exp Med 6 January 2020; 217 (1): e20190972. doi: https://doi.org/10.1084/jem.20190972
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:99677
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:05 Nov 2019 19:24
Last Modified:08 Jul 2020 22:08

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