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Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

Longabaugh, William J. R. and Zeng, Weihua and Zhang, Jingli A. and Hosokawa, Hiroyuki and Jansen, Camden S. and Li, Long and Romero-Wolf, Maile and Liu, Pentao and Kueh, Hao Yuan and Mortazavi, Ali and Rothenberg, Ellen V. (2017) Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network. Proceedings of the National Academy of Sciences of the United States of America, 114 (23). pp. 5800-5807. ISSN 0027-8424. PMCID PMC5468679. https://resolver.caltech.edu/CaltechAUTHORS:20170202-145154883

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Abstract

T-cell development from hematopoietic progenitors depends on multiple transcription factors, mobilized and modulated by intrathymic Notch signaling. Key aspects of T-cell specification network architecture have been illuminated through recent reports defining roles of transcription factors PU.1, GATA-3, and E2A, their interactions with Notch signaling, and roles of Runx1, TCF-1, and Hes1, providing bases for a comprehensively updated model of the T-cell specification gene regulatory network presented herein. However, the role of lineage commitment factor Bcl11b has been unclear. We use self-organizing maps on 63 RNA-seq datasets from normal and perturbed T-cell development to identify functional targets of Bcl11b during commitment and relate them to other regulomes. We show that both activation and repression target genes can be bound by Bcl11b in vivo, and that Bcl11b effects overlap with E2A-dependent effects. The newly clarified role of Bcl11b distinguishes discrete components of commitment, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://dx.doi.org/10.1073/pnas.1610617114DOIArticle
http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1610617114/-/DCSupplementalPublisherSupporting Information
http://www.pnas.org/external-ref?link_type=NCBIGEO&access_num=GSE89198Related ItemRNA-seq data
http://www.pnas.org/external-ref?link_type=NCBIGEO&access_num=GSE93572Related ItemChIP-seq data
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468679/PubMed CentralArticle
ORCID:
AuthorORCID
Hosokawa, Hiroyuki0000-0002-9592-2889
Kueh, Hao Yuan0000-0001-6272-6673
Mortazavi, Ali0000-0002-4259-6362
Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2017 National Academy of Sciences. Edited by Neil H. Shubin, The University of Chicago, Chicago, IL, and approved January 30, 2017 (received for review October 25, 2016). We thank Georgi Marinov and Barbara Wold for advice; Igor Antoshechkin of the Millard and Muriel Jacobs Genetics and Genomics Center for sequencing; Henry Amrhein, Diane Trout, and Sagar Damle for data curation; Diana Perez, Josh Verceles, and Rochelle Diamond for flow cytometry and cell sorting; Rochelle Diamond for laboratory management; and Lorena Sandoval, Scott Washburn, and Robert Butler III for supervision of the mice (all at the California Institute of Technology). This work was supported by NIH New Innovator Award DP2GM111100 (to A.M.); NIH Grants R01HD073113 (to W.J.R.L.), K99HL119638A (to H.Y.K.), and RC2CA148278, R01CA90233, R01AI083514, and R01AI95943 (to E.V.R.); the L. A. Garfinkle Memorial Laboratory Fund and the Al Sherman Foundation; the Caltech-City of Hope Biomedical Research Initiative; and the Albert Billings Ruddock Professorship (E.V.R.). W.J.R.L. and W.Z. contributed equally to this work. Author contributions: A.M. and E.V.R. designed research; W.Z., J.A.Z., H.H., L.L., M.R.-W., and H.Y.K. performed research; W.J.R.L., P.L., and A.M. contributed new reagents/analytic tools; W.J.R.L., W.Z., J.A.Z., H.H., C.S.J., M.R.-W., H.Y.K., A.M., and E.V.R. analyzed data; and W.J.R.L., W.Z., and E.V.R. wrote the paper. The authors declare no conflict of interest. This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, ”Gene Regulatory Networks and Network Models in Development and Evolution,” held April 12–14, 2016, at the Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering in Irvine, CA. The complete program and video recordings of most presentations are available on the NAS website at www.nasonline.org/Gene_Regulatory_Networks. This article is a PNAS Direct Submission. Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (RNA-seq data accession no. GSE89198; ChIP-seq data accession no. GSE93572). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1610617114/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
NIHDP2GM111100
NIHR01HD073113
NIHK99HL119638A
NIHRC2CA148278
NIHR01CA90233
NIHR01AI083514
NIHR01AI95943
Louis A. Garfinkle Memorial Laboratory FundUNSPECIFIED
Al Sherman FoundationUNSPECIFIED
Caltech-City of Hope Biomedical InitiativeUNSPECIFIED
Albert Billings Ruddock ProfessorshipUNSPECIFIED
Subject Keywords:Bcl11b; Notch-delta signaling; PU.1; E2A; commitment
Issue or Number:23
PubMed Central ID:PMC5468679
Record Number:CaltechAUTHORS:20170202-145154883
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170202-145154883
Official Citation:William J. R. Longabaugh, Weihua Zeng, Jingli A. Zhang, Hiroyuki Hosokawa, Camden S. Jansen, Long Li, Maile Romero-Wolf, Pentao Liu, Hao Yuan Kueh, Ali Mortazavi, and Ellen V. Rothenberg Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network PNAS 2017 114 (23) 5800-5807; published ahead of print June 6, 2017, doi:10.1073/pnas.1610617114
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73993
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:07 Jun 2017 15:54
Last Modified:29 Oct 2019 22:53

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