TY - JOUR
T1 - TCF-1 and HEB cooperate to establish the epigenetic and transcription profiles of CD4 + CD8 + thymocytes
AU - Emmanuel, Akinola Olumide
AU - Arnovitz, Stephen
AU - Haghi, Leila
AU - Mathur, Priya S.
AU - Mondal, Soumi
AU - Quandt, Jasmin
AU - Okoreeh, Michael K.
AU - Maienschein-Cline, Mark
AU - Khazaie, Khashayarsha
AU - Dose, Marei
AU - Gounari, Fotini
N1 - Funding Information:
We thank H. Kawamoto (RIKEN Research Center for Allergy and Immunology) for reagents; M. Mandal for help with ATAC–seq; B. Kee, M. Clark, A. Khan, and A. Bendelac for advice; and M. Krishnan for helpful suggestions. This work was supported by National Institutes of Health grants R21AI076720, R01AI108682, and U54CA193419, and an ASH bridge grant (to F.G.), and R01CA160436 (to K.K). Further support came from the Chicago Biomedical Consortium (to F.G.) and UL1TR002003 (to M.M.-C.). A.O.E. was supported by an NIH minority supplement; P.S.M. was supported by Institutional NRSA T32 HL07605 and is currently supported as an LLS Fellow; J.Q. was supported by an AAI Careers in Immunology Fellowship; and M.K.O. is a T32HD007009 recipient.
Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Thymocyte development requires a complex orchestration of multiple transcription factors. Ablating either TCF-1 or HEB in CD4 + CD8 + thymocytes elicits similar developmental outcomes including increased proliferation, decreased survival, and fewer late Tcra rearrangements. Here, we provide a mechanistic explanation for these similarities by showing that TCF-1 and HEB share ~7,000 DNA-binding sites genome wide and promote chromatin accessibility. The binding of both TCF-1 and HEB was required at these shared sites for epigenetic and transcriptional gene regulation. Binding of TCF-1 and HEB to their conserved motifs in the enhancer regions of genes associated with T cell differentiation promoted their expression. Binding to sites lacking conserved motifs in the promoter regions of cell-cycle-associated genes limited proliferation. TCF-1 displaced nucleosomes, allowing for chromatin accessibility. Importantly, TCF-1 inhibited Notch signaling and consequently protected HEB from Notch-mediated proteasomal degradation. Thus, TCF-1 shifts nucleosomes and safeguards HEB, thereby enabling their cooperation in establishing the epigenetic and transcription profiles of CD4 + CD8 + thymocytes.
AB - Thymocyte development requires a complex orchestration of multiple transcription factors. Ablating either TCF-1 or HEB in CD4 + CD8 + thymocytes elicits similar developmental outcomes including increased proliferation, decreased survival, and fewer late Tcra rearrangements. Here, we provide a mechanistic explanation for these similarities by showing that TCF-1 and HEB share ~7,000 DNA-binding sites genome wide and promote chromatin accessibility. The binding of both TCF-1 and HEB was required at these shared sites for epigenetic and transcriptional gene regulation. Binding of TCF-1 and HEB to their conserved motifs in the enhancer regions of genes associated with T cell differentiation promoted their expression. Binding to sites lacking conserved motifs in the promoter regions of cell-cycle-associated genes limited proliferation. TCF-1 displaced nucleosomes, allowing for chromatin accessibility. Importantly, TCF-1 inhibited Notch signaling and consequently protected HEB from Notch-mediated proteasomal degradation. Thus, TCF-1 shifts nucleosomes and safeguards HEB, thereby enabling their cooperation in establishing the epigenetic and transcription profiles of CD4 + CD8 + thymocytes.
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U2 - 10.1038/s41590-018-0254-4
DO - 10.1038/s41590-018-0254-4
M3 - Article
C2 - 30420627
AN - SCOPUS:85056458014
SN - 1529-2908
VL - 19
SP - 1366
EP - 1378
JO - Nature immunology
JF - Nature immunology
IS - 12
ER -