TCF-1 and HEB cooperate to establish the epigenetic and transcription profiles of CD4+CD8+ thymocytes

Akinola Olumide Emmanuel, Stephen Arnovitz, Leila Haghi, Priya S. Mathur, Soumi Mondal, Jasmin Quandt, Michael K. Okoreeh, Mark Maienschein-Cline, Khashayarsha Khazaie, Marei Dose, Fotini Gounari

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1366-1378
Number of pages13
JournalNature Immunology
Volume19
Issue number12
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Emmanuel, A. O., Arnovitz, S., Haghi, L., Mathur, P. S., Mondal, S., Quandt, J., Okoreeh, M. K., Maienschein-Cline, M., Khazaie, K., Dose, M., & Gounari, F. (2018). TCF-1 and HEB cooperate to establish the epigenetic and transcription profiles of CD4+CD8+ thymocytes. Nature Immunology, 19(12), 1366-1378. https://doi.org/10.1038/s41590-018-0254-4