TCF-1 and HEB cooperate to establish the epigenetic and transcription profiles of CD4+CD8+ thymocytes. (December 2018)

• Record Type: Journal Article
• Authors: Emmanuel, Akinola; Arnovitz, Stephen; Haghi, Leila; Mathur, Priya; Mondal, Soumi; Quandt, Jasmin; Okoreeh, Michael; Maienschein-Cline, Mark; Khazaie, Khashayarsha; Dose, Marei; Gounari, Fotini
• Is Part Of: Nature immunology. Volume 19:Number 12(2018)
• Page Start: 1366
• Page End: 1378
• Publication Date: 2018-12
• Subjects: Immunology -- Periodicals; 571.9605
• DOI: 10.1038/s41590-018-0254-4
• Languages: English
• ISSNs: 1529-2908

Abstract

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 lateTcra 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. Thymocyte development requires a complex orchestration of multiple transcription factors. Gournari and colleagues find that Tcf-1 and HEB cooperate to establish the epigenetic and transcription profiles of CD4+ CD8+ thymocytes