| First Author | Emmanuel AO | Year | 2018 |
| Journal | Nat Immunol | Volume | 19 |
| Issue | 12 | Pages | 1366-1378 |
| PubMed ID | 30420627 | Mgi Jnum | J:282378 |
| Mgi Id | MGI:6380748 | Doi | 10.1038/s41590-018-0254-4 |
| Citation | Emmanuel AO, et al. (2018) TCF-1 and HEB cooperate to establish the epigenetic and transcription profiles of CD4(+)CD8(+) thymocytes. Nat Immunol 19(12):1366-1378 |
| abstractText | 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. |
