| First Author | Michelson DA | Year | 2023 |
| Journal | J Exp Med | Volume | 220 |
| Issue | 10 | PubMed ID | 37399024 |
| Mgi Jnum | J:339562 | Mgi Id | MGI:7505686 |
| Doi | 10.1084/jem.20230461 | Citation | Michelson DA, et al. (2023) Hnf4 activates mimetic-cell enhancers to recapitulate gut and liver development within the thymus. J Exp Med 220(10) |
| abstractText | Mimetic cells are medullary thymic epithelial cells (mTECs) that mimic extra-thymic cell types to tolerize T cells to self-antigens. Here, we dissected the biology of entero-hepato mTECs, mimetic cells expressing gut- and liver-associated transcripts. Entero-hepato mTECs conserved their thymic identity yet accessed wide swaths of enterocyte chromatin and transcriptional programs via the transcription factors Hnf4alpha and Hnf4gamma. Deletion of Hnf4alpha and Hnf4gamma in TECs ablated entero-hepato mTECs and downregulated numerous gut- and liver-associated transcripts, with a primary contribution from Hnf4gamma. Loss of Hnf4 impaired enhancer activation and CTCF redistribution in mTECs but did not impact Polycomb-mediated repression or promoter-proximal histone marks. By single-cell RNA sequencing, Hnf4 loss produced three distinct effects on mimetic cell state, fate, and accumulation. Serendipitously, a requirement for Hnf4 in microfold mTECs was discovered, which exposed a requirement for Hnf4gamma in gut microfold cells and the IgA response. Study of Hnf4 in entero-hepato mTECs thus revealed mechanisms of gene control in the thymus and periphery alike. |
