title: HDAC3 Is a Master Regulator of mTEC Development.
abstract: The thymus provides a unique microenvironment enabling development and selection of T lymphocytes. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process by facilitating negative selection of self-reactive thymocytes and the generation of Foxp3(+) regulatory T cells. Although studies have highlighted the non-canonical nuclear factor κB (NF-κB) pathway as the key regulator of mTEC development, comprehensive understanding of the molecular pathways regulating this process still remains incomplete. Here, we demonstrate that the development of functionally competent mTECs is regulated by the histone deacetylase 3 (Hdac3). Although histone deacetylases are global transcriptional regulators, this effect is highly specific only to Hdac3, as neither Hdac1 nor Hdac2 inactivation caused mTEC ablation. Interestingly, Hdac3 induces an mTEC-specific transcriptional program independently of the previously recognized RANK-NFκB signaling pathway. Thus, our findings uncover yet another layer of complexity of TEC lineage divergence and highlight Hdac3 as a major and specific molecular switch crucial for mTEC differentiation.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Goldfarb
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Noam
authors.initials: N
authors.lastname: Kadouri
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ben
authors.initials: B
authors.lastname: Levi
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Sela
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Herzig
authors.affiliation: University of Chicago Medical Centre, Chicago, IL 60637, USA.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Cohen
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Centre, Boston, MA 02215, USA.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hollenberg
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: jakub.abramson@weizmann.ac.il.
authors.forename: Jakub
authors.initials: J
authors.lastname: Abramson
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D056970:Co-Repressor Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000201:enzymology*; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006655:Histone Deacetylases / Q000172:deficiency / Q000378:metabolism*; D007108:Immune Tolerance; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D060168:Thymocytes / Q000166:cytology* / Q000201:enzymology*; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
chemical_list: D056970:Co-Repressor Proteins; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D016328:NF-kappa B; D051880:Receptors, Notch; D000099186:Histone Deacetylase 3