HDAC3 Is a Master Regulator of mTEC Development

Publication date: Available online 7 April 2016
Source:Cell Reports
Author(s): Yael Goldfarb, Noam Kadouri, Ben Levi, Asaf Sela, Yonatan Herzig, Ronald N. Cohen, Anthony N. Hollenberg, Jakub Abramson
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.

Graphical abstract

Teaser

Goldfarb et al. show that Hdac3 is essential for normal development and function of medullary thymic epithelial cells (mTECs) independently of non-canonical NFκB signaling. Their findings highlight Hdac3 as a master switch inducing the mTEC transcriptional program in immature TECs.


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