Analysis of the transcriptional profiles of developing thymocytes has shown that T lineage commitment is associated with loss of stem cell and early progenitor gene signatures and the acquisition of T cell gene signatures. Less well understood are the epigenetic alterations that accompany or enable these transcriptional changes. Here, we show that the histone demethylase Lsd1 (Kdm1a) performs a key role in extinguishing stem/progenitor transcriptional programs in addition to key repressive gene programs during thymocyte maturation. Deletion of Lsd1 caused a block in late T cell development and resulted in overexpression of interferon response genes as well as genes regulated by the Gfi1, Bcl6, and, most prominently, Bcl11b transcriptional repressors in CD4+CD8+ thymocytes. Transcriptional overexpression in Lsd1-deficient thymocytes was not always associated with increased H3K4 trimethylation at gene promoters, indicating that Lsd1 indirectly affects the expression of many genes. Together, these results identify a critical function for Lsd1 in the epigenetic regulation of multiple repressive gene signatures during T cell development.
The histone demethylase Lsd1 regulates multiple repressive gene programs during T cell development
Disclosures: The authors declare no competing interests exist.
- Award Id(s): 1ZIAHD001803
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Daniel B. Stamos, Lauren M. Clubb, Apratim Mitra, Laura B. Chopp, Jia Nie, Yi Ding, Arundhoti Das, Harini Venkataganesh, Jan Lee, Dalal El-Khoury, LiQi Li, Avinash Bhandoola, Remy Bosselut, Paul E. Love; The histone demethylase Lsd1 regulates multiple repressive gene programs during T cell development. J Exp Med 6 December 2021; 218 (12): e20202012. doi: https://doi.org/10.1084/jem.20202012
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