A requirement for Lysine-specific histone demethylase 1A (Lsd1) for T cell development

Abstract

Abstract Lysine-specific demethylase 1A (Lsd1), also known as Kdm1a, is a part of the histone demethylase family of enzymes. Histone demethylases are key epigenetic regulatory proteins of the mammalian genome that participate in chromatin remodeling. It has been shown that Lsd1 mediates H3K4me2/me1 histone demethylation, and this event has been connected with gene repression in hematopoietic stem cells (HSC) and HSC maintenance. While Lsd1’s role in plasma cell differentiation and as a therapeutic target in cancer are well established, its role in T cell development has not been examined. To investigate Lsd1’s role in T cell development, we used the CD2i-Cre system to conditionally delete Lsd1 in immature double negative (DN) thymocytes. Here we show that deletion of Lsd1 causes a severe reduction in total thymocyte numbers attributable to a defect at the CD8+CD4−CD3lo intermediate single positive (ISP) stage. In addition, Lsd1 deficient T cells are reduced in number, exhibit a memory phenotype, and express low surface levels of T cell antigen receptor (TCR) as assessed by TCRβ and CD3 staining. Together, these findings identify an important role for Lsd1 in T cell maturation and indicate that regulation of H3K4 histone demethylation is essential at several critical stages of thymocyte development.