The histone demethylase Lsd1 regulates multiple repressive gene programs during T cell development

Abstract

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.

Ablation of Lsd1 induces viral mimicry in thymocytes and promotes the development of innate-memory T cells

“…However, no YFP-positive thymic B cells were observed. Our data suggested that the B cells were unlikely trans-differentiated from T lineages, consistent with a recent work which also failed to induce myeloid, B cell, and NK cells from Lsd1-deleted thymic progenitor T cells in the OP9-DL1 system [22]. We supposed that they were stimulated by the abnormal upregulation of IFN-γ in the thymic environment after Lsd1-deletion.…”

“…Considering the similar frequencies of YFP + thymic NK cells in KO mice compared with control mice, we speculated it to be resulted from reactive hyperplasia but not transdifferentiation. Consistently, previous investigation also observed the increased B cells and NK cells in the thymus in Lsd1 / CD2-Cre mice, but not in Lsd1 / CD2-Cre DN thymocyte cultures on OP9-DL1 cells [22]. In summary, the observed increased number of other lineage cells is not caused by the trans-differentiation from T cells.…”

“…The overexpression of EREs resulted in a general IFN response in thymocytes and increased IFN-γ expression levels. Consistently, overexpression of interferon response genes was observed after the deletion of Lsd1 by Cd2-Cre [22]. However, the researchers left a question that the overexpressed genes in Lsd1-deleted thymocytes were not always associated with increased H3K4 methylation and concluded that Lsd1 indirectly affects their expression.…”

“…We evaluated whether the Lsd1 directly regulate the modi cation of H3K4me1/2 at the IFN responsive genes,. by analyzing the publicly available chromatin immunoprecipitation sequencing (ChIP-seq) data obtained from thymocytes in which Lsd1 was knocked out at the DN stage by CD2-Cre recombinase [22]. Unexpectedly, as shown in Fig.…”

“…Subsequently, several groups reported that Lsd1 was required for the germinal center formation and humoral immune response [19][20][21]. Recently, Lsd1 was found to regulate multiple repressive gene programs during T cell development [22]. In addition, Lsd1 inhibition in mature peripheral T cells increases the persistence of the progenitor exhausted CD8 + T cells, leading to a durable response to PD-1 blockade therapy [23].…”