Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
Bioinformatics and Scientific Programing Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
J Exp Med. 2021 Dec 6;218(12). doi: 10.1084/jem.20202012. Epub 2021 Nov 2.
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.
对发育中的胸腺细胞的转录谱分析表明，T 细胞谱系的确定与干细胞和早期祖细胞基因特征的丧失以及 T 细胞基因特征的获得有关。不太清楚的是伴随或促成这些转录变化的表观遗传改变。在这里，我们表明组蛋白去甲基酶 LSD1（Kdm1a）除了在胸腺细胞成熟过程中关键的抑制性基因程序外，还在熄灭干细胞/祖细胞转录程序中发挥关键作用。Lsd1 的缺失导致晚期 T 细胞发育受阻，并导致干扰素反应基因以及由 Gfi1、Bcl6 和最突出的 Bcl11b 转录抑制因子调节的基因在 CD4+CD8+胸腺细胞中的过度表达。Lsd1 缺陷的胸腺细胞中转录过度表达并不总是与基因启动子处 H3K4 三甲基化的增加相关，表明 Lsd1 间接地影响许多基因的表达。总之，这些结果表明 Lsd1 在 T 细胞发育过程中多个抑制性基因特征的表观遗传调控中具有关键功能。
