Epigenetic activation during Th17 cell differentiation is impaired after TRIM28 deletion. Epigenetic activation during Th17 cell differentiation is impaired after TRIM28 deletion

Cell fate decision is mediated by epigenetic mechanisms. We have analyzed naive T cell differentiation into Th17 cells, which is regulated by environmental cytokines and their downstream transcription factors. RORγt is a lineage-specific master transcription factor for Th17 cells. Although epigenetic mechanisms have been implicated in Th17 cell differentiation, how transcription factors interact to activate epigenetic program is unclear. Here we show that tripartite motif containing 28 (TRIM28) expression in Th17 cells is required for cytokine production and autoimmune diseases. Genome-wide occupancy analysis reveals that TRIM28 bound regions contain many super-enhancers, which are impaired after TRIM28 or STAT3 but not RORγt deletion. Importantly, TRIM28 exists in a complex with STAT3 and RORγt; TRIM28 recruitment to the Il17 gene requires STAT3, and further promotes RORγt recruitment. TRIM28 thus is a key player in the epigenetic activation during T cell differentiation. Overall design: Examination of the H3K27Ac modifications in 2 WT and 2 TRIM28KO cells

细胞命运决定由表观遗传机制介导。我们已对初始T细胞向Th17细胞的分化过程展开分析，该过程受环境细胞因子及其下游转录因子的调控。视黄酸相关孤儿受体γt（RORγt）是Th17细胞的谱系特异性主控转录因子。尽管已有研究将表观遗传机制与Th17细胞分化建立关联，但转录因子如何相互作用以激活表观遗传程序，目前仍未明确。本研究证实，Th17细胞中三基序蛋白28（TRIM28）的表达是细胞因子产生与自身免疫疾病发生的必要条件。全基因组结合位点分析显示，TRIM28的结合区域包含大量超级增强子，这类增强子的功能在TRIM28或信号转导与转录激活因子3（STAT3）缺失后会受损，但在RORγt缺失后不受影响。尤为关键的是，TRIM28可与STAT3及RORγt形成复合物；TRIM28向Il17基因位点的募集依赖于STAT3，并可进一步促进RORγt的募集。由此可见，TRIM28是T细胞分化过程中表观遗传激活的关键调控因子。实验整体设计：检测2组野生型（WT）细胞与2组TRIM28敲除（TRIM28KO）细胞的H3K27乙酰化（H3K27Ac）修饰水平。