CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF.

Initiation and maintenance of transcriptional states are critical for controlling normal tissue homeostasis and differentiation. The cyclin dependent kinases CDK8 and CDK19 (Mediator kinases) are regulatory components of Mediator, a highly conserved complex that orchestrates enhancer-mediated transcriptional output. While Mediator kinases have been implicated in the transcription of genes necessary for development and growth, its function in mammals has not been well defined. Using genetically defined models and pharmacological inhibitors, we showed that CDK8 and CDK19 function in a redundant manner to regulate intestinal lineage specification in humans and mice. The Mediator kinase module bound and phosphorylated key components of the chromatin remodeling complex switch/sucrose non-fermentable (SWI/SNF) in intestinal epithelial cells. Concomitantly, SWI/SNF and MED12-Mediator colocalized at distinct lineage-specifying enhancers in a CDK8/19–dependent manner. Thus, these studies reveal a transcriptional mechanism of intestinal cell specification, coordinated by the interaction between the chromatin remodeling complex SWI/SNF and Mediator kinase.

转录状态的起始和维持对于控制正常组织内稳态和分化至关重要。细胞周期蛋白依赖性激酶CDK8和CDK19（中介体激酶）是中介体的调节成分，中介体是一种高度保守的复合物，它协调增强子介导的转录输出。虽然中介体激酶与发育和生长所必需的基因转录有关，但其在哺乳动物中的功能尚未明确界定。利用基因确定的模型和药理抑制剂，我们表明CDK8和CDK19以冗余的方式发挥作用，调节人类和小鼠的肠道谱系特化。中介体激酶模块结合并磷酸化肠道上皮细胞中染色质重塑复合物转换/蔗糖不发酵（SWI/SNF）的关键成分。同时，SWI/SNF和MED12 - 中介体以依赖CDK8/19的方式共定位在不同的谱系特异性增强子上。因此，这些研究揭示了一种肠道细胞特化的转录机制，由染色质重塑复合物SWI/SNF和中介体激酶之间的相互作用所协调。