GEMC1 and MCIDAS interactions with SWI/SNF complexes regulate the multiciliated cell-specific transcriptional program.

Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain, airway or reproductive organs. Differentiation of MCCs requires the sequential action of the Geminin family transcriptional activators, GEMC1 and MCIDAS, that both interact with E2F4/5-DP1. How these factors activate transcription and the extent to which they play redundant functions remains poorly understood. Here, we demonstrate that the transcriptional targets and proximal proteomes of GEMC1 and MCIDAS are highly similar. However, we identified distinct interactions with SWI/SNF subcomplexes; GEMC1 interacts primarily with the ARID1A containing BAF complex while MCIDAS interacts primarily with BRD9 containing ncBAF complexes. Treatment with a BRD9 inhibitor impaired MCIDAS-mediated activation of several target genes and compromised the MCC differentiation program in multiple cell based models. Our data suggest that the differential engagement of distinct SWI/SNF subcomplexes by GEMC1 and MCIDAS is required for MCC-specific transcriptional regulation and mediated by their distinct C-terminal domains.

多纤毛细胞（MCCs）从其顶端表面伸出数十到数百根可动纤毛，以促进哺乳动物大脑、呼吸道或生殖器官中液体或配子的运动。MCCs的分化需要Geminin家族转录激活因子GEMC1和MCIDAS的顺序作用，这两种因子都与E2F4/5 - DP1相互作用。这些因子如何激活转录以及它们在多大程度上发挥冗余功能仍知之甚少。在此，我们证明GEMC1和MCIDAS的转录靶点和近端蛋白质组高度相似。然而，我们发现它们与SWI/SNF亚复合物存在不同的相互作用；GEMC1主要与含ARID1A的BAF复合物相互作用，而MCIDAS主要与含BRD9的ncBAF复合物相互作用。用BRD9抑制剂处理会损害MCIDAS介导的几个靶基因的激活，并在多个基于细胞的模型中破坏MCC分化程序。我们的数据表明，GEMC1和MCIDAS与不同的SWI/SNF亚复合物的差异性结合是MCC特异性转录调控所必需的，且由它们不同的C末端结构域介导。