Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus non-ciliated cells [RNA-seq]

Members of the NSL histone acetyltransferase complex are involved in multi-organ developmental syndromes. While the NSL complex is known for its importance in early development, its role in fully differentiated cells remains enigmatic. Using a kidney-specific model, we discovered that deletion of NSL complex members KANSL2 or KANSL3 in post-mitotic podocytes led to catastrophic kidney dysfunction. A systematic comparison of two primary differentiated cell types revealed that the NSL complex is a master regulator of intraciliary transport genes in both dividing and non-dividing cells. NSL complex ablation led to loss of cilia and impaired sonic hedgehog pathway in ciliated fibroblasts. By contrast, non-ciliated podocytes responded with altered microtubule dynamics and obliterated podocyte functions. Finally, overexpression of wild type but not a double zinc-finger (ZF-ZF)-domain mutant of KANSL2 rescued the transcriptional defects, revealing a critical function of this domain in NSL complex assembly and function. Thus, the NSL complex targets exhibit bifurcation of functions to enable diversity of specialized outcomes in differentiated cells. Comparative gene expression profiling analysis of RNA-seq data for WT (nCre) and KO (KANSL2-pKO, KANSL3-pKO ) podocytes. Comparative gene expression profiling analysis of RNA-seq data for WT (KANSL2-iWT, KANSL3-iWT) and KO (KANSL2-iKO, KANSL3-iKO) MEFs .