Journal
SCIENCE ADVANCES
Volume 9, Issue 34, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.adh5598
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Members of the NSL histone acetyltransferase complex play a role in multiorgan developmental syndromes. While its importance in early development is known, its function in fully differentiated cells is still unclear. A study using a kidney-specific model found that deletion of NSL complex members KANSL2 or KANSL3 led to catastrophic kidney dysfunction in postmitotic podocytes. The NSL complex was found to regulate intraciliary transport genes in both dividing and nondividing cells, leading to loss of cilia and impaired sonic hedgehog pathway in ciliated fibroblasts and altered microtubule dynamics and obliterated podocyte functions in nonciliated podocytes.
Members of the NSL histone acetyltransferase complex are involved in multiorgan 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 postmitotic podocytes led to catastrophic kidney dysfunction. Systematic comparison of two primary differentiated cell types reveals the NSL complex as a master regulator of intraciliary transport genes in both dividing and nondividing cells. NSL complex ablation led to loss of cilia and impaired sonic hedgehog pathway in ciliated fibroblasts. By contrast, nonciliated 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 exhibits bifurcation of functions to enable diversity of specialized outcomes in differentiated cells.
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