Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells

Abstract

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.

Processivity and specificity of histone acetylation by the male-specific lethal complex

“…In the DCC, MOF is thought to acetylate H4K16 with high specificity, a feature that appears to be conserved in human MSL complexes ( 19 , 27 ). However, as part of the NSL complex, MOF has been reported to acetylate H4K5, K8 and K12 ( 19 , 22 ). This notion is supported by a systematic analysis of KAT activities in female Drosophila cells, which showed that depletion of the key NSL subunit NSL1 leads to reduced H4K5ac (and statistically not robust K8ac) in addition to lower H4K16ac ( 27 ).…”

KAT8 beyond Acetylation: A Survey of Its Epigenetic Regulation, Genetic Variability, and Implications for Human Health

“…KAT8 also plays a pivotal role in T-cell maturation, where its deletion leads to severe defects in T-cell receptor rearrangement and a consequential increase in genomic instability [47]. The NSL complex, particularly through its components KANSL2 and KANSL3, is essential for the transcriptional regulation of intraciliary transport genes that influence cilia assembly and microtubule dynamics [48]. This regulatory activity is crucial for cellular differentiation, which impacts kidney health, by maintaining podocyte function, as the deletion of KANSL2 or KANSL3 in podocytes leads to severe kidney dysfunction [48].…”

“…The NSL complex, particularly through its components KANSL2 and KANSL3, is essential for the transcriptional regulation of intraciliary transport genes that influence cilia assembly and microtubule dynamics [48]. This regulatory activity is crucial for cellular differentiation, which impacts kidney health, by maintaining podocyte function, as the deletion of KANSL2 or KANSL3 in podocytes leads to severe kidney dysfunction [48]. Furthermore, studies show that KAT8 influences acute myeloid leukemia (AML) differentiation by suppressing MN1 (meningioma 1) expression, a gene associated with rapid leukemia onset when overexpressed [49].…”