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

Tsang, Tsz Hong; Wiese, Meike; Helmstädter, Martin; Stehle, Thomas; Seyfferth, Janine; Shvedunova, Maria; Holz, Herbert; Walz, Gerd; Akhtar, Asifa

doi:10.1126/sciadv.adh5598

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

MPS-Authors

Tsang, Tsz Hong
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Wiese, Meike
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Stehle, Thomas
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Seyfferth, Janine
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Shvedunova, Maria
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Holz, Herbert
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Akhtar, Asifa
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Tsang, T. H., Wiese, M., Helmstädter, M., Stehle, T., Seyfferth, J., Shvedunova, M., et al. (2023). Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells. Science Advances, 9: eadh5598. doi:10.1126/sciadv.adh5598.

Cite as: https://hdl.handle.net/21.11116/0000-000D-B226-F

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.