Cargando…
Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells
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...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10456878/ https://www.ncbi.nlm.nih.gov/pubmed/37624894 http://dx.doi.org/10.1126/sciadv.adh5598 |
_version_ | 1785096805129650176 |
---|---|
author | Tsang, Tsz Hong Wiese, Meike Helmstädter, Martin Stehle, Thomas Seyfferth, Janine Shvedunova, Maria Holz, Herbert Walz, Gerd Akhtar, Asifa |
author_facet | Tsang, Tsz Hong Wiese, Meike Helmstädter, Martin Stehle, Thomas Seyfferth, Janine Shvedunova, Maria Holz, Herbert Walz, Gerd Akhtar, Asifa |
author_sort | Tsang, Tsz Hong |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10456878 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-104568782023-08-26 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 Sci Adv Biomedicine and Life Sciences 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. American Association for the Advancement of Science 2023-08-25 /pmc/articles/PMC10456878/ /pubmed/37624894 http://dx.doi.org/10.1126/sciadv.adh5598 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Tsang, Tsz Hong Wiese, Meike Helmstädter, Martin Stehle, Thomas Seyfferth, Janine Shvedunova, Maria Holz, Herbert Walz, Gerd Akhtar, Asifa Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells |
title | Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells |
title_full | Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells |
title_fullStr | Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells |
title_full_unstemmed | Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells |
title_short | Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells |
title_sort | transcriptional regulation by the nsl complex enables diversification of ift functions in ciliated versus nonciliated cells |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10456878/ https://www.ncbi.nlm.nih.gov/pubmed/37624894 http://dx.doi.org/10.1126/sciadv.adh5598 |
work_keys_str_mv | AT tsangtszhong transcriptionalregulationbythenslcomplexenablesdiversificationofiftfunctionsinciliatedversusnonciliatedcells AT wiesemeike transcriptionalregulationbythenslcomplexenablesdiversificationofiftfunctionsinciliatedversusnonciliatedcells AT helmstadtermartin transcriptionalregulationbythenslcomplexenablesdiversificationofiftfunctionsinciliatedversusnonciliatedcells AT stehlethomas transcriptionalregulationbythenslcomplexenablesdiversificationofiftfunctionsinciliatedversusnonciliatedcells AT seyfferthjanine transcriptionalregulationbythenslcomplexenablesdiversificationofiftfunctionsinciliatedversusnonciliatedcells AT shvedunovamaria transcriptionalregulationbythenslcomplexenablesdiversificationofiftfunctionsinciliatedversusnonciliatedcells AT holzherbert transcriptionalregulationbythenslcomplexenablesdiversificationofiftfunctionsinciliatedversusnonciliatedcells AT walzgerd transcriptionalregulationbythenslcomplexenablesdiversificationofiftfunctionsinciliatedversusnonciliatedcells AT akhtarasifa transcriptionalregulationbythenslcomplexenablesdiversificationofiftfunctionsinciliatedversusnonciliatedcells |