Cargando…

Essential Nonredundant Function of the Catalytic Activity of Histone Deacetylase 2 in Mouse Development

The class I histone deacetylases (HDACs) HDAC1 and HDAC2 play partially redundant roles in the regulation of gene expression and mouse development. As part of multisubunit corepressor complexes, these two deacetylases exhibit both enzymatic and nonenzymatic functions. To examine the impact of the ca...

Descripción completa

Detalles Bibliográficos
Autores principales: Hagelkruys, Astrid, Mattes, Katharina, Moos, Verena, Rennmayr, Magdalena, Ringbauer, Manuela, Sawicka, Anna, Seiser, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719423/
https://www.ncbi.nlm.nih.gov/pubmed/26598605
http://dx.doi.org/10.1128/MCB.00639-15
_version_ 1782410936457363456
author Hagelkruys, Astrid
Mattes, Katharina
Moos, Verena
Rennmayr, Magdalena
Ringbauer, Manuela
Sawicka, Anna
Seiser, Christian
author_facet Hagelkruys, Astrid
Mattes, Katharina
Moos, Verena
Rennmayr, Magdalena
Ringbauer, Manuela
Sawicka, Anna
Seiser, Christian
author_sort Hagelkruys, Astrid
collection PubMed
description The class I histone deacetylases (HDACs) HDAC1 and HDAC2 play partially redundant roles in the regulation of gene expression and mouse development. As part of multisubunit corepressor complexes, these two deacetylases exhibit both enzymatic and nonenzymatic functions. To examine the impact of the catalytic activities of HDAC1 and HDAC2, we generated knock-in mice expressing catalytically inactive isoforms, which are still incorporated into the HDAC1/HDAC2 corepressor complexes. Surprisingly, heterozygous mice expressing catalytically inactive HDAC2 die within a few hours after birth, while heterozygous HDAC1 mutant mice are indistinguishable from wild-type littermates. Heterozygous HDAC2 mutant mice show an unaltered composition but reduced associated deacetylase activity of corepressor complexes and exhibit a more severe phenotype than HDAC2-null mice. They display changes in brain architecture accompanied by premature expression of the key regulator protein kinase C delta. Our study reveals a dominant negative effect of catalytically inactive HDAC2 on specific corepressor complexes resulting in histone hyperacetylation, transcriptional derepression, and, ultimately, perinatal lethality.
format Online
Article
Text
id pubmed-4719423
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher American Society for Microbiology
record_format MEDLINE/PubMed
spelling pubmed-47194232016-02-13 Essential Nonredundant Function of the Catalytic Activity of Histone Deacetylase 2 in Mouse Development Hagelkruys, Astrid Mattes, Katharina Moos, Verena Rennmayr, Magdalena Ringbauer, Manuela Sawicka, Anna Seiser, Christian Mol Cell Biol Articles The class I histone deacetylases (HDACs) HDAC1 and HDAC2 play partially redundant roles in the regulation of gene expression and mouse development. As part of multisubunit corepressor complexes, these two deacetylases exhibit both enzymatic and nonenzymatic functions. To examine the impact of the catalytic activities of HDAC1 and HDAC2, we generated knock-in mice expressing catalytically inactive isoforms, which are still incorporated into the HDAC1/HDAC2 corepressor complexes. Surprisingly, heterozygous mice expressing catalytically inactive HDAC2 die within a few hours after birth, while heterozygous HDAC1 mutant mice are indistinguishable from wild-type littermates. Heterozygous HDAC2 mutant mice show an unaltered composition but reduced associated deacetylase activity of corepressor complexes and exhibit a more severe phenotype than HDAC2-null mice. They display changes in brain architecture accompanied by premature expression of the key regulator protein kinase C delta. Our study reveals a dominant negative effect of catalytically inactive HDAC2 on specific corepressor complexes resulting in histone hyperacetylation, transcriptional derepression, and, ultimately, perinatal lethality. American Society for Microbiology 2016-01-19 /pmc/articles/PMC4719423/ /pubmed/26598605 http://dx.doi.org/10.1128/MCB.00639-15 Text en Copyright © 2016 Hagelkruys et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 Unported license (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Articles
Hagelkruys, Astrid
Mattes, Katharina
Moos, Verena
Rennmayr, Magdalena
Ringbauer, Manuela
Sawicka, Anna
Seiser, Christian
Essential Nonredundant Function of the Catalytic Activity of Histone Deacetylase 2 in Mouse Development
title Essential Nonredundant Function of the Catalytic Activity of Histone Deacetylase 2 in Mouse Development
title_full Essential Nonredundant Function of the Catalytic Activity of Histone Deacetylase 2 in Mouse Development
title_fullStr Essential Nonredundant Function of the Catalytic Activity of Histone Deacetylase 2 in Mouse Development
title_full_unstemmed Essential Nonredundant Function of the Catalytic Activity of Histone Deacetylase 2 in Mouse Development
title_short Essential Nonredundant Function of the Catalytic Activity of Histone Deacetylase 2 in Mouse Development
title_sort essential nonredundant function of the catalytic activity of histone deacetylase 2 in mouse development
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719423/
https://www.ncbi.nlm.nih.gov/pubmed/26598605
http://dx.doi.org/10.1128/MCB.00639-15
work_keys_str_mv AT hagelkruysastrid essentialnonredundantfunctionofthecatalyticactivityofhistonedeacetylase2inmousedevelopment
AT matteskatharina essentialnonredundantfunctionofthecatalyticactivityofhistonedeacetylase2inmousedevelopment
AT moosverena essentialnonredundantfunctionofthecatalyticactivityofhistonedeacetylase2inmousedevelopment
AT rennmayrmagdalena essentialnonredundantfunctionofthecatalyticactivityofhistonedeacetylase2inmousedevelopment
AT ringbauermanuela essentialnonredundantfunctionofthecatalyticactivityofhistonedeacetylase2inmousedevelopment
AT sawickaanna essentialnonredundantfunctionofthecatalyticactivityofhistonedeacetylase2inmousedevelopment
AT seiserchristian essentialnonredundantfunctionofthecatalyticactivityofhistonedeacetylase2inmousedevelopment