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Histone H3.3 maintains genome integrity during mammalian development

Histone H3.3 is a highly conserved histone H3 replacement variant in metazoans and has been implicated in many important biological processes, including cell differentiation and reprogramming. Germline and somatic mutations in H3.3 genomic incorporation pathway components or in H3.3 encoding genes h...

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Autores principales: Jang, Chuan-Wei, Shibata, Yoichiro, Starmer, Joshua, Yee, Della, Magnuson, Terry
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511213/
https://www.ncbi.nlm.nih.gov/pubmed/26159997
http://dx.doi.org/10.1101/gad.264150.115
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author Jang, Chuan-Wei
Shibata, Yoichiro
Starmer, Joshua
Yee, Della
Magnuson, Terry
author_facet Jang, Chuan-Wei
Shibata, Yoichiro
Starmer, Joshua
Yee, Della
Magnuson, Terry
author_sort Jang, Chuan-Wei
collection PubMed
description Histone H3.3 is a highly conserved histone H3 replacement variant in metazoans and has been implicated in many important biological processes, including cell differentiation and reprogramming. Germline and somatic mutations in H3.3 genomic incorporation pathway components or in H3.3 encoding genes have been associated with human congenital diseases and cancers, respectively. However, the role of H3.3 in mammalian development remains unclear. To address this question, we generated H3.3-null mouse models through classical genetic approaches. We found that H3.3 plays an essential role in mouse development. Complete depletion of H3.3 leads to developmental retardation and early embryonic lethality. At the cellular level, H3.3 loss triggers cell cycle suppression and cell death. Surprisingly, H3.3 depletion does not dramatically disrupt gene regulation in the developing embryo. Instead, H3.3 depletion causes dysfunction of heterochromatin structures at telomeres, centromeres, and pericentromeric regions of chromosomes, leading to mitotic defects. The resulting karyotypical abnormalities and DNA damage lead to p53 pathway activation. In summary, our results reveal that an important function of H3.3 is to support chromosomal heterochromatic structures, thus maintaining genome integrity during mammalian development.
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spelling pubmed-45112132016-01-01 Histone H3.3 maintains genome integrity during mammalian development Jang, Chuan-Wei Shibata, Yoichiro Starmer, Joshua Yee, Della Magnuson, Terry Genes Dev Research Paper Histone H3.3 is a highly conserved histone H3 replacement variant in metazoans and has been implicated in many important biological processes, including cell differentiation and reprogramming. Germline and somatic mutations in H3.3 genomic incorporation pathway components or in H3.3 encoding genes have been associated with human congenital diseases and cancers, respectively. However, the role of H3.3 in mammalian development remains unclear. To address this question, we generated H3.3-null mouse models through classical genetic approaches. We found that H3.3 plays an essential role in mouse development. Complete depletion of H3.3 leads to developmental retardation and early embryonic lethality. At the cellular level, H3.3 loss triggers cell cycle suppression and cell death. Surprisingly, H3.3 depletion does not dramatically disrupt gene regulation in the developing embryo. Instead, H3.3 depletion causes dysfunction of heterochromatin structures at telomeres, centromeres, and pericentromeric regions of chromosomes, leading to mitotic defects. The resulting karyotypical abnormalities and DNA damage lead to p53 pathway activation. In summary, our results reveal that an important function of H3.3 is to support chromosomal heterochromatic structures, thus maintaining genome integrity during mammalian development. Cold Spring Harbor Laboratory Press 2015-07-01 /pmc/articles/PMC4511213/ /pubmed/26159997 http://dx.doi.org/10.1101/gad.264150.115 Text en © 2015 Jang et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Jang, Chuan-Wei
Shibata, Yoichiro
Starmer, Joshua
Yee, Della
Magnuson, Terry
Histone H3.3 maintains genome integrity during mammalian development
title Histone H3.3 maintains genome integrity during mammalian development
title_full Histone H3.3 maintains genome integrity during mammalian development
title_fullStr Histone H3.3 maintains genome integrity during mammalian development
title_full_unstemmed Histone H3.3 maintains genome integrity during mammalian development
title_short Histone H3.3 maintains genome integrity during mammalian development
title_sort histone h3.3 maintains genome integrity during mammalian development
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511213/
https://www.ncbi.nlm.nih.gov/pubmed/26159997
http://dx.doi.org/10.1101/gad.264150.115
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