title: Histone H3.3 maintains genome integrity during mammalian development.
abstract: 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.
authors.affiliation: Department of Genetics, Carolina Center for Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA.
authors.forename: Chuan-Wei
authors.initials: CW
authors.lastname: Jang
authors.affiliation: Department of Genetics, Carolina Center for Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Shibata
authors.affiliation: Department of Genetics, Carolina Center for Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Starmer
authors.affiliation: Department of Genetics, Carolina Center for Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA.
authors.forename: Della
authors.initials: D
authors.lastname: Yee
authors.affiliation: Department of Genetics, Carolina Center for Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Magnuson
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D005298:Fertility / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics*; D048788:Growth and Development / Q000235:genetics*; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation
chemical_list: D006570:Heterochromatin; D006657:Histones
keywords: apoptosis; cell proliferation; genome integrity; histone H3.3; mouse embryonic development; transcriptional regulation