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Contribution of the Two Genes Encoding Histone Variant H3.3 to Viability and Fertility in Mice
Authors:Michelle C W Tang  Shelley A Jacobs  Deidre M Mattiske  Yu May Soh  Alison N Graham  An Tran  Shu Ly Lim  Damien F Hudson  Paul Kalitsis  Moira K O’Bryan  Lee H Wong  Jeffrey R Mann
Institution:1. Department of Zoology, The University of Melbourne, Melbourne, Victoria, Australia.; 2. Genetics Theme, Murdoch Children’s Research Institute, Parkville, Victoria, Australia.; 3. Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia.; 4. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia.; Australia National University, UNITED STATES,
Abstract:Histones package DNA and regulate epigenetic states. For the latter, probably the most important histone is H3. Mammals have three near-identical H3 isoforms: canonical H3.1 and H3.2, and the replication-independent variant H3.3. This variant can accumulate in slowly dividing somatic cells, replacing canonical H3. Some replication-independent histones, through their ability to incorporate outside S-phase, are functionally important in the very slowly dividing mammalian germ line. Much remains to be learned of H3.3 functions in germ cell development.Histone H3.3 presents a unique genetic paradigm in that two conventional intron-containing genes encode the identical protein. Here, we present a comprehensive analysis of the developmental effects of null mutations in each of these genes. H3f3a mutants were viable to adulthood. Females were fertile, while males were subfertile with dysmorphic spermatozoa. H3f3b mutants were growth-deficient, dying at birth. H3f3b heterozygotes were also growth-deficient, with males being sterile because of arrest of round spermatids. This sterility was not accompanied by abnormalities in sex chromosome inactivation in meiosis I. Conditional ablation of H3f3b at the beginning of folliculogenesis resulted in zygote cleavage failure, establishing H3f3b as a maternal-effect gene, and revealing a requirement for H3.3 in the first mitosis. Simultaneous ablation of H3f3a and H3f3b in folliculogenesis resulted in early primary oocyte death, demonstrating a crucial role for H3.3 in oogenesis.These findings reveal a heavy reliance on H3.3 for growth, gametogenesis, and fertilization, identifying developmental processes that are particularly susceptible to H3.3 deficiency. They also reveal partial redundancy in function of H3f3a and H3f3b, with the latter gene being generally the most important.
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