Histone H3.3 regulates dynamic chromatin states during spermatogenesis

Abstract

The histone variant H3.3 is involved in diverse biological processes, including development, transcriptional memory and transcriptional reprogramming, as well as diseases, including most notably malignant brain tumors. Recently, we developed a knockout mouse model for the H3f3b gene, one of two genes encoding H3.3. Here, we show that targeted disruption of H3f3b results in a number of phenotypic abnormalities, including a reduction in H3.3 histone levels, leading to male infertility, as well as abnormal sperm and testes morphology. Additionally, null germ cell populations at specific stages in spermatogenesis, in particular spermatocytes and spermatogonia, exhibited increased rates of apoptosis. Disruption of H3f3b also altered histone post-translational modifications and gene expression in the testes, with the most prominent changes occurring at genes involved in spermatogenesis. Finally, H3f3b null testes also exhibited abnormal germ cell chromatin reorganization and reduced protamine incorporation. Taken together, our studies indicate a major role for H3.3 in spermatogenesis through regulation of chromatin dynamics.

Histone Variant H3.3: A versatile H3 variant in health and in disease

“…The function of H3.3 in early embryo development H3.3 takes part in various stages of development, such as gametogenesis, fertilization and differentiation (Bush et al, 2013;Lin et al, 2013;Tang et al, 2015;Wen et al, 2014a;Yuen et al, 2014) (Figure 2A). Knockout animal models for H3.3 or H3.3-specific chaperones have revealed the essential functions of H3.3 during development (Garrick et al, 2006;Michaelson et al, 1999;Roberts et al, 2002;Tang et al, 2015).…”

“…These phenotypes in both mice and Drosophila suggest that H3.3 is critical for fertility. H3.3 is expressed throughout the mouse seminiferous tubule, and depletion of H3f3b resulted in male testes atrophy, abnormal sperm morphology, and was also shown to disrupt the expression patterns of spermatogenesis-related genes (Yuen et al, 2014). In mammalian males, the X and Y chromosomes are transcriptionally silenced during the meiosis of spermatogenesis, a process called meiotic sex-chromosome inactivation (MSCI).…”

“…However, not all nucleosomes were replaced, with a small number of H3.3-containing nucleosomes being retained. These nucleosomes are enriched in all those genomic regions that are important for development (Yuen et al, 2014). In mouse sperm, H3.3 is enriched at high-CpG rich promoters that are not methylated (Erkek et al, 2013).…”

Chemical “Diversity” of Chromatin Through Histone Variants and Histone Modifications

“…Loss of H3.3 through genetic disruption resulted in infertility and defects in spermatogenesis in mice [34,35]. During normal spermatogenesis, histones are replaced by protamines in the mature sperm, but small amounts of H3.3 are retained at regions of the genome important for zygotic development.…”

“…During normal spermatogenesis, histones are replaced by protamines in the mature sperm, but small amounts of H3.3 are retained at regions of the genome important for zygotic development. Mice that harbor targeted disruption of the H3f3b gene not only have disrupted expression of spermatogenesis-related genes, but also have defects in the histone-to-protamine replacement during spermatogenesis [35]. H3.3 also has a role in maintaining proper chromatin structure during the initial stages of embryonic development, and loss of H3.3 often leads to missegregation of chromosomes [33,34].…”