Biparental contributions of the H2A.B histone variant control embryonic development in mice

Abstract

Histone variants expand chromatin functions in eukaryote genomes. H2A.B genes are testis-expressed short histone H2A variants that arose in placental mammals. Their biological functions remain largely unknown. To investigate their function, we generated a knockout (KO) model that disrupts all 3 H2A.B genes in mice. We show that H2A.B KO males have globally altered chromatin structure in postmeiotic germ cells. Yet, they do not show impaired spermatogenesis or testis function. Instead, we find that H2A.B plays a crucial role postfertilization. Crosses between H2A.B KO males and females yield embryos with lower viability and reduced size. Using a series of genetic crosses that separate parental and zygotic contributions, we show that the H2A.B status of both the father and mother, but not of the zygote, affects embryonic viability and growth during gestation. We conclude that H2A.B is a novel parental-effect gene, establishing a role for short H2A histone variants in mammalian development. We posit that parental antagonism over embryonic growth drove the origin and ongoing diversification of short histone H2A variants in placental mammals.

Novel Classes and Evolutionary Turnover of Histone H2B Variants in the Mammalian Germline

“…To begin to explore their function, we examined their expression in mammals. Similar analyses had previously revealed putative germline-specific functions of many rapidly evolving H2A variants ( Molaro et al 2018 , 2020 ). Prior studies have shown that some H2B variants are primarily expressed in testes of rodents, bull, or human.…”

Novel classes and evolutionary turnover of histone H2B variants in the mammalian germline

“…To begin to explore their function, we examined their expression in mammals. Similar analyses had previously revealed putative germline-specific functions of many rapidly evolving H2A variants (Molaro, et al 2018; Molaro, et al 2020). Prior studies have shown that some H2B variants are primarily expressed in testes of rodents, bull, or human.…”

“…Although several H2B variants appear to be highly enriched in the male germline, this does not eliminate the possibility that they might play important roles during oogenesis and early embryogenesis. For example, the H2A.B variant is testis-enriched in expression but nevertheless plays key roles in oogenesis and post-implantation development in mice (Molaro, et al 2020).…”

An actin-related protein that is most highly expressed in Drosophila testes is critical for embryonic development

“…The ‘out-of-testis’ hypothesis predicts that the male germline provides an initial ‘gene nursery’ for evolutionary innovation, with diversification subsequently broadening its expression profile ( Assis and Bachtrog, 2013 ; Vinckenbosch et al, 2006 ; Nyberg and Carthew, 2017 ). Recent studies of histone variants, which were originally thought to be ‘testis-specific’ in Drosophila and mammals, based on RT-PCR data, demonstrated that their expression and function also extends to females ( Kursel et al, 2021 ; Molaro, 2020 ). Similarly, Umbrea, which is highly testis-enriched, is required for chromosome segregation more broadly ( Ross et al, 2013 ).…”