Chd5 orchestrates chromatin remodelling during sperm development

Abstract

One of the most remarkable chromatin remodeling processes occurs during spermiogenesis, the post-meiotic phase of sperm development during which histones are replaced with sperm-specific protamines to repackage the genome into the highly compact chromatin structure of mature sperm. Here we identify Chromodomain helicase DNA binding protein 5 (Chd5) as a master regulator of the histone-to-protamine chromatin remodeling process. Chd5 deficiency leads to defective sperm chromatin compaction and male infertility in mice, mirroring the observation of low CHD5 expression in testes of infertile men. Chd5 orchestrates a cascade of molecular events required for histone removal and replacement, including histone 4 (H4) hyperacetylation, histone variant expression, nucleosome eviction, and DNA damage repair. Chd5 deficiency also perturbs expression of transition proteins (Tnp1/Tnp2) and protamines (Prm1/2). These findings define Chd5 as a multi-faceted mediator of histone-to-protamine replacement and depict the cascade of molecular events underlying chromatin remodeling during this process of extensive chromatin remodeling.

TSSK6 is required for γH2AX formation and the histone-to-protamine transition during spermiogenesis

“…Thus, incomplete Prm2 processing of the chromatin-associated precursor and intermediate(s) occurs in the absence of TSSK6. Numerous studies have implicated altered Prm1 or Prm2 amounts, and aberrant processing of Prm2 precursor and intermediate(s) in sterility in mice (Bao and Bedford, 2016;Hernández-Hernández et al, 2016;Li et al, 2014;Lu et al, 2010;Rathke et al, 2014;Wu et al, 2000;Yuen et al, 2014) and humans (Carrell et al, 2007;Oliva, 2006;Torregrosa et al, 2006). We interpret the defects in the histone-to-protamine transition, as evidenced by altered histone and protamine homeostasis in the chromatin of Tssk6-KO spermatids and sperm, as the cause for infertility in the null mice.…”

“…Conversely, TSSK6 was found to be essential for the production of γH2AX, removal of histones (H3 and H4) and effective processing of the Prm2 precursor and intermediate (s). Most of the core nucleosomal histones are displaced from the chromatin during steps 9-12 of spermiogenesis in the mouse, and condensed spermatids or sperm retain only small residual amounts of histones H3 and H4 (Li et al, 2014;Meistrich et al, 2003). Increased retention of histone H3 and H4 in spermatids/sperm has been closely linked to male infertility in many gene-KO mouse models (Bell et al, 2014;Li et al, 2014;Lu et al, 2010;Zhuang et al, 2014).…”

“…Most of the core nucleosomal histones are displaced from the chromatin during steps 9-12 of spermiogenesis in the mouse, and condensed spermatids or sperm retain only small residual amounts of histones H3 and H4 (Li et al, 2014;Meistrich et al, 2003). Increased retention of histone H3 and H4 in spermatids/sperm has been closely linked to male infertility in many gene-KO mouse models (Bell et al, 2014;Li et al, 2014;Lu et al, 2010;Zhuang et al, 2014). Prm2 is synthesized as a precursor protein that binds to the chromatin and then undergoes proteolytic processing giving rise to several intermediates and finally mature Prm2 (Balhorn, 2007;Wu et al, 2000).…”

“…The molecular basis of nuclear condensation is poorly understood but involves key events such as expression of testis-specific histone variants, post-translational modifications of histones, transient DNA strand breaks and transcriptional silencing. Several post-translational modifications of histones, such as acetylation, phosphorylation, ubiquitination and methylation, all facilitate the displacement of histones from chromatin and gene regulation in spermatids (Govin et al, 2004;Li et al, 2014;Rathke et al, 2014;Zhuang et al, 2014). Modified histones are recognized by 'reader' proteins, which are often components of chromatin-remodeling complexes that are involved in the histone-to-protamine transition.…”

Paternal contribution to development: Sperm genetic damage and repair in fish

“…The former are consequence of failures in the recombination process during meiosis, in the cell renewal by apoptosis induction during spermatogenesis (Shaha et al 2010) or during chromatin remodeling at spermiogenesis (Hendrich and Bickmore 2001;Li et al 2014;Rathke et al 2014). Moreover, membranes from immature spermatozoa are very susceptible to suffer lipid peroxidation, whose products are genotoxic and mutagenic and can affect to the mature ones (Aitken et al 2014).…”