Abstract
To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo.
Highlights
During gametogenesis, male and female germ cells are epigenetically reprogrammed as they undergo sex-specific differentiation into functional gametes
We report that perturbing sperm chromatin composition by altering PAR metabolism in male mice leads to differential gene expression during the maternal-to-embryo transition in individual progeny 2cell embryos derived from crosses with wild-type females
Inhibition of PAR synthesis by PJ34 or disruption of normal PAR glycohydrolase (PARG) activity in the Parg(110)2/2 mouse leads to abnormal chromatin remodeling with retention of histones in sperm [29]. (B) Natural mating of Parg(110)2/2 males or males treated with PJ34 with wild-type control females was used to obtain 2-cell stage embryos (2CE) for genome-wide transcriptional profiling at the individual embryo level using microarrays and high throughput sequencing (HTS)
Summary
Male and female germ cells are epigenetically reprogrammed as they undergo sex-specific differentiation into functional gametes. Chromatin in male and female pronuclei continues to be epigenetically remodeled prior to the first round of DNA replication and first cleavage. These changes include changes in the complement of histones associated with DNA as well as DNA demethylation. During the post-meiotic steps of spermatogenesis, termed spermiogenesis, the haploid germ cells (spermatids) undergo dramatic chromatin remodeling that entails replacement of most histones with small, highly basic protamines that facilitate extensive condensation of sperm nuclei (Fig. 1A) [2,3]. In contrast to maternal chromatin, whose DNA remains packaged in nucleosomes, paternal chromatin following fertilization undergoes a rapid decondensation of the compact sperm head and reestablishment of nucleosomal chromatin by replacement of protamines with maternally-derived histones
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