Nucleosomes in mammalian sperm: conveying paternal epigenetic inheritance or subject to reprogramming between generations?

Abstract

The genome of mammalian sperm is largely packaged by sperm-specific proteins termed protamines. The presence of some residual nucleosomes has, however, emerged as a potential source of paternal epigenetic inheritance between generations. Sperm nucleosomes bear important regulatory histone marks and locate at gene-regulatory regions, functional elements, and intergenic regions. It is unclear whether sperm nucleosomes are retained at specific genomic locations in a deterministic manner or are randomly preserved due to inefficient exchange of histones by protamines. Recent studies indicate heterogeneity in chromatin packaging within sperm populations and an extensive reprogramming of paternal histone marks post fertilization. Obtaining single-sperm nucleosome distributions is fundamental to estimating the potential of sperm-borne nucleosomes in instructing mammalian embryonic development and in the transmission of acquired phenotypes.

Figure 1

Overview illustrating the exchange of nucleosomes by protamines during mammalian spermiogenesis (Box 1). Nucleosomes consist of 147 bp of DNA wrapped around a histone octamer core containing two copies of the core histones H2A, H2B, H3, and H4. Beyond H4, variants of each core histone incorporate into the genome during meiosis and spermiogenesis. The H2AL2 variant interacts with and contributes to the deposition of TNPs and/or PRMs into chromatin. Several histone PTMs are upregulated at the onset of spermatid elongation. H4 acetylation (H4ac) and potentially other PTMs facilitate histone displacement partly by engaging nucleosome-removing machineries. Conversely, histone PTMs such as butyrylation (Bu) repel certain of such activities. PTMs on TNPs and PRMs regulate incorporation in and removal of these proteins from chromatin, as well as compaction of chromatin. Detailed understanding on the actual mechanisms of histone displacement, retention, and TNP/PRM loading is largely missing. Similarly, the extent by which paternal nucleosomes are exchanged by maternal histones at fertilization remains unclear. Ac: acetylation, P: phosphorylation, Ub: ubiquitination.

Figure 2

Retention of nucleosomes within the mammalian sperm genome. (a) Overview of nucleosome distribution and composition within the mammalian sperm genome. Sperm DNA methylation (blue), CpG density (green), and nucleosome enrichments (orange) are displayed at representative types of genomic loci (black). Current data on nucleosome enrichments represent relative nucleosome abundances in bulk sperm populations. Sperm histone distributions differ between studies, leading to two main models: high abundance of nucleosomes at promoter and distal gene-regulatory regions predominantly lacking DNA methylation and overlapping CpG-rich sequences (upper orange) or preferential retention at intergenic regions and repetitive elements (lower orange). Absolute nucleosome enrichment maps obtained with orthogonal methodologies will help to understand whether specific genomic loci are preferentially packaged by nucleosomes or protamines in sperm. (b) Potential modes of heterogeneity in nucleosome retention between individual spermatozoa. Left: nucleosomes or protamines could package defined regions of the sperm genome in a homogeneous mode in most individual spermatozoa (rows) within a population. This would reflect a finely controlled and deterministic exchange of nucleosomes by protamines. Right: inefficiencies in histone replacement could instead render some nucleosomes randomly distributed within the genome of spermatozoa (middle) or lead to severe defects in histone displacement in a fraction of spermatozoa (right).