Sperm histone H3 lysine 4 trimethylation is altered in a genetic mouse model of transgenerational epigenetic inheritance

Abstract

Advancing the molecular knowledge surrounding fertility and inheritance has become critical given the halving of sperm counts in the last 40 years, and the rise in complex disease which cannot be explained by genetics alone. The connection between both these trends may lie in alterations to the sperm epigenome and occur through environmental exposures. Changes to the sperm epigenome are also associated with health risks across generations such as metabolic disorders and cancer. Thus, it is imperative to identify the epigenetic modifications that escape reprogramming during spermatogenesis and embryogenesis. Here, we aimed to identify the chromatin signature(s) involved in transgenerational phenotypes in our genetic mouse model of epigenetic inheritance that overexpresses the histone demethylase KDM1A in their germ cells. We used sperm-specific chromatin immunoprecipitation followed by in depth sequencing (ChIP-seq), and computational analysis to identify whether differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3), and histone H3 lysine 27 trimethylation (H3K27me3) serve as mechanisms for transgenerational epigenetic inheritance through the paternal germline. Our analysis on the sperm of KDM1A transgenic males revealed specific changes in H3K4me3 enrichment that predominantly occurred independently from bivalent H3K4me3/H3K27me3 regions. Many regions with altered H3K4me3 enrichment in sperm were identified on the paternal allele of the pre-implantation embryo. These findings suggest that sperm H3K4me3 functions in the transmission of non-genetic phenotypes transgenerationally.

High Efficiency RNA Extraction From Sperm Cells Using Guanidinium Thiocyanate Supplemented With Tris(2-Carboxyethyl)Phosphine

“…During the last stages of spermatogenesis, most histones are replaced by protamines in sperm and only 1-8% are retained in mouse and 10-15% in human. Histones are retained principally at genomic regions such as transcription start sites, promoters and enhancers (Jung et al, 2017;Yamaguchi et al, 2018;Lismer et al, 2020). Protamines have different properties to histones, and in contrast to histones, they are highly enriched in disulfide bonds.…”

A global approach to addressing the policy, research and social challenges of male reproductive health

“…How can we examine the impact of MRH on any offspring conceived naturally or through Medically Assisted Reproduction (MAR)? Moreover, compelling data are emerging that the environment (diet, toxicants and body mass index) can induce changes in the sperm epigenome and that these changes can be transmitted to the embryo to influence development and health ( Donkin et al , 2016 ; Ly et al , 2017 ; Lismer et al , 2020 ). This epigenetic contribution to the offspring suggests intergenerational biological effects driven by sperm.…”

Epigenetic Mechanisms of Paternal Stress in Offspring Development and Diseases

“…There is ample evidence that sperm histone modification affects the health and phenotype of offspring. Kimmins et al used a genetically transgenic mouse model to confirm that H3K4me3 was significantly upregulated in mouse sperm overexpressing the demethylase Kdm1a and that developmental genes were highly enriched in target difference analysis [ 69 , 70 ]. H3K4me3 in the sperm of transgenic mice escaped the epigenetic reprogramming of the fertilized egg [ 69 ].…”

“…Kimmins et al used a genetically transgenic mouse model to confirm that H3K4me3 was significantly upregulated in mouse sperm overexpressing the demethylase Kdm1a and that developmental genes were highly enriched in target difference analysis [ 69 , 70 ]. H3K4me3 in the sperm of transgenic mice escaped the epigenetic reprogramming of the fertilized egg [ 69 ]. The male offspring with cocaine infusions increased the expression of Bdnf and the acetylation of H3 histone in the cortex, resulting in cocaine resistance and enhancing the binding of acetylated H3 histone to BDNF promoter in cocaine paternal sperm [ 71 ].…”