Sperm epigenetic alterations contribute to inter- and transgenerational effects of paternal exposure to long-term psychological stress via evading offspring embryonic reprogramming

Xiaoguo Zheng,Hanshu Wang,C Yan Cheng,Yunbo Qiao,Zhenhua Li,Guishuan Wang,Fei Sun,Xinzhi Zhao,Yuchuan Zhou

doi:10.1038/s41421-021-00343-5

Abstract

Paternal life experiences impact offspring health via germline, and epigenetic inheritance provides a potential mechanism. However, global reprogramming during offspring embryogenesis and gametogenesis represents the largest hurdle to conceptualize it. Yet, detailed characterization of how sperm epigenetic alterations carrying “environmental memory” can evade offspring embryonic reprogramming remains elusive. Here, mice exposed to long-term restraint stress were employed to study the mechanisms underlying inter- and transgenerational effects of paternal exposure to a long-term psychological stress. We found that stress could induce paternal inheritance of reproductive, behavioral, and metabolic disorders. Bisulfite methylation profiling of 18 sperm and 12 embryo samples of three consecutive generations identified inter- and transgenerational inheritance of paternal Differential DNA Methylation Regions (DMRs) at frequencies ~11.36% and 0.48%, respectively. These DMRs related to genes with functional implications for psychological stress response, and tissue inheritance of these DMRs passed paternal disorders epigenetically to offspring. More importantly, these DMRs evaded offspring embryonic reprogramming through erasure and subsequent reestablishment, but not via un-erasure way. Nonetheless, their reestablishment proportions in the primitive streak (E7.5) stage were altered. Furthermore, sncRNA-seq revealed that stress-induced tsRNA, miRNA and rsRNA dysregulation in paternal sperm might play important roles in DMRs occurrence and paternal inheritance. These finding implied that sperm epigenetic alterations contribute to inter- and transgenerational effects of paternal exposure to long-term psychological stress, and highlighted the possible underlying molecular mechanism.

Highlights

Human epidemiological studies and animal models provide strong evidence supporting the hypothesis that parental life experiences, such as hunger[1,2], unhealthy diet orZheng et al Cell Discovery (2021)7:101 sequences, and multiple mechanisms have been proposed to account for non-DNA sequence-based inheritance in mammals
With respect to our concentration on paternal inheritance, we only examined the phenotypic alteration of the male descendants in subsequent analyses
We found that the DNA methylation patterns and the levels of these DNA Methylation Regions (DMRs) could be intergenerationally inherited by F1 tissues (Fig. 4h, i and Supplementary Fig. S3h, i)

Summary

Introduction

Zheng et al Cell Discovery (2021)7:101 sequences, and multiple mechanisms have been proposed to account for non-DNA sequence-based inheritance in mammals These include chemical modifications of DNA and histones, or transfer of small regulatory RNAs complementary to genomic sequences[19]. These widely studied epigenetic marks add another layer of genome information and provide a source of heritable phenotypic changes that is non-DNA primary sequence-based[20]. Epigenetic marks, including DNA methylation, histone modifications, and small non-coding RNAs (sncRNAs), have been found to play critical roles in transgenerational and intergenerational inheritance of environmental or endogenous factors-induced phenotypic alterations in animals[5,10,12]

Methods

Results

Conclusion