Early life stress affects the transcription and chromatin accessibility of spermatogonial cells

Abstract

Adversity in early life has lasting effects on the physiology and behavior of exposed individuals and their descendants. In mice, early-life stress alters the RNA content of adult sperm, and this RNA is sufficient to transmit some of the effects to the offspring who were never exposed. However, sperm cells are not yet formed during the early postnatal window in which the exposure occurs. Spermatogonial cells (SPGs), which give rise to them, are present at that time, but whether they respond to the exposure and maintain a molecular signature of it into adulthood is unknown. Here we show that early-life stress alters both the transcriptome and the chromatin accessibility of mouse SPGs, and that a molecular signature of the exposure remains detectable in adulthood. One day after exposure ended, the transcriptional response was extensive, with proliferation and nucleosome-organization programs coordinately up-regulated. In adulthood, the transcriptional response was modest and dominated by coordinately down-regulated gene programs. Single-cell profiling of the whole testis localized the adult response to spermatogonial stem cells (SSCs) and to genes involved in spermatogenesis. At the chromatin level, accessibility shifted one day after exposure at binding motifs for signal-responsive transcription factor families, and in adulthood at a different set of families, in both cases at primed enhancers. These data demonstrate that SPGs respond to an early postnatal environmental exposure and identify them as a candidate origin of the molecular changes later found in adult sperm.