Don't Play with Histones

Abstract

Studies over the last few years have shown that factors such as paternal diet and toxicant exposure can have epigenetic effects on offspring, and some of these reports have hinted that these effects can persist to the next generation—a transgenerational effect. A new study in mice suggests that modifications to histones may be behind such observations, and strengthens the evidence for a transgenerational effect [1]. During spermatogenesis, sperm DNA undergo massive chromatin reorganization, a process that is an active area of investigation. Most nucleosomes are ejected and replaced with protamines, but some nucleosomes remain. In the new study, Keith Siklenka and Serap Erkek disrupted sperm histones by overexpressing a histone-modifying enzyme during spermatogenesis. Overexpressing this enzyme resulted in reduced levels of a key histone, H3K4me2 (histone three modified with two methyl groups at lysine position 4). H3K4me2 is associated with numerous genes in sperm, including developmental genes. This single perturbation resulted in multiple effects on offspring, which had a host of developmental problems, ranging from malformed digits to spinal defects—and many died within weeks of birth. These effects occurred also in the next generation, the ‘‘grandchildren’’ of male mice overexpressing this factor, suggestive of a transgenerational effect. For instance, about 25 percent of these ‘‘grandchildren’’ died within 21 days of birth (n 1⁄4 158)—in comparison, about 8 percent of offspring from control wild-type fathers died by this age (n 1⁄4 238). The effects seemed to persist to the subsequent generation, but were attenuated. Three generations after transgene exposure, the effect was not measurable. The researchers observed no major changes in DNA methylation patterns in sperm, and found no evidence of increased mutation. Instead, the researchers showed that perturbing histone modification with the H3K4me2 transgene resulted in massive shifts in RNA profiles of the sperm of transgenic mice, and similar shifts were observed in sperm of littermate brothers that were never exposed to the transgene themselves. The embryos resulting from such sperm also had altered gene expression patterns, which could in turn affect sperm development. Although the exact mechanism behind the observations of transgenerational effects is not clear, these findings open the door to further experiments testing the role of chromatin modifications.