A Role for Histones in Paternal Epigenetic Inheritance
A group of children grew up in the same neighborhoods of Quebec in the late 1960’s, but only some of them would reach their fifth birthday. In one of the first studies of its kind, Fabia and Thuy combed through hospital records to ask what made these children different from their healthy peers. They found that of the children who had died, significantly more of their fathers worked as painters, automobile mechanics, or miners, fields that exposed these men to high levels of hydrocarbons . Since this study was published in 1974, more epidemiological studies have shown that conditions experienced by fathers can affect the lives of their descendants .
How fathers transmit epigenetic information to their offspring is poorly understood. Sperm DNA loses the majority of its histone packaging and is repackaged with protamines, small basic proteins that tightly compact the DNA , raising the question of if and/or how histone modifications in fathers are passed on to their descendants. New work by Tabuchi et al uses the model organism C. elegans to investigate the fundamental questions of histone-based epigenetic inheritance in sperm.
Tabuchi et al first asked how the genome is packaged in C. elegans sperm. The amount of histones that remain in sperm varies from organism to organism with about 1-10% in mammals to 100% remaining in zebrafish. Using MNase-seq, they found that C. elegans sperm retains 100% of its histones, and through ChIP-seq analysis for repressive H3K27me3 marks and active H3K36me3 and H3K4me3 marks, they saw that the sperm retained these histone-modifications across the genome.
The researchers next asked how gene expression in female and male germlines correlated with active or repressive histone modifications seen in sperm, oocytes, and early embryos. They found that genes expressed in both spermatogenic and oogenic germlines, called sex-independent genes, were marked with active H3K36me3. Silent genes, those not expressed in either spermatogenic or oogenic germlines, only had the repressive H3K27me3 mark. Intriguingly, however, for genes solely expressed in the spermatogenesis germline, sperm histones bore both active H3K36me3 and repressive H3K27me3 marks. In the oocyte and early embryo, these genes were only marked by H3K27me3, suggesting that the unique combination of histone marks in sperm may be a specific feature of sperm chromatin.
An additional surprise arose when the researchers looked at oogenesis-enriched genes and found that the majority of these genes were marked with active chromatin marks in sperm (78% with H3K36me3 and 75% with H3K4me3), oocytes, and early embryos. Additional analysis by RNA-seq and single-molecule FISH of both male and female germlines demonstrated that these oogenesis-enriched genes are expressed in both spermatogenesis and oogenic germlines. The authors suggest that transcribing these genes in male germlines may be important for maintaining them in an open chromatin state in sperm. Taken together, these analyses of histone modifications in sperm and germline gene expression indicate that C. elegans sperm carry an epigenetic memory of spermatogenesis gene expression.
The researchers next asked if the histone marks in sperm are both required and sufficient for the development of the germline. To ask if histone modifications are required, Tabuchi et al assessed the fertility of worms that had inherited sperm chromosomes without H3K27me3. Most of these worms developed into sterile adults, demonstrating that epigenetic information encoded in sperm is necessary for proper germline development of offspring.
Next, to ask if the histone marks on sperm are sufficient for the development of the germline of the next generation, the researchers used a mutant that, instead of combining the genetic information from the oocyte and the sperm at the one cell stage, segregates the genetic material from the sperm into one daughter cell and the genetic material from the oocyte into the other. Worms whose germline was only derived from the sperm genome developed into fertile adults, indicating that the sperm epigenome is sufficient for proper germline development.
Overall, this work demonstrates that epigenetic information in C. elegans sperm are transmitted to offspring in the form of histone modifications and that epigenetic information from sperm is both required and sufficient from proper germline development in the next generation. Because human sperm retains 10-15% of histones , it is possible that histone-based epigenetic memory may be one way that life experiences of fathers can affect the lives of their children.
Original article: Tabuchi TM, Rechtsteiner A, Jeffers TE, Egelhofer TA, Murphy CT, Strome S (2018). Caenorhabditis elegans sperm carry a histone-based epigenetic memory of both spermatogenesis and oogenesis. Nat Commun., 9 (1): 4310. DOI: 10.1038/s41467-018-06236-8.
 Miller D, Brinkworth M, and Iles D (2010). Paternal DNA packaging in spermatozoa: more than the sum of its parts? DNA, histones, protamines and epigenetics. Reproduction, 139 (2): 287-301. DOI: 10.1530/REP-09-0281.