Does a father's lifestyle impact his children's health and development? Heredity can be passed from parent to child through DNA sequence and through packaging of DNA into distinct types of chromatin. The latter, termed epigenetics, can be influenced by environmental inputs, such as parental lifestyle. In contrast to our growing understanding of maternal epigenetic contributions to progeny development, paternal epigenetic contributions and their underlying mechanisms are relatively unexplored. The long-term objective of my research is to determine how a father's lifestyle influences his sperm quality, sperm epigenetics, and his offspring's development. This proposal approaches this objective by defining the sperm epigenome in the model organism C. elegans and elucidating the role of histone modifications in paternal epigenetic contributions to offspring. The nematode C. elegans has emerged as a powerful model to study transgenerational epigenetic inheritance. Our lab has shown that detectable levels of histone modifications are retained in C. elegans sperm and transmitted to embryos via sperm. Therefore, defining the sperm epigenome in C. elegans will serve as a foundation to further advance our understanding of transgenerational inheritance of paternal memory. The central issue that my proposal addresses is: what roles, if any, does paternal epigenetic contributions serve on developing offspring? AIM 1 will define the sperm epigenome by revealing the genome-wide distributions of unmodified and modified histones in C. elegans sperm using ChIP-seq.
AIM 2 will determine if histone modifications on sperm chromatin are retained or reprogrammed in fertilized embryos. To determine histone modifications on paternal chromatin, ChIP assays will be performed from viable hybrid embryos (from crossing the standard strain N2 Bristol and the Hawaiian isolate), and single-nucleotide polymorphisms will be used to distinguish paternal and maternal chromosomes.
AIM 3 will elucidate how loss of sperm histone modifications affects development of offspring, and if altered patterns of histone modifications and gene expression are transmitted to offspring via sperm. I will globally or locally alter gene expression and histone modification patterns in the paternal germline using mutants, and determine if such alterations persist in sperm and embryos using ChIP assays and transcript profiling. My postdoctoral training will expand my knowledge of germ cell biology and epigenetics, and provide me with bioinformatic and genetic tools essential to establish myself as an independent researcher. Furthermore, my proposed project will advance our understanding of sperm epigenetics and reveal the molecular mechanisms for paternal epigenetic effects. Ultimately, the outcome of this study may help us understand how sperm epigenetics influences embryo development, infertility, and human disease.
The object of this proposal is to study fathers'contributions to child health and development through DNA packaging components in sperm, specifically marked histones. Since such studies are difficult in humans, this study will utilize the powerful model organism C. elegans to elucidate how the packaging and modifications of sperm chromatin impact development of offspring. This is relevant to public health, because the molecular insights gained will advance our knowledge in reproductive science and human disease, and may help to explain some of the mysterious cases of infertility that millions of people experience today.
