Proper development requires that gene expression information be transmitted across generations and through development. Both sperm and egg supply the embryo with gene expression information in the form of marked histones that pattern the genome into repressed and expressed chromatin domains. These patterns must be transmitted through cell divisions to specify proper gene expression in the developing embryo. However, the mechanisms by which chromatin states are propagated through embryogenesis and the impact these states have on later gene expression are not understood. The long-term objective of this research is to understand how chromatin inheritance shapes progeny gene expression patterns. This proposal approaches this objective by elucidating how inherited chromatin states are maintained through cell division and what impact altered chromatin inheritance has on progeny gene expression and development. This proposal aims to 1) define the chromatin landscapes across maternally and paternally inherited genomes in early embryos and determine the gene expression patterns that arise from those genomes in adult germlines and 2) determine how altered patterns of chromatin inheritance are propagated during embryogenesis and what gene expression and developmental consequences result from that altered inheritance. To achieve aim 1, I will distinguish parental DNA associated with different histone marks by performing chromatin immunoprecipitation followed by sequencing in embryos that inherit sperm and egg genomes from worm strains containing DNA polymorphisms. I will allow some embryos to develop to adults and use the DNA polymorphisms to assign parental origin to transcripts isolated from adult germlines. To achieve aim 2, I will generate embryos that inherit sperm chromosomes lacking the repressive mark H3K27me3. I will test 2 models of how altered patterns of H3K27me3 are transmitted through embryogenesis. I will analyze the worms that develop from this altered inheritance for patterns of misexpression and developmental defects. My preliminary data demonstrate that the two gametes contribute some different patterns of genome marking and that both are important in specifying proper development in progeny and grand-progeny. Ultimately, understanding the roles that histone marks serve in transmission of gene expression patterns across generations will shed light on the broader mechanism of transgenerational inheritance and how environmentally induced alterations to the parental epigenome can be transmitted to future generations and can impact health, longevity, and disease.
This research is aimed at elucidating how gene expression information is transmitted across generations and through development and how perturbations to this process can lead to developmental defects, disease, and cancer. Ultimately, understanding the mechanism of this transmission will shed light on the broader mechanism of transgenerational inheritance and how parental experience can alter the information delivered to offspring and can impact the health and longevity of future generations. !
