Oocytes and sperm are terminally differentiated cells that can give rise to a multicellular organism after fertilization despite using an identical genetic template. How this happens has intrigued biologists for decades and has helped spur advancements in the understanding of the cellular epigenome. The epigenome is comprised of several types of chemical modifications on either histone proteins or the DNA itself. Collectively, these epigenetic modifications stabilize gene expression patterns and establish cellular identity. In somatic cells these epigenetic states are maintained through many mitotic divisions, but are largely cleared in the germline and early embryos to ensure proper development, and/ or prevent the inheritance of acquired epigenetic information across generations. Despite the two waves of genome-wide reprogramming in embryos and germ cells, inheritance of non-genetic information has been observed in various organisms including humans. These observations have raised fundamental questions - Do gametes convey epigenetic information to the zygote? What is the molecular nature of an epigenetic carrier across generations? A logical and reasonable carrier of epigenetic memory are histone proteins, but whether the parental histones are physically inherited or have a functional role in embryonic development remains unknown due to technical and experimental limitations. Therefore, to overcome these challenges we have developed cutting edge genetic and molecular tools to visualize and track maternal and paternal histones in the early embryo and during the first few divisions. Based on previous literature and my preliminary data, I hypothesize that maternal and paternal histones are retained in the zygote, and persist across multiple embryonic cell divisions. To address these questions, I will use a combination of mouse genetics, early embryonic manipulations, immunohistochemical, single-molecule resolution imaging techniques. These studies will provide fundamental insights into whether histones can serve as informational carriers of epigenetic memory. Additionally, completion of this work will provide me with critical scientific and technical training, as outlined in my training plan, which will be foundational for a successful career as an independent scientist studying the core principles that dictate our early development.
It has been recognized for decades that parents transmit information to their children and grandchildren via a string of nucleotides (A, C, G, and T) that makes up the DNA sequence, however, a number of recent studies have suggested that additional information layered on top of the DNA sequence or the protein that package the DNA ( histones) , a.k.a Epigenetic modifications, can serve as informational carriers from parents to offspring. In this project, I aim to determine if and whether the parental histone proteins can transmit information intergenrationally. Understanding the molecular carriers of epigenetic memory will have great implications for animal/human health and fitness, and will potentially explain idiopathic cases of infertility, birth defects, and miscarriage.
