Study epigenetic inheritance during development and across generations using multiple model organisms

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Abstract of the funded parent award R35 GM127075: The process of DNA replication allows the genetic information of a cell to be copied and transferred reliably to its daughter cells through cell divisions. However, if DNA replication and cell division were carried out in a symmetric manner, it would result in a cluster of tumor cells instead of a multicellular organism. For example, an adult human being has more than 30 trillion cells comprised of more than 200 cell types. All these different cells with distinct appearances and functions originate from a single cell—a fertilized egg. Therefore, a central question to understanding any multicellular organism is how cells become different while faithfully maintaining the same genetic material. Addressing this question also has far-reaching impact on human health. This is because even though most cells in our bodies carry identical DNA sequences, only a subset of these sequences turn on expression at the proper time, in the right place, and with the precise level during development and homeostasis. It is the distinct epigenetic information contained in each cell type that defines its unique gene expression. In eukaryotic cells, an important epigenetic regulation is through post-translational modifications of histones. Every ~147-bp double helix DNA wraps around an octamer structure composed of histone H2A, H2B, H3, and H4 proteins, each in two copies. Incorporation of new histones onto the DNA mainly occurs during DNA replication, which, in addition to copying the genome, requires duplication of the epigenome. However, how the epigenetic information contained in the parental cell can be maintained or changed in the daughter cells remains largely unknown. This question is extremely difficult to study because the epigenome is composed of numerous components that dynamically change their composition. This question is also extremely crucial for understanding the fundamental principles of biology and developing new treatments for human diseases, since mis- regulation of epigenetic information could lead to developmental defects or diseases such as infertility, birth defects, neurodegenerative disease, muscular dystrophy, diabetes, and many forms of cancer