Wednesday, February 5, 2025
2/5/2025
Project Summary: Segregation of DNA into open euchromatin and more condensed heterochromatin is fundamental to eukaryotic genome organization. Chromatin accessibility influences cell-fate choice in development and its dysregulation is common in disease. While the presence of euchromatic and heterochromatic compartments has been appreciated for over a century, we still know almost nothing about the mechanisms that drive the initial, rapid fractionation of genomes into these distinct domains during embryogenesis. Moreover, although we and others have shown that the large-scale de novo establishment of heterochromatin is tightly linked to the onset of zygotic gene expression in animals, the transcriptional consequences of accelerating or delaying heterochromatin establishment during this early window of vertebrate development are not known. My laboratory focuses on Histone H3 lysine 9 trimethyl (H3K9me3) marked heterochromatin, which forms the major blocks of heterochromatin in vertebrates. H3K9me3 marked heterochromatin is required for the silencing of transposons, suppression of inappropriate recombination, proper chromosome segregation and appropriate transcription of developmentally important genes. Here, we propose an innovative program combining genetic, genomic and molecular biology approaches, which seeks to uncover the mechanisms that control the large- scale de novo establishment of H3K9me3 marked heterochromatin during early vertebrate embryogenesis and to define the consequences of shifting the timing of heterochromatin establishment in the embryo. We choose zebrafish as a model because there are clear parallels between heterochromatin regulation in zebrafish and in mammals, and because external fertilization of the zebrafish embryo facilitates the molecular interrogation of chromatin in very early development. Over the course of our studies, we will elucidate the functions of several newly identified regulators of heterochromatin establishment, test requirements for zygotic transcripts in directing de novo heterochromatin formation and clarify the relationship between 5-methylcytosine and H3K9me3 in early embryogenesis. We will also identify early developmental programs that are impacted by altering the timeline of heterochromatin establishment in the embryo. This research is significant, as it addresses critical and long-standing knowledge gaps in our understanding of heterochromatin formation and function during early vertebrate embryogenesis. Understanding how heterochromatin is first established during development, and its functions in regulating early transcription is necessary for us to understand how heterochromatin misregulation contributes to disease, and how we might intervene to reset aberrant chromatin states using targeted therapies.
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