Date of Award
Spring 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Genetics
First Advisor
Giraldez, Antonio
Abstract
Following fertilization, the zebrafish embryo experiences significant reprogramming events to erase the inherited program of the terminally differentiated gametes, paving the way for the establishment of the zygotic program, which will drive the early steps of embryonic development. An essential step within this process is zygotic genome activation (ZGA), which refers to the time of development when the zygotic genome goes from being largely transcriptionally inactive to a gradual onset of transcriptional activity. In zebrafish, this process coincides with the deposition of many histone modifications associated with the positive regulation of transcription. Here, to explore the function of these transcription-associated marks during ZGA, I use a series of small-molecule inhibitors to screen against histone-modifying enzymes that cause gastrulation defects, as this tends to indicate defects in zygotic genome activation. I find that inhibitors against the acetyltransferases KAT2A and KAT8 tend to block gastrulation. Meanwhile, those against the H3K4 histone methyltransferase, KMT2, allow for the development of the embryo past gastrulation and do not prevent transcriptional appear to prevent transcriptional onset. While transcription is not globally downregulated, some transcripts are preferentially affected by the removal of the mark. Interestingly, inhibiting the eraser of H3K4me3, KDM5 blocks development at gastrulation. Given that this and other studies suggest that the activity of several epigenetic modifiers is essential for the correct regulation of Zygotic genome activation, I use the overexpression of lysine(K) to arginine(R) mutant histones in a histone-deficient background to interrogate the role of the histone modifications independent of any other enzymatic activity of the epigenetic modifier. In particular, to study the role of H3K27 in the onset of ZGA. Preventing the modification of the H3 tail blocks gastrulation and downregulated transcription in embryos injected with the mutant version of the histone. Interestingly, in mutants where only one lysine is replaced at a time, only K27R mutants mimic the developmental phenotype and the downregulation of transcription. All of these suggest a role for H3 lysine tail modifications in regulating ZGA and a critical role for K27.
Recommended Citation
Benitez Ortiz, Maria De Jesus, "Histone Regulation of the Maternal to Zygotic Transition: The Role of Histone Modifications on Zygotic Genome Activation" (2024). Yale Graduate School of Arts and Sciences Dissertations. 1429.
https://elischolar.library.yale.edu/gsas_dissertations/1429
