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Epigenetic Regulation of the Sex Chromosomes and 3D Chromatin Organization in Male Germ Cells

Alavattam, Kris G
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563527048714711

Abstract Details

2019, PhD, University of Cincinnati, Medicine: Cancer and Cell Biology.
Germ cell development is a remarkable story. Developing germ cells undergo large-scale, dynamic programs of gene expression that are essential for fertility, unlike any found in somatic cells. The rewiring of transcription networks takes place when germ cells enter meiosis, a critical period for preparing the gamete genome and the acquisition of totipotency following fertilization. In meiosis, it is thought that dynamic forms of germline chromatin organization support diverse forms of epigenetic programming and gene regulation, yet it is poorly understood how the spatiotemporal organization of germ cell chromatin facilitates the epigenomes and transcriptomes necessary for the next generation of life. To address this, I undertook two major research projects: The first seeks to understand the molecular mechanisms of meiotic sex chromosome inactivation, an essential event in male germ cell development, through genetic analyses of a protein network that directs epigenetic regulation of the sex chromosomes. The second project employs Next-Generation Sequencing technologies to understand how the spatiotemporal organization of male germ cell chromatin facilitates and relates to vitally important transcriptomes and epigenomes. In the first project, first published in 2016 (PMID: 27760317), I and a small team analyze meiosis in eight mouse models deficient for various DNA damage response (DDR) factors, including Fanconi anemia (FA) proteins. We reveal a network of FA and DDR proteins in which FA core factors FANCA, FANCB, and FANCC are essential for FANCD2 foci formation, whereas BRCA1 (FANCS), MDC1, and RNF8 are required for BRCA2 (FANCD1) and SLX4 (FANCP) accumulation on the sex chromosomes during meiosis. Furthermore, FA proteins modulate distinct histone marks on the sex chromosomes. Our data suggest that RNF8 integrates the FA- BRCA pathway. We reveal distinct functions for FA proteins and illuminate the male sex chromosomes as a model to dissect the function of the FA-BRCA pathway. In the second project, first published in 2019 (PMID: 30778237), our team performs Hi-C analyses to examine 3D chromatin organization in male germ cells. We show that the highly compartmentalized 3D chromatin organization characteristic of interphase nuclei is attenuated in meiotic prophase I. Meiotic prophase I is predominated by short-range intrachromosomal interactions that represent a condensed form akin to that of mitotic chromosomes. Unlike mitotic chromosomes, meiotic chromosomes display weak genomic compartmentalization, weak topologically associating domains, and localized point interactions. Genomic compartmentalization increases in sperm development. The X chromosome lacks domain organization during meiotic sex chromosome inactivation. We propose that male meiosis occurs amid the global reprogramming of 3D chromatin organization and that strengthening of chromatin compartmentalization takes place in spermiogenesis to prepare the next generation of life. Our Hi-C study was published amid two related manuscripts on the functional significance of chromatin organization in male germ cells; I conclude with a discussion of findings, both overlapping and distinct, from these three reports. Also, in considering the mechanistic relationships between DDR pathways and the high-order chromatin organization of the sex chromosomes, I integrate and reflect on findings from my two projects. I consider all of these studies and put forward ideas and questions.
Satoshi Namekawa, Ph.D. (Committee Chair)
Paul Andreassen, Ph.D. (Committee Member)
Artem Barski, Ph.D. (Committee Member)
Chunying Du, Ph.D. (Committee Member)
Carolyn Price, Ph.D. (Committee Member)
202 p.
Biology
Spermatogenesis; Meiosis; Epigenetics; Chromatin; DNA damage response; Sex chromosomes

Recommended Citations

Citations

  • Alavattam, K. G. (2019). Epigenetic Regulation of the Sex Chromosomes and 3D Chromatin Organization in Male Germ Cells [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563527048714711

    APA Style (7th edition)

  • Alavattam, Kris. Epigenetic Regulation of the Sex Chromosomes and 3D Chromatin Organization in Male Germ Cells. 2019. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563527048714711.

    MLA Style (8th edition)

  • Alavattam, Kris. "Epigenetic Regulation of the Sex Chromosomes and 3D Chromatin Organization in Male Germ Cells." Doctoral dissertation, University of Cincinnati, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563527048714711

    Chicago Manual of Style (17th edition)

ucin1563527048714711
210
© 2019, some rights reserved.Creative Commons License Epigenetic Regulation of the Sex Chromosomes and 3D Chromatin Organization in Male Germ Cells by Kris G Alavattam is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.