Key words: Mammalian Genetics/Genomics/Development/Mouse Models of Human Disease
PRC2’s histone H3 lysine-27 methylation activity plays a pivotal role in cellular homeostasis maintenance, cell lineage specification, and disease development through maintaining chromatin structure and transcriptional programs. Genome-wide H3K27 methylation is restored in daughter cells for cell identity maintenance during cell proliferation and are also transmitted into next generation through gametes for gene regulation in early embryogenesis. The epigenetic memory of H3K27me landscapes is determined by the temporospatial control of PRC2 recruitment and assembly on targeting chromatin loci. The interaction between PRC2 and chromatin is mediated through a complicated process involving repressive transcriptional states, CpG-rich DNA elements, chromatin-binding proteins, DNA modifications, histone modifications, and noncoding RNAs. This process is particularly important for mammalian spermatogenesis, which requires numerous epigenetic changes to accompany the transition from somatic, diploid precursors to mature, haploid gametes. Faithful execution of the meiotic program requires that the genome undergoes large-scale changes to histone and DNA modifications as well as to chromatin structure, all of which require the action of a large number of chromatin modifying pathways. Homologous recombination occurs during the first meiotic prophase. DNA double-strand breaks (DSBs) are induced, and repair at these breaks generates DNA recombination between homologous chromosomes. Many of the factors required for repair of stress-induced DNA damage in somatic cells function during male meiosis. In addition to their well-characterized roles in transcriptional regulation, chromatin-remodeling complexes also have roles in DNA repair. Because male germ cell development is characterized by DSBs and dynamic changes to gene expression patterns, including a transition from somatic to germ-cell-specific genes, global repression of transposon activity, and meiotic sex chromosome inactivation, it stands to reason that this process is particularly sensitive to the activity of several epigenetic regulators known to influence meiotic recombination. Experiments are addressing the mechanisms by which PRC1/2 and SWI/SNF subunits regulate epigenetic memory during spermatogenesis, as well as defining how associations between complexes and lncRNAs shape the male epigenome during meiosis.
The eukaryotic genome is stored in the nucleus as chromatin, a dynamic structure of DNA and histone proteins. Chromatin contains a vast array of features that directs how, when, and where genomic DNA is made accessible by regulatory machinery. Nucleosomes are the core units of chromatin and are highly dynamic structures. Nucleosomes can be variable in histone protein composition, undergo a wide array of post-translational modifications, and are subject to changes in their localization at genomic sites. These variations in nucleosome biology instruct cells how to utilize epigenomic loci and the underlying DNA sequences. As a result, regulation of chromatin delivers precise instructions to cells leading to secondary processes that are physiologically critical. Thus, beyond serving as a DNA storage molecule, chromatin serves as a template that enables cells to leverage multivalent signals surrounding genomic sites as instructions to cellular machinery for biological programs. There are three categories of proteins and enzymes that modify chromatin by depositing, removing or recognizing post-translational modifications (PTMs) of the histone, categorized as writers, erasers, and readers, respectively. A fourth class of chromatin modifiers consists of ATP-dependent chromatin remodelers that regulate nucleosome positioning. These complexes are multi-subunit molecular machines that mobilize nucleosomes by breaking histone-DNA contacts using ATP hydrolysis. The SWI/SNF family of chromatin remodelers are the subject of this proposal. It was not until The Cancer Genome Atlas (TCGA) program began to sequence over 20,000 primary cancer and matched normal samples spanning 33 cancer types that it became clear that there are widespread mutations in SWI/SNF subunits in a variety of cancers. These data established SWI/SNF complexes as major factors in tumor biology. The work outlined here analyzes the regulation of assembly and genomic targeting of biochemically distinct forms of SWI/SNF chromatin remodeling complexes, and how these processes impact the functional and phenotypic diversity of remodelers. Experiments are addressing (i) changes to the composition and assembly of the SWI/SNF complex in liver and liver cancer cells, and (ii) the relevance of functional interactions between SWI/SNF complex subunits and RNAs.
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Terry Magnuson in UNC Genetics News
April 25, 2022
Department of Genetics Publications April 10th – 23rd, 2022
Department of Genetics faculty, postdocs, students and collaborators published 18 papers during April 10th – 23rd, 2022.
January 17, 2022
Department of Genetics Publications January 2nd – 15th 2022
Department of Genetics faculty, postdocs, students and collaborators published eleven papers during January 2nd – 15th, 2022.
November 29, 2021
Department of Genetics Publications November 14th – 27th 2021
Department of Genetics faculty, postdocs, students and collaborators published 16 papers during November 14th – 27th 2021.
September 9, 2021
Drs. Terry Magnuson and Shawn Ahmed awarded equipment supplements from NIGMS
Drs. Terry Magnuson and Shawn Ahmed awarded equipment supplements from NIGMS
August 10, 2021
Mutant Mouse Resource & Research Center (MMRRC) at UNC Awarded a NIH Supplement for Development of COVID-19 Related Resources
The MMRRC at UNC, led by Dr. Terry Magnuson (Vice Chancellor for Research and Distinguished Professor of Genetics), was awarded a $500,000 supplement from the NIH to develop and validate two new animal model resources to support research activities related to pathogenic coronaviruses (including SARS-CoV2).
April 15, 2021
Dr. Terry Magnuson Reappointed Vice Chancellor for Research
Following the completion of administrative review, Dr. Terry Magnuson (Kay M. & Van L. Weatherspoon Eminent Distinguished Professor of Genetics) has been reappointed as Vice Chancellor for Research for another five-year term.
November 6, 2020
UNC Researchers Lead International Consortium to Improve Understanding of Genetics of Mouse Models
An international consortium led by UNC Departments of Genetics and Computer Science published a manuscript on the development and testing of a new tool to enhance the value of the laboratory mouse in biomedical research.
November 2, 2020
Department of Genetics Publications for October 11-31, 2020
Department of Genetics faculty, postdocs, students and collaborators published 18 papers during October 11-31, 2020. Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer. Fernandez-Martinez A, Krop IE, Hillman DW, Polley MY, Parker JS, Huebner L, Hoadley KA, …
August 28, 2020
MMRRC Awarded Administrative Supplement from NIH Office of the Director
Dr. Terry Magnuson, Vice Chancellor for Research and Kay M. and Van L. Weatherspoon Eminent Distinguished Professor of Genetics was awarded an administrative supplement to the U42 Cooperative Agreement “A Carolina Center to Characterize and Maintain Mutant Mice”.
June 29, 2020
Department of Genetics Publications for June 14-27, 2020
Department of Genetics faculty, postdocs, students and collaborators published nine papers during June 14-27, 2020.