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Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2014)

Abstract

Nucleosome Occupancy and Modification in C. elegans Dosage Compensation

By

Christine Gail Preston

Doctor of Philosophy in Molecular and Cell Biology

University of California, Berkeley

Professor Barbara J. Meyer, Chair

Species with sex-determining chromosomes have also evolved sex chromosome dosage compensation, a process equalizing the sex chromosome gene expression of males (1X) to that of the females (2X). Dosage compensation strategies in well-studied model organisms evolved independently, however certain themes are constant between the different systems. Chromatin modifications are key components of dosage compensated X chromosomes in Drosophila and mammals, and recent reports have independently implicated the histone 4 lysine 20 monomethy mark, and nucleosome occupancy at X-chromosome promoters as playing roles in C. elegans dosage compensation. Here I report important advances in our understanding of the role of chromatin in C. elegans dosage compensation and general biological processes.

In chapter 2, I report our findings into the role of the H4K20 histone methyl transferase, set-1, in C. elegans. H4K20me1 is a histone modification associated with a wide variety of cellular functions, including condensed chromatin and transcriptional regulation. H4K20me1 is enriched on the dosage compensated X chromosomes in XX hermaphrodites, and this enrichment has been proposed to play an integral role in dosage compensation in worms. Here I report work that shows the major role of H4K20me1 in C. elegans is not X-chromosome dosage compensation, and instead that the mark is playing important roles in non-sex-specific functions, including the regulation of gene expression on all chromosomes.

In chapter 3, I report findings about the underlying mononucleosome structure at transcriptional start sites as well as DCC binding sites. I show that, similar to the situation at human promoters, C. elegans promoters have high, DNA-specified nucleosome occupancy covering promoter regions. These active promoters are remodeled in vivo, and the majority of the promoters consist of a canonical active promoter formation, with a nucleosome depleted region (NDR) upstream of the TSS, and well positioned nucleosome arrays emanating in either direction from the NDR. I also report that, in contrast to previous reports, promoters on the X chromosome are not uniquely higher in nucleosome occupancy; which had previously been postulated to be related to X-specific repression in somatic, sex-specific chromosome dosage compensation and in germline silencing.

    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2017)
    Chromatin modification and higher-order chromosome structure play key roles in gene regulation, but their functional interplay in controlling gene expression is elusive. We have discovered the machinery and mechanism underlying the dynamic enrichment of histone modification H4K20me1 on hermaphrodite X chromosomes during C. elegans dosage compensation and demonstrated H4K20me1's pivotal role in regulating higher-order chromosome structure and X-chromosome-wide gene expression. The structure and the activity of the dosage compensation complex (DCC) subunit DPY-21 define a Jumonji demethylase subfamily that converts H4K20me2 to H4K20me1 in worms and mammals. Selective inactivation of demethylase activity eliminates H4K20me1 enrichment in somatic cells, elevates X-linked gene expression, reduces X chromosome compaction, and disrupts X chromosome conformation by diminishing the formation of topologically associating domains (TADs). Unexpectedly, DPY-21 also associates with autosomes of germ cells in a DCC-independent manner to enrich H4K20me1 and trigger chromosome compaction. Our findings demonstrate the direct link between chromatin modification and higher-order chromosome structure in long-range regulation of gene expression.
      Cover page: Dynamic Control of X Chromosome Conformation and Repression by a Histone H4K20 Demethylase
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2022)
      BACKGROUND: Identification of clinically significant genetic alterations involved in human disease has been dramatically accelerated by developments in next-generation sequencing technologies. However, the infrastructure and accessible comprehensive curation tools necessary for analyzing an individual patient genome and interpreting genetic variants to inform healthcare management have been lacking. RESULTS: Here we present the ClinGen Variant Curation Interface (VCI), a global open-source variant classification platform for supporting the application of evidence criteria and classification of variants based on the ACMG/AMP variant classification guidelines. The VCI is among a suite of tools developed by the NIH-funded Clinical Genome Resource (ClinGen) Consortium and supports an FDA-recognized human variant curation process. Essential to this is the ability to enable collaboration and peer review across ClinGen Expert Panels supporting users in comprehensively identifying, annotating, and sharing relevant evidence while making variant pathogenicity assertions. To facilitate evidence-based improvements in human variant classification, the VCI is publicly available to the genomics community. Navigation workflows support users providing guidance to comprehensively apply the ACMG/AMP evidence criteria and document provenance for asserting variant classifications. CONCLUSIONS: The VCI offers a central platform for clinical variant classification that fills a gap in the learning healthcare system, facilitates widespread adoption of standards for clinical curation, and is available at https://curation.clinicalgenome.org.
        Cover page: ClinGen Variant Curation Interface: a variant classification platform for the application of evidence criteria from ACMG/AMP guidelines.
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