Browsing by Subject "Chromatin remodelling"

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    Author Correction: Lipid exposure activates gene expression changes associated with estrogen receptor negative breast cancer
    (Springer Nature, 2023-03-13) Yadav, Shivangi; Virk, Ranya; Chung, Carolina H.; Bustamante Eduardo, Mariana; VanDerway, David; Chen, Duojiao; Burdett, Kirsten; Gao, Hongyu; Zeng, Zexian; Ranjan, Manish; Cottone, Gannon; Xuei, Xiaoling; Chandrasekaran, Sriram; Backman, Vadim; Chatterton, Robert; Khan, Seema Ahsan; Clare, Susan E.; Medical and Molecular Genetics, School of Medicine
    Correction to: npj Breast Cancer 10.1038/s41523-022-00422-0, published online 04 May 2022 In this article, funding from the National Institutes of Health (award number R01CA228272) was inadvertently omitted. The original article has been corrected.
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    Lipid exposure activates gene expression changes associated with estrogen receptor negative breast cancer
    (Springer Nature, 2022-05-04) Yadav, Shivangi; Virk, Ranya; Chung, Carolina H.; Bustamante Eduardo, Mariana; VanDerway, David; Chen, Duojiao; Burdett, Kirsten; Gao, Hongyu; Zeng, Zexian; Ranjan, Manish; Cottone, Gannon; Xuei, Xiaoling; Chandrasekaran, Sriram; Backman, Vadim; Chatterton, Robert; Khan, Seema Ahsan; Clare, Susan E.; Medical and Molecular Genetics, School of Medicine
    Improved understanding of local breast biology that favors the development of estrogen receptor negative (ER-) breast cancer (BC) would foster better prevention strategies. We have previously shown that overexpression of specific lipid metabolism genes is associated with the development of ER- BC. We now report results of exposure of MCF-10A and MCF-12A cells, and mammary organoids to representative medium- and long-chain polyunsaturated fatty acids. This exposure caused a dynamic and profound change in gene expression, accompanied by changes in chromatin packing density, chromatin accessibility, and histone posttranslational modifications (PTMs). We identified 38 metabolic reactions that showed significantly increased activity, including reactions related to one-carbon metabolism. Among these reactions are those that produce S-adenosyl-L-methionine for histone PTMs. Utilizing both an in-vitro model and samples from women at high risk for ER- BC, we show that lipid exposure engenders gene expression, signaling pathway activation, and histone marks associated with the development of ER- BC.
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    Uncoupling of p97 ATPase activity has a dominant negative effect on protein extraction
    (Springer Nature, 2019-07-17) Rycenga, Halley B.; Wolfe, Kelly B.; Yeh, Elizabeth S.; Long, David T.; Pharmacology & Toxicology, IU School of Medicine
    p97 is a highly abundant, homohexameric AAA+ ATPase that performs a variety of essential cellular functions. Characterized as a ubiquitin-selective chaperone, p97 recognizes proteins conjugated to K48-linked polyubiquitin chains and promotes their removal from chromatin and other molecular complexes. Changes in p97 expression or activity are associated with the development of cancer and several related neurodegenerative disorders. Although pathogenic p97 mutations cluster in and around p97's ATPase domains, mutant proteins display normal or elevated ATPase activity. Here, we show that one of the most common p97 mutations (R155C) retains ATPase activity, but is functionally defective. p97-R155C can be recruited to ubiquitinated substrates on chromatin, but is unable to promote substrate removal. As a result, p97-R155C acts as a dominant negative, blocking protein extraction by a similar mechanism to that observed when p97's ATPase activity is inhibited or inactivated. However, unlike ATPase-deficient proteins, p97-R155C consumes excess ATP, which can hinder high-energy processes. Together, our results shed new insight into how pathogenic mutations in p97 alter its cellular function, with implications for understanding the etiology and treatment of p97-associated diseases.