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      Epigenomes in Cardiovascular Disease

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          Abstract

          If unifying principles could be revealed for how the same genome encodes different eukaryotic cells and for how genetic variability and environmental input are integrated to impact cardiovascular health, grand challenges in basic cell biology and translational medicine may succumb to experimental dissection. A rich body of work in model systems has implicated chromatin-modifying enzymes, DNA methylation, noncoding RNAs, and other transcriptome-shaping factors in adult health and in the development, progression, and mitigation of cardiovascular disease. Meanwhile, deployment of epigenomic tools, powered by next-generation sequencing technologies in cardiovascular models and human populations, has enabled description of epigenomic landscapes underpinning cellular function in the cardiovascular system. This essay aims to unpack the conceptual framework in which epigenomes are studied and to stimulate discussion on how principles of chromatin function may inform investigations of cardiovascular disease and the development of new therapies.

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          Cytoplasmic chromatin triggers inflammation in senescence and cancer

          Zhixun Dou, Kanad Ghosh, Maria Grazia Vizioli … (2017)
          Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing 1–3 . However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence 4,5 , a form of terminal cell cycle arrest associated with pro-inflammatory responses 6 . The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA sensing cGAS-STING pathway, leading to both short-term inflammation to restrain activated oncogene and chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype (SASP) in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.
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            Editing DNA Methylation in the Mammalian Genome.

            X. Shawn Liu, Hao Wu, Xiong Ji … (2016)
            Mammalian DNA methylation is a critical epigenetic mechanism orchestrating gene expression networks in many biological processes. However, investigation of the functions of specific methylation events remains challenging. Here, we demonstrate that fusion of Tet1 or Dnmt3a with a catalytically inactive Cas9 (dCas9) enables targeted DNA methylation editing. Targeting of the dCas9-Tet1 or -Dnmt3a fusion protein to methylated or unmethylated promoter sequences caused activation or silencing, respectively, of an endogenous reporter. Targeted demethylation of the BDNF promoter IV or the MyoD distal enhancer by dCas9-Tet1 induced BDNF expression in post-mitotic neurons or activated MyoD facilitating reprogramming of fibroblasts into myoblasts, respectively. Targeted de novo methylation of a CTCF loop anchor site by dCas9-Dnmt3a blocked CTCF binding and interfered with DNA looping, causing altered gene expression in the neighboring loop. Finally, we show that these tools can edit DNA methylation in mice, demonstrating their wide utility for functional studies of epigenetic regulation.
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              The selection and function of cell type-specific enhancers.

              Sven Heinz, Casey E. Romanoski, Christopher Benner … (2015)
              The human body contains several hundred cell types, all of which share the same genome. In metazoans, much of the regulatory code that drives cell type-specific gene expression is located in distal elements called enhancers. Although mammalian genomes contain millions of potential enhancers, only a small subset of them is active in a given cell type. Cell type-specific enhancer selection involves the binding of lineage-determining transcription factors that prime enhancers. Signal-dependent transcription factors bind to primed enhancers, which enables these broadly expressed factors to regulate gene expression in a cell type-specific manner. The expression of genes that specify cell type identity and function is associated with densely spaced clusters of active enhancers known as super-enhancers. The functions of enhancers and super-enhancers are influenced by, and affect, higher-order genomic organization.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Circ Res
                Journal ID (iso-abbrev): Circ. Res
                Journal ID (publisher-id): RES
                Title: Circulation Research
                Publisher: Lippincott Williams & Wilkins
                ISSN (Print): 0009-7330
                ISSN (Electronic): 1524-4571
                Publication date (Print): 25 May 2018
                Publication date (Electronic): 24 May 2018
                Volume: 122
                Issue: 11
                Pages: 1586-1607
                Affiliations
                [1]From the Departments of Anesthesiology, Medicine, and Physiology, David Geffen School of Medicine, University of California, Los Angeles.
                Author notes
                Correspondence to Thomas M. Vondriska, PhD, Departments of Anesthesiology, Medicine, and Physiology, David Geffen School of Medicine, University of California, Los Angeles, BH 557 CHS, 650 Charles Young Dr, Los Angeles, CA 90095. E-mail tvondriska@ 123456mednet.ucla.edu
                Article
                Accession ID: 00017
                DOI: 10.1161/CIRCRESAHA.118.311597
                PMC ID: 5976233
                PubMed ID: 29798902
                SO-VID: d3836a47-bad3-4c23-8ce3-df92ef6ad7da
                Copyright © © 2018 The Authors.
                License:

                Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.

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                Subject: 10037
                Subject: 10054
                Subject: 100800
                Subject: 10081
                Subject: Reviews
                Custom metadata
                OPEN-ACCESS TRUE

                Keywords: cardiovascular diseases,chromatin,epigenomics,genetics,transcriptome
                Data availability:
                Keywords: cardiovascular diseases, chromatin, epigenomics, genetics, transcriptome

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