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  1. Article ; Online: Chromatin Alterations in Neurological Disorders and Strategies of (Epi)Genome Rescue

    Marcin Janowski / Małgorzata Milewska / Peyman Zare / Aleksandra Pękowska

    Pharmaceuticals, Vol 14, Iss 765, p

    2021  Volume 765

    Abstract: Neurological disorders (NDs) comprise a heterogeneous group of conditions that affect the function of the nervous system. Often incurable, NDs have profound and detrimental consequences on the affected individuals’ lives. NDs have complex etiologies but ... ...

    Abstract Neurological disorders (NDs) comprise a heterogeneous group of conditions that affect the function of the nervous system. Often incurable, NDs have profound and detrimental consequences on the affected individuals’ lives. NDs have complex etiologies but commonly feature altered gene expression and dysfunctions of the essential chromatin-modifying factors. Hence, compounds that target DNA and histone modification pathways, the so-called epidrugs, constitute promising tools to treat NDs. Yet, targeting the entire epigenome might reveal insufficient to modify a chosen gene expression or even unnecessary and detrimental to the patients’ health. New technologies hold a promise to expand the clinical toolkit in the fight against NDs. (Epi)genome engineering using designer nucleases, including CRISPR-Cas9 and TALENs, can potentially help restore the correct gene expression patterns by targeting a defined gene or pathway, both genetically and epigenetically, with minimal off-target activity. Here, we review the implication of epigenetic machinery in NDs. We outline syndromes caused by mutations in chromatin-modifying enzymes and discuss the functional consequences of mutations in regulatory DNA in NDs. We review the approaches that allow modifying the (epi)genome, including tools based on TALENs and CRISPR-Cas9 technologies, and we highlight how these new strategies could potentially change clinical practices in the treatment of NDs.
    Keywords epigenetics ; transcriptional regulation ; cis-regulatory elements ; nervous system ; chromatin structure ; histone modifications ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
    Subject code 570
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article: Genome Organization Drives Chromosome Fragility

    Canela, Andres / Aleksandra Pekowska / Amanda Day / André Nussenzweig / Elsa Callen / Erez Lieberman Aiden / Hongliang Zhang / Kyong-Rim Kieffer-Kwon / Nancy Wong / Peter D. Aplan / Peter J. Mckinnon / Rafael Casellas / Seolkyoung Jung / Su-Chen Huang / Suhas S.P. Rao / Yaakov Maman / Yves Pommier

    Cell. 2017 July 27, v. 170

    2017  

    Abstract: In this study, we show that evolutionarily conserved chromosome loop anchors bound by CCCTC-binding factor (CTCF) and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that ... ...

    Abstract In this study, we show that evolutionarily conserved chromosome loop anchors bound by CCCTC-binding factor (CTCF) and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy rewire DNA cleavage sites to novel loop anchors. While transcription- and replication-coupled genomic rearrangements have been well documented, we demonstrate that DSBs formed at loop anchors are largely transcription-, replication-, and cell-type-independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in cancer. Thus, loop anchors serve as fragile sites that generate DSBs and chromosomal rearrangements.[Display omitted]
    Keywords chromosome aberrations ; chromosomes ; DNA ; DNA damage ; genome ; genomics ; interphase ; neoplasms ; topology
    Language English
    Dates of publication 2017-0727
    Size p. 507-521.e18.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2017.06.034
    Database NAL-Catalogue (AGRICOLA)

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  3. Article: Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions

    Grubert, Fabian / Judith B. Zaugg / Maya Kasowski / Oana Ursu / Damek V. Spacek / Alicia R. Martin / Peyton Greenside / Rohith Srivas / Doug H. Phanstiel / Aleksandra Pekowska / Nastaran Heidari / Ghia Euskirchen / Wolfgang Huber / Jonathan K. Pritchard / Carlos D. Bustamante / Lars M. Steinmetz / Anshul Kundaje / Michael Snyder

    Cell. 2015 Aug. 27, v. 162

    2015  

    Abstract: Deciphering the impact of genetic variants on gene regulation is fundamental to understanding human disease. Although gene regulation often involves long-range interactions, it is unknown to what extent non-coding genetic variants influence distal ... ...

    Abstract Deciphering the impact of genetic variants on gene regulation is fundamental to understanding human disease. Although gene regulation often involves long-range interactions, it is unknown to what extent non-coding genetic variants influence distal molecular phenotypes. Here, we integrate chromatin profiling for three histone marks in lymphoblastoid cell lines (LCLs) from 75 sequenced individuals with LCL-specific Hi-C and ChIA-PET-based chromatin contact maps to uncover one of the largest collections of local and distal histone quantitative trait loci (hQTLs). Distal QTLs are enriched within topologically associated domains and exhibit largely concordant variation of chromatin state coordinated by proximal and distal non-coding genetic variants. Histone QTLs are enriched for common variants associated with autoimmune diseases and enable identification of putative target genes of disease-associated variants from genome-wide association studies. These analyses provide insights into how genetic variation can affect human disease phenotypes by coordinated changes in chromatin at interacting regulatory elements.
    Keywords autoimmune diseases ; chromatin ; genes ; genetic variation ; genome-wide association study ; histones ; human diseases ; humans ; phenotype ; quantitative trait loci ; regulatory sequences
    Language English
    Dates of publication 2015-0827
    Size p. 1051-1065.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2015.07.048
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    In stock of ZB MED Bonn / Germany

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  4. Article: Myc Regulates Chromatin Decompaction and Nuclear Architecture during B Cell Activation

    Kieffer-Kwon, Kyong-Rim / Adriel Casellas / Aleksandra Pekowska / Brian Glenn St. Hilaire / Charles Gregory / David Levens / Diana Stavreva / Elizabeth Finn / Erez Lieberman Aiden / Eric Batchelor / Evan Stevens / Ewy Mathe / Francesco Tomassoni Ardori / Gordon Hager / Hari Shroff / Jianliang Xu / Keisuke Nimura / Laura Baranello / Lino Tessarollo /
    Marei Dose / Maria Aurelia Ricci / Maria Pia Cosma / Melike Lakadamyali / Michael McAndrew / Monique Floer / Peng Dong / Rafael Casellas / Robert D. Phair / Seolkyoung Jung / Steevenson Nelson / Steven M. Johnson / Su-Chen Huang / Suhas S.P. Rao / Tom Misteli / Wendy Dubois / Wolfgang Resch / Ying Zheng / Zhe Liu

    Molecular cell. 2017 Aug. 17, v. 67, no. 4

    2017  

    Abstract: 50 years ago, Vincent Allfrey and colleagues discovered that lymphocyte activation triggers massive acetylation of chromatin. However, the molecular mechanisms driving epigenetic accessibility are still unknown. We here show that stimulated lymphocytes ... ...

    Abstract 50 years ago, Vincent Allfrey and colleagues discovered that lymphocyte activation triggers massive acetylation of chromatin. However, the molecular mechanisms driving epigenetic accessibility are still unknown. We here show that stimulated lymphocytes decondense chromatin by three differentially regulated steps. First, chromatin is repositioned away from the nuclear periphery in response to global acetylation. Second, histone nanodomain clusters decompact into mononucleosome fibers through a mechanism that requires Myc and continual energy input. Single-molecule imaging shows that this step lowers transcription factor residence time and non-specific collisions during sampling for DNA targets. Third, chromatin interactions shift from long range to predominantly short range, and CTCF-mediated loops and contact domains double in numbers. This architectural change facilitates cognate promoter-enhancer contacts and also requires Myc and continual ATP production. Our results thus define the nature and transcriptional impact of chromatin decondensation and reveal an unexpected role for Myc in the establishment of nuclear topology in mammalian cells.
    Keywords acetylation ; adenosine triphosphate ; B-lymphocytes ; chromatin ; DNA ; energy ; epigenetics ; histones ; image analysis ; lymphocyte proliferation ; mammals ; topology ; transcription (genetics) ; transcription factors
    Language English
    Dates of publication 2017-0817
    Size p. 566-578.e10.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2017.07.013
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Bonn / Germany

    Z 2005/501: Show issues

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