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  1. Article ; Online: A

    Donohue, Laura K H / Guo, Margaret G / Zhao, Yang / Jung, Namyoung / Bussat, Rose T / Kim, Daniel S / Neela, Poornima H / Kellman, Laura N / Garcia, Omar S / Meyers, Robin M / Altman, Russ B / Khavari, Paul A

    Cell genomics

    2022  Volume 2, Issue 11

    Abstract: Gene expression is controlled by transcription factors (TFs) that bind cognate DNA motif sequences ... ...

    Abstract Gene expression is controlled by transcription factors (TFs) that bind cognate DNA motif sequences in
    Language English
    Publishing date 2022-10-05
    Publishing country United States
    Document type Journal Article
    ISSN 2666-979X
    ISSN (online) 2666-979X
    DOI 10.1016/j.xgen.2022.100191
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: easyCLIP analysis of RNA-protein interactions incorporating absolute quantification.

    Porter, Douglas F / Miao, Weili / Yang, Xue / Goda, Grant A / Ji, Andrew L / Donohue, Laura K H / Aleman, Maria M / Dominguez, Daniel / Khavari, Paul A

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 1569

    Abstract: Quantitative criteria to identify proteins as RNA-binding proteins (RBPs) are presently lacking, as are criteria to define RBP target RNAs. Here, we develop an ultraviolet (UV) cross-linking immunoprecipitation (CLIP)-sequencing method, easyCLIP. ... ...

    Abstract Quantitative criteria to identify proteins as RNA-binding proteins (RBPs) are presently lacking, as are criteria to define RBP target RNAs. Here, we develop an ultraviolet (UV) cross-linking immunoprecipitation (CLIP)-sequencing method, easyCLIP. easyCLIP provides absolute cross-link rates, as well as increased simplicity, efficiency, and capacity to visualize RNA libraries during sequencing library preparation. Measurement of >200 independent cross-link experiments across >35 proteins identifies an RNA cross-link rate threshold that distinguishes RBPs from non-RBPs and defines target RNAs as those with a complex frequency unlikely for a random protein. We apply easyCLIP to the 33 most recurrent cancer mutations across 28 RBPs, finding increased RNA binding per RBP molecule for KHDRBS2 R168C, A1CF E34K and PCBP1 L100P/Q cancer mutations. Quantitating RBP-RNA interactions can thus nominate proteins as RBPs and define the impact of specific disease-associated RBP mutations on RNA association.
    MeSH term(s) Animals ; Binding Sites ; Humans ; Immunoprecipitation ; RNA/chemistry ; RNA/metabolism ; RNA/radiation effects ; RNA-Binding Proteins/chemistry ; RNA-Binding Proteins/metabolism ; RNA-Binding Proteins/radiation effects ; Ultraviolet Rays
    Chemical Substances RNA-Binding Proteins ; RNA (63231-63-0)
    Language English
    Publishing date 2021-03-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-21623-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Integrative analyses highlight functional regulatory variants associated with neuropsychiatric diseases.

    Guo, Margaret G / Reynolds, David L / Ang, Cheen E / Liu, Yingfei / Zhao, Yang / Donohue, Laura K H / Siprashvili, Zurab / Yang, Xue / Yoo, Yongjin / Mondal, Smarajit / Hong, Audrey / Kain, Jessica / Meservey, Lindsey / Fabo, Tania / Elfaki, Ibtihal / Kellman, Laura N / Abell, Nathan S / Pershad, Yash / Bayat, Vafa /
    Etminani, Payam / Holodniy, Mark / Geschwind, Daniel H / Montgomery, Stephen B / Duncan, Laramie E / Urban, Alexander E / Altman, Russ B / Wernig, Marius / Khavari, Paul A

    Nature genetics

    2023  Volume 55, Issue 11, Page(s) 1876–1891

    Abstract: Noncoding variants of presumed regulatory function contribute to the heritability of neuropsychiatric disease. A total of 2,221 noncoding variants connected to risk for ten neuropsychiatric disorders, including autism spectrum disorder, attention deficit ...

    Abstract Noncoding variants of presumed regulatory function contribute to the heritability of neuropsychiatric disease. A total of 2,221 noncoding variants connected to risk for ten neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, major depression, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder and schizophrenia, were studied in developing human neural cells. Integrating epigenomic and transcriptomic data with massively parallel reporter assays identified differentially-active single-nucleotide variants (daSNVs) in specific neural cell types. Expression-gene mapping, network analyses and chromatin looping nominated candidate disease-relevant target genes modulated by these daSNVs. Follow-up integration of daSNV gene editing with clinical cohort analyses suggested that magnesium transport dysfunction may increase neuropsychiatric disease risk and indicated that common genetic pathomechanisms may mediate specific symptoms that are shared across multiple neuropsychiatric diseases.
    MeSH term(s) Humans ; Autism Spectrum Disorder/genetics ; Bipolar Disorder/genetics ; Schizophrenia/genetics ; Obsessive-Compulsive Disorder/genetics ; Obsessive-Compulsive Disorder/psychology ; Depressive Disorder, Major/genetics ; Attention Deficit Disorder with Hyperactivity/genetics
    Language English
    Publishing date 2023-10-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/s41588-023-01533-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The dynamic, combinatorial cis-regulatory lexicon of epidermal differentiation.

    Kim, Daniel S / Risca, Viviana I / Reynolds, David L / Chappell, James / Rubin, Adam J / Jung, Namyoung / Donohue, Laura K H / Lopez-Pajares, Vanessa / Kathiria, Arwa / Shi, Minyi / Zhao, Zhixin / Deep, Harsh / Sharmin, Mahfuza / Rao, Deepti / Lin, Shin / Chang, Howard Y / Snyder, Michael P / Greenleaf, William J / Kundaje, Anshul /
    Khavari, Paul A

    Nature genetics

    2021  Volume 53, Issue 11, Page(s) 1564–1576

    Abstract: Transcription factors bind DNA sequence motif vocabularies in cis-regulatory elements (CREs) to modulate chromatin state and gene expression during cell state transitions. A quantitative understanding of how motif lexicons influence dynamic regulatory ... ...

    Abstract Transcription factors bind DNA sequence motif vocabularies in cis-regulatory elements (CREs) to modulate chromatin state and gene expression during cell state transitions. A quantitative understanding of how motif lexicons influence dynamic regulatory activity has been elusive due to the combinatorial nature of the cis-regulatory code. To address this, we undertook multiomic data profiling of chromatin and expression dynamics across epidermal differentiation to identify 40,103 dynamic CREs associated with 3,609 dynamically expressed genes, then applied an interpretable deep-learning framework to model the cis-regulatory logic of chromatin accessibility. This analysis framework identified cooperative DNA sequence rules in dynamic CREs regulating synchronous gene modules with diverse roles in skin differentiation. Massively parallel reporter assay analysis validated temporal dynamics and cooperative cis-regulatory logic. Variants linked to human polygenic skin disease were enriched in these time-dependent combinatorial motif rules. This integrative approach shows the combinatorial cis-regulatory lexicon of epidermal differentiation and represents a general framework for deciphering the organizational principles of the cis-regulatory code of dynamic gene regulation.
    MeSH term(s) Cell Differentiation/genetics ; Chromatin/genetics ; Epidermis/physiology ; Epigenome ; Gene Expression Regulation ; Genes, Reporter ; Genome-Wide Association Study ; Humans ; Keratinocytes/cytology ; Keratinocytes/physiology ; Models, Genetic ; Neural Networks, Computer ; Regulatory Elements, Transcriptional ; Skin Diseases/genetics ; Transcription Factors/genetics
    Chemical Substances Chromatin ; Transcription Factors
    Language English
    Publishing date 2021-10-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/s41588-021-00947-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas.

    Ryan, Russell J H / Petrovic, Jelena / Rausch, Dylan M / Zhou, Yeqiao / Lareau, Caleb A / Kluk, Michael J / Christie, Amanda L / Lee, Winston Y / Tarjan, Daniel R / Guo, Bingqian / Donohue, Laura K H / Gillespie, Shawn M / Nardi, Valentina / Hochberg, Ephraim P / Blacklow, Stephen C / Weinstock, David M / Faryabi, Robert B / Bernstein, Bradley E / Aster, Jon C /
    Pear, Warren S

    Cell reports

    2017  Volume 21, Issue 3, Page(s) 784–797

    Abstract: Gain-of-function Notch mutations are recurrent in mature small B cell lymphomas such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), but the Notch target genes that contribute to B cell oncogenesis are largely unknown. We performed ... ...

    Abstract Gain-of-function Notch mutations are recurrent in mature small B cell lymphomas such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), but the Notch target genes that contribute to B cell oncogenesis are largely unknown. We performed integrative analysis of Notch-regulated transcripts, genomic binding of Notch transcription complexes, and genome conformation data to identify direct Notch target genes in MCL cell lines. This B cell Notch regulome is largely controlled through Notch-bound distal enhancers and includes genes involved in B cell receptor and cytokine signaling and the oncogene MYC, which sustains proliferation of Notch-dependent MCL cell lines via a Notch-regulated lineage-restricted enhancer complex. Expression of direct Notch target genes is associated with Notch activity in an MCL xenograft model and in CLL lymph node biopsies. Our findings provide key insights into the role of Notch in MCL and other B cell malignancies and have important implications for therapeutic targeting of Notch-dependent oncogenic pathways.
    MeSH term(s) Animals ; B-Lymphocytes/metabolism ; Biopsy ; Cell Differentiation/genetics ; Cell Line, Tumor ; Enhancer Elements, Genetic/genetics ; Gene Expression Regulation, Neoplastic ; Gene Rearrangement ; Humans ; Lymph Nodes/metabolism ; Lymph Nodes/pathology ; Lymphoma, B-Cell/genetics ; Lymphoma, B-Cell/pathology ; Mice ; Oncogenes ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Receptors, Notch/genetics ; Receptors, Notch/metabolism ; Signal Transduction ; Tumor Microenvironment ; Xenograft Model Antitumor Assays
    Chemical Substances Proto-Oncogene Proteins c-myc ; Receptors, Notch
    Language English
    Publishing date 2017-10-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2017.09.066
    Database MEDical Literature Analysis and Retrieval System OnLINE

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