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3 results on '"genetics [Enhancer Elements, Genetic]"'

1. Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease

Author

Clemens R. Scherzer, Ganqiang Liu, Ferenc Müller, David Gritsch, Patrizia Rizzu, Peter T. Nelson, Xianjun Dong, Cornelis Blauwendraat, Boris Guennewig, John S. Mattick, Joseph J. Locascio, Yunfei Bai, Zhixiang Liao, Peter Heutink, Tao Wang, Matthew P. Frosch, Charles H. Adler, Yavor Hadzhiev, Thomas G. Beach, Richard L.M. Faull, John C. Hedreen, and Antony A. Cooper

Subjects
Male, 0301 basic medicine, Quantitative Trait Loci, Enhancer RNAs, Biology, genetics [Mental Disorders], Genome, Article, 03 medical and health sciences, 0302 clinical medicine, pathology [Brain], Dopamine, ddc:570, medicine, Animals, Humans, physiology [Dopaminergic Neurons], Enhancer, Zebrafish, Regulation of gene expression, genetics [Quantitative Trait Loci], Dopaminergic Neurons, Mental Disorders, General Neuroscience, Brain, Genetic Variation, pathology [Mental Disorders], genetics [Enhancer Elements, Genetic], Human brain, biology.organism_classification, genetics [Genetic Variation], 3. Good health, Enhancer Elements, Genetic, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, Expression quantitative trait loci, Female, Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract

Enhancers function as DNA logic gates and may control specialized functions of billions of neurons. Here we show a tailored program of noncoding genome elements active in situ in physiologically distinct dopamine neurons of the human brain. We found 71,022 transcribed noncoding elements, many of which were consistent with active enhancers and with regulatory mechanisms in zebrafish and mouse brains. Genetic variants associated with schizophrenia, addiction, and Parkinson’s dis- ease were enriched in these elements. Expression quantitative trait locus analysis revealed that Parkinson’s disease-associated variants on chromosome 17q21 cis-regulate the expression of an enhancer RNA in dopamine neurons. This study shows that enhancers in dopamine neurons link genetic variation to neuropsychiatric traits.

Published
2018

2. An atlas of human long non-coding RNAs with accurate 5′ ends

Author

Yukio Nakamura, Mickal Mendez, Julian Gough, Jessica Severin, Owen J. L. Rackham, Dave Tang, A. Maxwell Burroughs, Masayoshi Itoh, Timo Lassmann, Carsten O. Daub, Leonard Lipovich, Erik Arner, Yoshihide Hayashizaki, Sarah Djebali, Soichi Kojima, Magda Babina, Shohei Noma, Piero Carninci, Hideya Kawaji, Sebastian Schmeier, Peter Heutink, Yulia A. Medvedeva, Tanvir Alam, Alison C. Testa, Elena Denisenko, Marina Lizio, Christine A. Wells, Chi Wai Yip, Akira Hasegawa, Jordan A. Ramilowski, Alistair R. R. Forrest, Michiel J. L. de Hoon, Harukazu Suzuki, Takeya Kasukawa, Nicolas Bertin, Thomas M. Poulsen, Imad Abugessaisa, Jayson Harshbarger, Chung-Chau Hon, Ctr Life Sci Technol, Div Gen Technol, Tsurumi Ku, RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Omics Sci Ctr, Tsurumi Ku, Ctr Translat Med, Canc Sci Inst Singapore, National University of Singapore (NUS), Human Longev Singapore Pte Ltd, Dept Comp Sci, Life Sci, University of Bristol [Bristol], Cardiovasc & Metab Disorders, Duke-NUS Medical School [Singapore], Inst Nat & Math Sci, Biotechnol Res Inst Drug Discovery BRD, Natl Inst Adv Ind Sci & Technol, Prevent Med & Diag Innovat Program, Natl Lib Med, Natl Ctr Biotechnol Informat, Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Ctr Gen Regulat CRG, Barcelona Institute of Science and Technology (BIST), Universitat Pompeu Fabra [Barcelona] (UPF), Computat Biosci Res Ctr, Comp Elect & Math Sci & Engn Div, King Abdullah University of Science and Technology (KAUST), Biotechnol Res Ctr, Inst Bioengn, the Russian Academy of Sciences [Moscow, Russia] (RAS), Vavilov Inst Gen Genet, Russian Academy of Sciences [Moscow] (RAS), QEII Med Ctr, Harry Perkins Inst Med Res, The University of Western Australia (UWA), Med Res Ctr, Ctr Mol Med & Genet, Wayne State University [Detroit], Sch Med, Dept Neurol, Dept Comp Sci, North Dakota State University (NDSU), Telethon Kids Inst, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Dept Dermatol & Allergy, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Australian Inst Bioengn & Nanotechno, University of Queensland [Brisbane], Fac Med, Dept Anat & Neurosci, University of Melbourne, CLST Div Biofunct Dynam Imaging, BioResource Ctr, Cell Engn Div, Université de Tsukuba = University of Tsukuba, Dept Biosci & Nutr, Karolinska Institute, QEII Med Ctr, Harry Perkins Inst Med Re, Duke NUS Medical School, Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-École nationale supérieure agronomique de Toulouse [ENSAT], Universitat Pompeu Fabra [Barcelona], Russian Academy of Sciences, Wayne State University, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, and University of Tsukuba

Subjects
0301 basic medicine, RNA Stability, [SDV]Life Sciences [q-bio], genetics [Transcriptome], Datasets as Topic, genetics [RNA, Long Noncoding], Genome, Epigenesis, Genetic, 0302 clinical medicine, Databases, Genetic, Promoter Regions, Genetic, Cells, Cultured, Conserved Sequence, Genetics, Regulation of gene expression, Multidisciplinary, genetics [Organ Specificity], Genomics, Enhancer Elements, Genetic, annotation, Organ Specificity, 030220 oncology & carcinogenesis, RNA, Long Noncoding, ddc:500, pr interval, transcription, architecture, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, genetics [RNA, Messenger], 03 medical and health sciences, seq, evolution, genetics [Conserved Sequence], Humans, genetics [Genome, Human], RNA, Messenger, Gene, Internet, genetics [Quantitative Trait Loci], Genome, Human, Gene Expression Profiling, genetics [Enhancer Elements, Genetic], Molecular Sequence Annotation, landscape, gene-expression, Cap analysis gene expression, promoter usage, Gene expression profiling, chemistry [RNA, Long Noncoding], 030104 developmental biology, Gene Expression Regulation, genetics [Promoter Regions, Genetic], Expression quantitative trait loci, genome-wide association, Human genome, Transcriptome, Genome-Wide Association Study
Abstract

Long non-coding RNAs (lncRNAs) are largely heterogeneous and functionally uncharacterized. Here, using FANTOM5 cap analysis of gene expression (CAGE) data, we integrate multiple transcript collections to generate a comprehensive atlas of 27,919 human lncRNA genes with high-confidence 5' ends and expression profiles across 1,829 samples from the major human primary cell types and tissues. Genomic and epigenomic classification of these lncRNAs reveals that most intergenic lncRNAs originate from enhancers rather than from promoters. Incorporating genetic and expression data, we show that lncRNAs overlapping trait-associated single nucleotide polymorphisms are specifically expressed in cell types relevant to the traits, implicating these lncRNAs in multiple diseases. We further demonstrate that lncRNAs overlapping expression quantitative trait loci (eQTL)-associated single nucleotide polymorphisms of messenger RNAs are co-expressed with the corresponding messenger RNAs, suggesting their potential roles in transcriptional regulation. Combining these findings with conservation data, we identify 19,175 potentially functional lncRNAs in the human genome.

Published
2017

3. Restricted leucine zipper dimerization and specificity of DNA recognition of the melanocyte master regulator MITF

Author

Vivian Pogenberg, Margret H. Ogmundsdottir, Kristin Bergsteinsdottir, Alexander Schepsky, Eiríkur Steingrímsson, Morlin Milewski, Matthias Wilmanns, Bengt Phung, and Viktor Deineko

Subjects
Models, Molecular, chemistry [Microphthalmia-Associated Transcription Factor], Leucine zipper, Zipper, Molecular Sequence Data, Basic helix-loop-helix leucine zipper transcription factors, genetics [DNA-Binding Proteins], Biology, DNA-binding protein, Mice, ddc:570, metabolism [Microphthalmia-Associated Transcription Factor], Genetics, genetics [Leucine Zippers], Animals, Humans, STXBP1, Waardenburg Syndrome, Amino Acid Sequence, Transcription factor, Leucine Zippers, Microphthalmia-Associated Transcription Factor, integumentary system, genetics [Enhancer Elements, Genetic], chemistry [DNA-Binding Proteins], Microphthalmia-associated transcription factor, genetics [Waardenburg Syndrome], Protein Structure, Tertiary, DNA-Binding Proteins, body regions, Enhancer Elements, Genetic, Mutation, metabolism [DNA-Binding Proteins], Dimerization, Sequence Alignment, genetics [Microphthalmia-Associated Transcription Factor], Protein Binding, Research Paper, Developmental Biology, IRF4
Abstract

Microphthalmia-associated transcription factor (MITF) is a master regulator of melanocyte development and an important oncogene in melanoma. MITF heterodimeric assembly with related basic helix–loop–helix leucine zipper transcription factors is highly restricted, and its binding profile to cognate DNA sequences is distinct. Here, we determined the crystal structure of MITF in its apo conformation and in the presence of two related DNA response elements, the E-box and M-box. In addition, we investigated mouse and human Mitf mutations to dissect the functional significance of structural features. Owing to an unusual three-residue shift in the leucine zipper register, the MITF homodimer shows a marked kink in one of the two zipper helices to allow an out-of-register assembly. Removal of this insertion relieves restricted heterodimerization by MITF and permits assembly with the transcription factor MAX. Binding of MITF to the M-box motif is mediated by an unusual nonpolar interaction by Ile212, a residue that is mutated in mice and humans with Waardenburg syndrome. As several related transcription factors have low affinity for the M-box sequence, our analysis unravels how these proteins discriminate between similar target sequences. Our data provide a rational basis for targeting MITF in the treatment of important hereditary diseases and cancer.

Published
2012

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