title: Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7.
abstract: What causes the tissue-specific pathology of diseases resulting from mutations in housekeeping genes? Specifically, in spinocerebellar ataxia type 7 (SCA7), a neurodegenerative disorder caused by a CAG-repeat expansion in ATXN7 (which encodes an essential component of the mammalian transcription coactivation complex, STAGA), the factors underlying the characteristic progressive cerebellar and retinal degeneration in patients were unknown. We found that STAGA is required for the transcription initiation of miR-124, which in turn mediates the post-transcriptional cross-talk between lnc-SCA7, a conserved long noncoding RNA, and ATXN7 mRNA. In SCA7, mutations in ATXN7 disrupt these regulatory interactions and result in a neuron-specific increase in ATXN7 expression. Strikingly, in mice this increase is most prominent in the SCA7 disease-relevant tissues, namely the retina and cerebellum. Our results illustrate how noncoding RNA-mediated feedback regulation of a ubiquitously expressed housekeeping gene may contribute to specific neurodegeneration.
authors.affiliation: MRC Functional Genomics Unit, University of Oxford, Oxford, UK.|University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, United Kingdom.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Tan
authors.affiliation: MRC Functional Genomics Unit, University of Oxford, Oxford, UK.|University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, United Kingdom.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Vance
authors.affiliation: University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, United Kingdom.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Varela
authors.affiliation: MRC Functional Genomics Unit, University of Oxford, Oxford, UK.|University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, United Kingdom.
authors.forename: Tamara
authors.initials: T
authors.lastname: Sirey
authors.affiliation: University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, United Kingdom.|University of Cape Town, Division of Human Genetics, Cape Town, South Africa.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Watson
authors.affiliation: University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, United Kingdom.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Curtis
authors.affiliation: Centre de Recherche de l'Institut du Cerveau et de la Moëlle épinière, Hôpital de la Pitié-Salpêtrière, Paris, France.|Université Pierre et Marie Curie-Paris 6, Paris, France.|Inserm, U 975, Paris, France.|CNRS, UMR 7225, Paris, France.|Département de Génétique et Cytogénétique, APHP, GH Pitié-Salpêtrière, Paris, France.
authors.forename: Martina
authors.initials: M
authors.lastname: Marinello
authors.affiliation: Centre de Recherche de l'Institut du Cerveau et de la Moëlle épinière, Hôpital de la Pitié-Salpêtrière, Paris, France.|Université Pierre et Marie Curie-Paris 6, Paris, France.|Inserm, U 975, Paris, France.|CNRS, UMR 7225, Paris, France.|Département de Génétique et Cytogénétique, APHP, GH Pitié-Salpêtrière, Paris, France.
authors.forename: Sandro
authors.initials: S
authors.lastname: Alves
authors.affiliation: Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Bruno
authors.initials: B
authors.lastname: Steinkraus
authors.affiliation: University of Oxford, Department of Biochemistry, Oxford, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Cooper
authors.affiliation: University of Oxford, Department of Biochemistry, Oxford, United Kingdom.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Nesterova
authors.affiliation: University of Oxford, Department of Biochemistry, Oxford, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Brockdorff
authors.affiliation: Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Tudor
authors.initials: T
authors.lastname: Fulga
authors.affiliation: Centre de Recherche de l'Institut du Cerveau et de la Moëlle épinière, Hôpital de la Pitié-Salpêtrière, Paris, France.|Université Pierre et Marie Curie-Paris 6, Paris, France.|Inserm, U 975, Paris, France.|CNRS, UMR 7225, Paris, France.|Département de Génétique et Cytogénétique, APHP, GH Pitié-Salpêtrière, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: Centre de Recherche de l'Institut du Cerveau et de la Moëlle épinière, Hôpital de la Pitié-Salpêtrière, Paris, France.|Université Pierre et Marie Curie-Paris 6, Paris, France.|Inserm, U 975, Paris, France.|CNRS, UMR 7225, Paris, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Sittler
authors.affiliation: MRC Functional Genomics Unit, University of Oxford, Oxford, UK.|University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, United Kingdom.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Oliver
authors.affiliation: University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, United Kingdom.|University of Cape Town, Division of Human Genetics, Cape Town, South Africa.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wood
authors.affiliation: MRC Functional Genomics Unit, University of Oxford, Oxford, UK.|University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, United Kingdom.
authors.forename: Chris P
authors.initials: CP
authors.lastname: Ponting
authors.affiliation: MRC Functional Genomics Unit, University of Oxford, Oxford, UK.|University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, United Kingdom.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Marques
mesh_terms: D000818:Animals; D000067719:Ataxin-7; D045744:Cell Line, Tumor; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D025461:Feedback, Physiological; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D061785:Transcription Initiation, Genetic
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D062085:RNA, Long Noncoding; D012333:RNA, Messenger