Antisense Transcription in Loci Associated to Hereditary Neurodegenerative Diseases

FANTOM Consortium

Research output: Contribution to journalArticle

Abstract

Natural antisense transcripts are common features of mammalian genes providing additional regulatory layers of gene expression. A comprehensive description of antisense transcription in loci associated to familial neurodegenerative diseases may identify key players in gene regulation and provide tools for manipulating gene expression. We take advantage of the FANTOM5 sequencing datasets that represent the largest collection to date of genome-wide promoter usage in almost 2000 human samples. Transcription start sites (TSSs) are mapped at high resolution by the use of a modified protocol of cap analysis of gene expression (CAGE) for high-throughput single molecule next-generation sequencing with Helicos (hCAGE). Here we present the analysis of antisense transcription at 17 loci associated to hereditary Alzheimer’s disease, Frontotemporal Dementia, Parkinson’s disease, Amyotrophic Lateral Sclerosis, and Huntington’s disease. We focused our analysis on libraries derived from brain tissues and primary cells. We also screened libraries from total blood and blood cell populations in the quest for peripheral biomarkers of neurodegenerative diseases. We identified 63 robust promoters in antisense orientation to genes associated to familial neurodegeneration. When applying a less stringent cutoff, this number increases to over 400. A subset of these promoters represents alternative TSSs for 24 FANTOM5 annotated long noncoding RNA (lncRNA) genes, in antisense orientation to 13 of the loci analyzed here, while the remaining contribute to the expression of additional transcript variants. Intersection with GWAS studies, sample ontology, and dynamic expression reveals association to specific genetic traits as well as cell and tissue types, not limited to neurodegenerative diseases. Antisense transcription was validated for a subset of genes, including those encoding for Microtubule-Associated Protein Tau, α-synuclein, Parkinsonism-associated deglycase DJ-1, and Leucin-Rich Repeat Kinase 2. This work provides evidence for the existence of additional regulatory mechanisms of the expression of neurodegenerative disease-causing genes by previously not-annotated and/or not-validated antisense long noncoding RNAs.

Original languageEnglish
Pages (from-to)5392-5415
Number of pages24
JournalMolecular Neurobiology
Volume56
Issue number8
DOIs
Publication statusPublished - 15 Aug 2019

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Nervous System Heredodegenerative Disorders
Neurodegenerative Diseases
Long Noncoding RNA
Genes
Transcription Initiation Site
Gene Expression
Libraries
Synucleins
Frontotemporal Dementia
Inborn Genetic Diseases
Microtubule-Associated Proteins
Genome-Wide Association Study
Huntington Disease
Amyotrophic Lateral Sclerosis
Regulator Genes
Parkinson Disease
Blood Cells
Alzheimer Disease
Phosphotransferases
Biomarkers

Cite this

@article{a88f87956e2c44d287e1764b15c76005,
title = "Antisense Transcription in Loci Associated to Hereditary Neurodegenerative Diseases",
abstract = "Natural antisense transcripts are common features of mammalian genes providing additional regulatory layers of gene expression. A comprehensive description of antisense transcription in loci associated to familial neurodegenerative diseases may identify key players in gene regulation and provide tools for manipulating gene expression. We take advantage of the FANTOM5 sequencing datasets that represent the largest collection to date of genome-wide promoter usage in almost 2000 human samples. Transcription start sites (TSSs) are mapped at high resolution by the use of a modified protocol of cap analysis of gene expression (CAGE) for high-throughput single molecule next-generation sequencing with Helicos (hCAGE). Here we present the analysis of antisense transcription at 17 loci associated to hereditary Alzheimer’s disease, Frontotemporal Dementia, Parkinson’s disease, Amyotrophic Lateral Sclerosis, and Huntington’s disease. We focused our analysis on libraries derived from brain tissues and primary cells. We also screened libraries from total blood and blood cell populations in the quest for peripheral biomarkers of neurodegenerative diseases. We identified 63 robust promoters in antisense orientation to genes associated to familial neurodegeneration. When applying a less stringent cutoff, this number increases to over 400. A subset of these promoters represents alternative TSSs for 24 FANTOM5 annotated long noncoding RNA (lncRNA) genes, in antisense orientation to 13 of the loci analyzed here, while the remaining contribute to the expression of additional transcript variants. Intersection with GWAS studies, sample ontology, and dynamic expression reveals association to specific genetic traits as well as cell and tissue types, not limited to neurodegenerative diseases. Antisense transcription was validated for a subset of genes, including those encoding for Microtubule-Associated Protein Tau, α-synuclein, Parkinsonism-associated deglycase DJ-1, and Leucin-Rich Repeat Kinase 2. This work provides evidence for the existence of additional regulatory mechanisms of the expression of neurodegenerative disease-causing genes by previously not-annotated and/or not-validated antisense long noncoding RNAs.",
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author = "{FANTOM Consortium} and Silvia Zucchelli and Stefania Fedele and Paolo Vatta and Raffaella Calligaris and Peter Heutink and Patrizia Rizzu and Masayoshi Itoh and Francesca Persichetti and Claudio Santoro and Hideya Kawaji and Timo Lassmann and Yoshihide Hayashizaki and Piero Carninci and Forrest, {Alistair R.R.} and Stefano Gustincich",
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Antisense Transcription in Loci Associated to Hereditary Neurodegenerative Diseases. / FANTOM Consortium.

In: Molecular Neurobiology, Vol. 56, No. 8, 15.08.2019, p. 5392-5415.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Antisense Transcription in Loci Associated to Hereditary Neurodegenerative Diseases

AU - FANTOM Consortium

AU - Zucchelli, Silvia

AU - Fedele, Stefania

AU - Vatta, Paolo

AU - Calligaris, Raffaella

AU - Heutink, Peter

AU - Rizzu, Patrizia

AU - Itoh, Masayoshi

AU - Persichetti, Francesca

AU - Santoro, Claudio

AU - Kawaji, Hideya

AU - Lassmann, Timo

AU - Hayashizaki, Yoshihide

AU - Carninci, Piero

AU - Forrest, Alistair R.R.

AU - Gustincich, Stefano

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AB - Natural antisense transcripts are common features of mammalian genes providing additional regulatory layers of gene expression. A comprehensive description of antisense transcription in loci associated to familial neurodegenerative diseases may identify key players in gene regulation and provide tools for manipulating gene expression. We take advantage of the FANTOM5 sequencing datasets that represent the largest collection to date of genome-wide promoter usage in almost 2000 human samples. Transcription start sites (TSSs) are mapped at high resolution by the use of a modified protocol of cap analysis of gene expression (CAGE) for high-throughput single molecule next-generation sequencing with Helicos (hCAGE). Here we present the analysis of antisense transcription at 17 loci associated to hereditary Alzheimer’s disease, Frontotemporal Dementia, Parkinson’s disease, Amyotrophic Lateral Sclerosis, and Huntington’s disease. We focused our analysis on libraries derived from brain tissues and primary cells. We also screened libraries from total blood and blood cell populations in the quest for peripheral biomarkers of neurodegenerative diseases. We identified 63 robust promoters in antisense orientation to genes associated to familial neurodegeneration. When applying a less stringent cutoff, this number increases to over 400. A subset of these promoters represents alternative TSSs for 24 FANTOM5 annotated long noncoding RNA (lncRNA) genes, in antisense orientation to 13 of the loci analyzed here, while the remaining contribute to the expression of additional transcript variants. Intersection with GWAS studies, sample ontology, and dynamic expression reveals association to specific genetic traits as well as cell and tissue types, not limited to neurodegenerative diseases. Antisense transcription was validated for a subset of genes, including those encoding for Microtubule-Associated Protein Tau, α-synuclein, Parkinsonism-associated deglycase DJ-1, and Leucin-Rich Repeat Kinase 2. This work provides evidence for the existence of additional regulatory mechanisms of the expression of neurodegenerative disease-causing genes by previously not-annotated and/or not-validated antisense long noncoding RNAs.

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KW - Long noncoding RNA

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