Antisense Transcription in Loci Associated to Hereditary Neurodegenerative Diseases

Silvia Zucchelli, Stefania Fedele, Paolo Vatta, Raffaella Calligaris, Peter Heutink, Patrizia Rizzu, Masayoshi Itoh, Francesca Persichetti, Claudio Santoro, Hideya Kawaji, Timo Lassmann, Yoshihide Hayashizaki, Piero Carninci, Alistair R. R. Forrest, Stefano Gustincich, FANTOM Consortium

Research output: Contribution to journalArticleAcademicpeer-review

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
Early online date2019
DOIs
Publication statusPublished - 15 Aug 2019

Cite this

Zucchelli, S., Fedele, S., Vatta, P., Calligaris, R., Heutink, P., Rizzu, P., ... FANTOM Consortium (2019). Antisense Transcription in Loci Associated to Hereditary Neurodegenerative Diseases. Molecular Neurobiology, 56(8), 5392-5415. https://doi.org/10.1007/s12035-018-1465-2