Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator.

Details

Serval ID
serval:BIB_C3BBE7F51AD8
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator.
Journal
Nature
Author(s)
Allou L., Balzano S., Magg A., Quinodoz M., Royer-Bertrand B., Schöpflin R., Chan W.L., Speck-Martins C.E., Carvalho D.R., Farage L., Lourenço C.M., Albuquerque R., Rajagopal S., Nampoothiri S., Campos-Xavier B., Chiesa C., Niel-Bütschi F., Wittler L., Timmermann B., Spielmann M., Robson M.I., Ringel A., Heinrich V., Cova G., Andrey G., Prada-Medina C.A., Pescini-Gobert R., Unger S., Bonafé L., Grote P., Rivolta C., Mundlos S., Superti-Furga A.
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Publication state
Published
Issued date
04/2021
Peer-reviewed
Oui
Volume
592
Number
7852
Pages
93-98
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks <sup>1</sup> , but the exact nature and extent of their involvement in human Mendelian disease is largely unknown. Here we show that genetic ablation of a lncRNA locus on human chromosome 2 causes a severe congenital limb malformation. We identified homozygous 27-63-kilobase deletions located 300 kilobases upstream of the engrailed-1 gene (EN1) in patients with a complex limb malformation featuring mesomelic shortening, syndactyly and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of En1 expression in the limb and a double dorsal-limb phenotype that recapitulates the human disease phenotype. Genome-wide transcriptome analysis in the developing mouse limb revealed a four-exon-long non-coding transcript within the deleted region, which we named Maenli. Functional dissection of the Maenli locus showed that its transcriptional activity is required for limb-specific En1 activation in cis, thereby fine-tuning the gene-regulatory networks controlling dorso-ventral polarity in the developing limb bud. Its loss results in the En1-related dorsal ventral limb phenotype, a subset of the full En1-associated phenotype. Our findings demonstrate that mutations involving lncRNA loci can result in human Mendelian disease.
Keywords
Animals, Cell Line, Chromatin/genetics, Disease Models, Animal, Extremities, Female, Homeodomain Proteins/genetics, Humans, Limb Deformities, Congenital/genetics, Mice, Mice, Transgenic, RNA, Long Noncoding/genetics, Sequence Deletion/genetics, Transcription, Genetic, Transcriptional Activation/genetics
Pubmed
Web of science
Create date
22/02/2021 12:43
Last modification date
05/05/2021 6:36
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