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

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Item Type:	Article
Title:	Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator
Creators Name:	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. and Superti-Furga, A.
Abstract:	Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks, 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:	Animal Disease Models, Cell Line, Chromatin, Congenital Limb Deformities, Extremities, Genetic Transcription, Homeodomain Proteins, Long Noncoding RNA, Sequence Deletion, Transcriptional Activation, Transgenic Mice, Animals, Mice
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	592
Number:	7852
Page Range:	93-98
Date:	1 April 2021
Official Publication:	https://doi.org/10.1038/s41586-021-03208-9
PubMed:	View item in PubMed

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