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Series GSE137331 Query DataSets for GSE137331
Status Public on Oct 25, 2020
Title Loss of Maenli lncRNA expression causes engrailed-1 dependent congenital limb malformations [ChIP-seq]
Organism Mus musculus
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Long non-coding RNAs (lncRNAs) can be important components in gene regulatory networks1, but we are only beginning to understand the nature and extent of their involvement in human Mendelian disease. Here we show that deletions of an unannotated lncRNA locus on human chromosome 2 cause a severe congenital limb malformation. Using exome sequencing and array CGH, we identified homozygous 27-63 kb deletions located 300 kb upstream of the engrailed-1 (EN1) gene 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 limb-specific En1 expression and a double dorsal limb phenotype, recapitulating the human malformation. Genome-wide analysis in the developing mouse limb revealed the presence of a 4-exon long non-coding transcript within the deleted region, which we named Maenli (for Master activator of En1 in the limb). Functional dissection of the Maenli locus showed that limb-specific En1 expression depends on transcription of Maenli and its loss resulted in the double dorsal limb phenotype. Concomitant monoallelic inactivation of En1 and Maenli in double heterozygous mice did not rescue the limb phenotype, indicating that En1 activation in the limb requires the cis-acting regulatory element Maenli. Moreover, our results strongly suggest that En1 activation is dependent on Maenli transcription, but not on the Maenli RNA itself. Thus, Maenli expression in the limb acts in cis to promote En1 transcriptional activation; its loss results in congenital malformation of the limbs, a subset of the full En1 associated phenotype. Together, our findings provide evidence that mutations involving lncRNAs loci can result in human Mendelian disease.
 
Overall design We used exome sequencing and array CGH to analyze patients' samples, CRISPR experiments to investigate the effect of the potential pathogenic variants, genome wide analysis to identify a new lncRNA locus, and functional studies to characterize the effect of the knockout lncRNA locus.
Web link https://doi.org/10.1038/s41586-021-03208-9
 
Contributor(s) Allou L
Citation missing Has this study been published? Please login to update or notify GEO.
Submission date Sep 12, 2019
Last update date Feb 09, 2021
Contact name Lila Allou
Organization name Max Planck Institute For Molecular Genetics
Department FG Development and Disease
Lab FG Mundlos
Street address 63-73 Ihnestrasse
City Berlin
ZIP/Postal code 14195
Country Germany
 
Platforms (1)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (39)
GSM4075512 Brain-E95-WT-Mm9-Rep1-1-H3K27ac-ChIP-L16552
GSM4075513 Brain-E95-WT-Mm9-Rep1-2-H3K27ac-ChIP-L16552
GSM4075514 Brain-E95-WT-Mm9-Rep1-H3K4me3-ChIP-L16554
This SubSeries is part of SuperSeries:
GSE137335 Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator
Relations
BioProject PRJNA565202
SRA SRP221476

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE137331_FLHL-E115-3xpA-Mm9-Merge-CTCF-ChIP.bw 845.6 Mb (ftp)(http) BW
GSE137331_FLHL-E115-3xpA-Mm9-Merge-H3K27ac-ChIP.bw 251.1 Mb (ftp)(http) BW
GSE137331_FLHL-E115-3xpA-Mm9-Merge-H3K4me1-ChIP.bw 1.8 Gb (ftp)(http) BW
GSE137331_FLHL-E115-3xpA-Mm9-Merge-H3K4me3-ChIP.bw 618.3 Mb (ftp)(http) BW
GSE137331_FLHL-E115-3xpA-Mm9-Merge-Rad21-ChIP.bw 882.5 Mb (ftp)(http) BW
GSE137331_FLHL-E115-Del27-Mm9-Merge-H3K4me3-ChIP.bw 494.6 Mb (ftp)(http) BW
GSE137331_FLHL-E115-WT-Mm9-Merge-CTCF-ChIP.bw 845.6 Mb (ftp)(http) BW
GSE137331_FLHL-E115-WT-Mm9-Merge-H3K27ac-ChIP.bw 251.1 Mb (ftp)(http) BW
GSE137331_FLHL-E115-WT-Mm9-Merge-H3K4me1-ChIP.bw 857.5 Mb (ftp)(http) BW
GSE137331_FLHL-E115-WT-Mm9-Merge-H3K4me3-ChIP.bw 279.2 Mb (ftp)(http) BW
GSE137331_FLHL-E115-WT-Mm9-Merge-Rad21-ChIP.bw 882.5 Mb (ftp)(http) BW
GSE137331_RAW.tar 2.3 Gb (http)(custom) TAR (of BW)
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Raw data are available in SRA
Processed data provided as supplementary file
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