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| Status |
Public on Jul 20, 2021 |
| Title |
Mesomelic Dysplasias Associated With The HOXD Locus Are Caused By Regulatory Reallocations [ChIP-Seq] |
| Sample organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Third-party reanalysis
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| Summary |
Some human families display severe shortening and bending of the radius and ulna, a condition referred to as mesomelic dysplasia. Many of these families contain chromosomal rearrangements at 2q31, where the human HOXD locus maps. In mice, the dominant X-ray-induced Ulnaless inversion of the HoxD gene cluster produces a similar phenotype suggesting that the same pathological mechanism is at work in humans and mice. A tentative hypothesis was proposed where the various alterations to the genomic structure of HOXD could translocate Hoxd13 near to proximal limb enhancers, leading to its deleterious gain-of-expression in the embryonic forelimb. We evaluated this hypothesis by engineering a ca. 1Mb large inversion including the HoxD gene cluster, in order to position Hoxd13 within a chromatin domain rich in proximal limb enhancers. We show that these enhancers contact and activate Hoxd13 in proximal cells, concomitant to the formation of a mesomelic dysplasia phenotype. A secondary mutation in the coding frame of the HOXD13 protein in-cis with the inversion completely rescued the limb alterations, demonstrating that ectopic HOXD13 is indeed the unique cause of this bone anomaly. Single cell expression analysis and evaluation of HOXD13 binding sites in cells from this ectopic expression domain suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.
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| Overall design |
Reanalysis of part of GSM3504924 and GSM3504925 (25 million reads from SRR8290670 and 25 million reads from SRR8290672) to be compared to CUT&RUN HOXD13. All steps of analysis are available in https://github.com/lldelisle/scriptsForBoltEtAl2021/blob/main/CUTandRUN/01_analysis_on_galaxy.sh .
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| Contributor(s) |
Bolt CC, Mascrez B, Lopez-Delisle L, Duboule D |
| Citation(s) |
34408147 |
| Submission date |
Jan 29, 2021 |
| Last update date |
Jun 03, 2024 |
| Contact name |
Lucille Lopez-Delisle |
| E-mail(s) |
lucille.delisle@epfl.ch
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| Organization name |
EPFL
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| Street address |
Station 19
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| City |
Lausanne |
| ZIP/Postal code |
1015 |
| Country |
Switzerland |
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| This SubSeries is part of SuperSeries: |
| GSE165495 |
Mesomelic Dysplasias Associated With The HOXD Locus Are Caused By Regulatory Reallocations |
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| Relations |
| Reanalysis of |
GSM3504924 |
| Reanalysis of |
GSM3504925 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE165761_E11.5_wt_WFL_ChIP_HOXA11_rep1.bw |
156.6 Mb |
(ftp)(http) |
BW |
| GSE165761_E11.5_wt_WFL_ChIP_HOXA11_rep1.narrowPeak.gz |
513.0 Kb |
(ftp)(http) |
NARROWPEAK |
| GSE165761_E11.5_wt_WFL_ChIP_HOXA11_rep2.bw |
146.1 Mb |
(ftp)(http) |
BW |
| GSE165761_E11.5_wt_WFL_ChIP_HOXA11_rep2.narrowPeak.gz |
734.5 Kb |
(ftp)(http) |
NARROWPEAK |
| Processed data are available on Series record |
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