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| Status |
Public on Jul 20, 2021 |
| Title |
Mesomelic Dysplasias Associated With The HOXD Locus Are Caused By Regulatory Reallocations [CUT&RUN] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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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 |
wild type and mutant (inv2) tissue samples were collected from E12.5 mouse embryos. Proximal limbs, distal limbs, and forebrain were collected and processed according to the CUT&RUN protocol described in Skene et al. Nature Protocols, 2018
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| Contributor(s) |
Bolt CC, Mascrez B, Lopez-Delisle L, Duboule D |
| Citation(s) |
34408147 |
| |
| Submission date |
Jan 25, 2021 |
| Last update date |
Jan 20, 2022 |
| Contact name |
Lucille Lopez-Delisle |
| E-mail(s) |
lucille.delisle@epfl.ch
|
| Organization name |
EPFL
|
| Street address |
Station 19
|
| City |
Lausanne |
| ZIP/Postal code |
1015 |
| Country |
Switzerland |
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| Platforms (2) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (9)
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| GSM5034644 |
E12.5 inv2 proximal forelimb CR_CTCF |
| GSM5034645 |
E12.5 inv2 distal forelimb CR_CTCF |
| GSM5034646 |
E12.5 wild type distal forelimb, replicate 1 CR_HOXD13 |
| GSM5034647 |
E12.5 wild type distal forelimb, replicate 2 CR_HOXD13 |
| GSM5034648 |
E12.5 inv2 posterior proximal forelimb, replicate 1 CR_HOXD13 |
| GSM5034649 |
E12.5 inv2 posterior proximal forelimb, replicate 2 CR_HOXD13 |
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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 |
| BioProject |
PRJNA694685 |
| SRA |
SRP303201 |
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