|
| Status |
Public on Oct 01, 2018 |
| Title |
Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis |
| Organism |
Mus musculus |
| Experiment type |
Other
|
| Summary |
The regulatory specificity of enhancers and their interaction with gene promoters is thought to be controlled by their sequence and the binding of transcription factors. By studying Pitx1, a regulator of hindlimb development, we show that dynamic changes in chromatin conformation can restrict the activity of enhancers. Inconsistent with its hindlimb-restricted expression, Pitx1 is controlled by an enhancer (Pen) that shows activity in forelimbs and hindlimbs. By Capture Hi-C and three-dimensional modeling of the locus, we demonstrate that forelimbs and hindlimbs have fundamentally different chromatin configurations, whereby Pen and Pitx1 interact in hindlimbs and are physically separated in forelimbs. Structural variants can convert the inactive into the active conformation, thereby inducing Pitx1 misexpression in forelimbs, causing partial arm-to-leg transformation in mice and humans. Thus, tissue-specific three-dimensional chromatin conformation can contribute to enhancer activity and specificity in vivo and its disturbance can result in gene misexpression and disease.
|
| |
|
| Overall design |
We used capture Hi-C enriching a 3Mb region at the Pitx1 locus in Mus musculus. We analysed four biological replicates of wild type and two biological replicates of CRISPR-Cas9 genome engineered structural variants and indel mutant tissues. Micro-dissected embryonic E11.5 forelimb and hindlimb tissues as well as E10.5 midbrain tissue were used as starting material. In total nine mouse mutants were used.
|
| |
|
| Contributor(s) |
Kragesteen BK, Andrey G |
| Citation(s) |
30262816 |
| Submission date |
Sep 11, 2017 |
| Last update date |
Aug 02, 2023 |
| Contact name |
Guillaume Andrey |
| E-mail(s) |
guillaume.andrey@unige.ch
|
| Phone |
+41223795703
|
| Organization name |
University of Geneva
|
| Department |
Department of Genetic Medicine and Development
|
| Street address |
Rue Michel-Servet 1
|
| City |
Geneva |
| ZIP/Postal code |
1211 |
| Country |
Switzerland |
| |
|
| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
|
| Samples (22)
|
|
| Relations |
| BioProject |
PRJNA404033 |
| SRA |
SRP117231 |
Less...
More...