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In Vivo Modeling of the Morbid Human Genome using Danio rerio
Published on: August 24, 2013
A misplaced lncRNA causes brachydactyly in humans
Philipp G Maass1, Andreas Rump, Herbert Schulz
1Experimental and Clinical Research Center, joint cooperation between Charité Medical Faculty and Max Delbrück Center for Molecular Medicine, Berlin, Germany.
The Journal of Clinical Investigation
|October 25, 2012
Summary
Chromosomal translocations disrupting gene regulation cause brachydactyly type E (BDE). A novel DNA and long noncoding RNA (lncRNA) element regulates gene expression through cis and trans interactions, revealing a feedback network.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Chromosomal translocations are linked to diseases and developmental disorders.
- Brachydactyly type E (BDE) is a rare condition affecting finger and toe bone development.
Purpose of the Study:
- To investigate the genetic basis of BDE in two families with translocations on chromosome 12p.
- To identify and characterize a novel regulatory element involved in gene expression and its role in BDE.
Main Methods:
- Chromosome conformation capturing to identify long-range cis-regulatory interactions.
- Gene silencing techniques (lncRNA, PTHLH, SOX9) to study gene networks.
- Analysis of gene expression in BDE patients.
Main Results:
- Translocations on chromosome 12p disrupted the cis-regulatory landscape, downregulating the parathyroid hormone-like hormone (PTHLH) gene.
- A novel regulatory element on chromosome 12q was identified, interacting with PTHLH (cis) and SOX9 (trans).
- This element harbors a long noncoding RNA (lncRNA) involved in a feedback mechanism with PTHLH and SOX9.
- In BDE patients, lncRNA was upregulated, and its occupancy at the PTHLH locus was reduced due to disrupted chromosomal association.
Conclusions:
- A novel cis- and trans-acting DNA and lncRNA regulatory feedback element has been identified.
- This element is reciprocally regulated by coding genes and plays a role in normal development.
- Findings offer a combinatorial view of how lncRNA-encoding enhancers affect gene expression.
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