The patients have single short fingers (metacarpals) and toes (metatarsals) and can be restricted in growth due to a shortened skeleton. This hereditary disease is called brachydactyly type E (Greek for short fingers). Three years ago Dr. Philipp G. Maass from the research group of Professor Friedrich C. Luft at the Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charit- Medical Faculty and the Max Delbr-ck Center for Molecular Medicine (MDC) in Berlin-Buch, has discovered an epigenetic mechanism, which, when dysregulated, causes this condition. Now, together with Dr. Sylvia B-hring (ECRC) he was able to show how this epigenetic regulator functions and influences the development of the skeleton and the extremities. Also, he shed light on a new principle of gene regulation (Journal of Clinical Investigation, doi: 10.1172/JCI65508)*.
The gene causing brachydactyly type E (BDE) is PTHLH (the abbreviation stands for parathyroid hormone like hormone), and belongs to a group of genes that regulate the development of cartilage and determine subsequent skeletal structure. The researchers investigated two families with BDE. The patients exhibit shortened metacarpals, involved in forming the hands and feet, but had no other clinical symptoms.
Up to now, more than ten different forms of brachydactyly are known. The features of the hands and feet are variable depending upon which type of brachydactyly a patient has. Sometimes, the brachydactyly can be associated with hypertension, mental retardation, or other medical problems.
Several new findings
The gene PTHLH is located on chromosome 12, one of the 46 chromosomes of the human genome. The gene exerts considerably influence on cartilage during development and early life. However, little was known about the regulation of this gene. Now, Dr. Maass, Dr. B-hring and Professor Luft have detected an epigenetic regulator for the gene PTHLH on chromosome 12 and in the course of their research made several new findings.
First, they could show, that the gene regulator interacts with genes over very long distances on the same chromosome (cis) and that it also is able to regulate genes on other chromosomes (trans). Thus, the tongue-twister name for this regulator: cis and trans-chromosomal communicator acting through DNA and noncoding RNA (CISTR-ACT).
Second, the team showed that because of a balanced translocation, CISTR-ACT is misplaced, so that the regulator no longer can properly influence PTHLH function.
Third, CISTR-ACT encodes a so-called long noncoding RNA that participates in the regulatory functions. This finding encompasses a new principle in gene regulation. Epigenetics refers to inherited mechanisms that occur without alterations in the DNA gene sequence. In this form of BDE, no change in the DNA sequence of coding genes is responsible for the condition.
Back to the first finding, the epigenetic regulator CISTR-ACT on chromosome 12 manages to get in touch with the gene PTHLH over a distance of 24 million base pairs. "The largest ever measured distance between a gene regulator and a gene on the same chromosome was around one million base-pairs", explains Dr. Maass. Furthermore, CISTR-ACT regulates another developmental gene (SOX9) on chromosome 17. "This finding is extraordinary," comments Dr. Maass.
How is this regulation possible? The researchers found the solution at the chromatin level, in which the chromosomes are densely packed. "Just imagine a ball of wool in which different threads actually touch each other at special points. At one point you have the gene, the other point symbolizes the gene regulator. "It is through this physical contact that CISTR-ACT regulates certain genes such as PTHLH very precisely in a specific tissue," Dr. Maass and Dr. B-hring explain. The researchers could thus show that huge chromosomal loops build up on chromosome 12. Moreover, the epigenetic regulator, CISTR-ACT on chromosome 12 is somehow able to get in touch with its target SOX9 on chromosome 17.
Translocation on different chromosomes