Scientists find impaired chromatin structure formation & imprinted gene involvement in Rett Syndrome
December 20, 2004 - A research team led by Terumi Kohwi-Shigematsu of the Life Sciences Division of Lawrence Berkeley National Laboratory has identified a gene, DLX5, that may play a role in the pathology of Rett Syndrome, a devastating neurological disorder diagnosed almost exclusively in girls. Their findings are reported in the January issue of Nature Genetics and currently available online. The team also found that Rett Syndrome is associated with impaired three-dimensional chromatin folding.
Children with Rett Syndrome (RTT) appear to develop normally until 6 to 18 months of age, when they enter a period of regression, losing speech and motor skills. Most develop repetitive hand movements, irregular breathing patterns, seizures and motor control problems. RTT leaves its victims profoundly disabled, requiring maximum assistance with every aspect of daily living.
Mutations in a gene called MECP2 (methyl CpG-binding protein 2) were identified in 1999 as the leading cause of RTT. MECP2 is believed to function as a transcriptional repressor of its downstream genes. When genes need to be silenced so that a protein is not produced in a given cell, methyl groups attach to CpG dinucleotides, which are often clustered in areas of the gene called CpG islands. MECP2 then binds to these methylated CpG sites, shutting down the gene's production of its protein.
Faulty over-expression of target genes caused by mutated MeCP2 is an underlying hypothesis explaining RTT symptoms. Although MeCP2 is expressed throughout the body, RTT is a disorder of the central nervous system and therefore it is crucial to identify MECP2's target genes in the brain.
Dr. Kohwi-Shigematsu and colleagues have identified an MECP2 target gene, DLX5, involved in the synthesis of GABA, gamma-aminobutyric acid, an important neurotransmitter. Interestingly, DLX5 is an imprinted gene, meaning its expression status depends on whether the gene came from the mother or the father. Misregulation of imprinted genes has been implicated in several neurological disorders. Dr. Kohwi-Shigemtsu found that patients with RTT have twice the normal amount of DLX5. The team then attempted to determine how normal MeCP2 regulates the DLX5 gene and how this regulation goes awry in RTT.
In an unexpected twist, the scientists found that methylation of CpG islands had no impact on expression of DLX5. In fact, the CpG islands associated with DLX5 were unmethylated in both paternal alleles. Some other mechanism must therefore be responsible.
Imagine DNA like a slinky that can be stretched out or compacted. Rather than wire, a basic structural component determining the architecture of this slinky is chromatin. In order for genes along the slinky to be expressed they must be accessible to certain enzymes, and therefore that section of the slinky must be stretched out. Tightly compacted sections are silent because the genes cannot be accessed. In normal mice, they found that MeCP2 formed chromatin loops of silenced DNA in the vicinity of DLX5 by bringing together two sequences separated by more than 10,000 base pairs. This silent chromatin loop configuration was not able to form in the brains of the RTT mouse models.
"The Rett Syndrome community, comprised of both scientists and afflicted families, eagerly awaits the identification of MECP2 target genes, as these genes will likely lead to therapeutic interventions. I congratulate Dr. Kohwi-Shigematsu and her team on their discovery and am pleased that funding from the Rett Syndrome Research Foundation (RSRF) will allow them the opportunity to continue their work and unravel if and how DLX5 contributes to Rett Syndrome symptoms," said Monica Coenraads, co-founder and Director of Research for RSRF. Future experiments will include the analysis of gene expression in the neighboring chromatin affected by the loss of the silent loop structure.
Dr. Terumi Kohwi-Shigematsu explains, "We think that a small difference in the level of proteins in neurons can exert a strong impact on brain function. Most likely, our finding that MeCP2 mutations lead to a loss of imprinting, subsequently resulting in a mild increase in DLX5 expression, represents such an idea. It is likely that MeCP2 has an important function in the fine tuning of the level of key proteins in the brain."
"Loss of silent chromatin looping and impaired imprinting of DLX5 in Rett syndrome," by Shin-ichi Horike, Shutao Cai, Masaru Miyano, Jan-Fang Chen, and Terumi Kohwi-Shigematsu, appears in the January issue of Nature Genetics. The paper is available online at http://www.nature.com/cgi-taf/dynapage.taf?file=/ng/journal/vaop/ncurrent/index.html This work was supported by the National Institutes of Health, the International Rett Syndrome Association and the Rett Syndrome Research Foundation.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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