Open chromatin and diabetes

Groop (2010 Open chromatin and diabetes risk, ) Nature Genetics 42, 190 – 192 (2010)
A new study has identified a large number of open chromatin regions harboring active regulatory elements in human pancreatic islets. A type 2 diabetes–associated SNP in TCF7L2 was found to be located in a region of allele-specific open chromatin and shows allele-specific enhancer activity, suggesting a potential mechanism for this disease association. The prevalence of type 2 diabetes (T2D) has increased rapidly worldwide over the past several decades, a phenomenon that has been ascribed to the collision between an inherited predisposition and a westernized environment. Although the disease is characterized by impairments in both the secretion and the action of insulin, an inability of pancreatic beta-cells to increase insulin secretion so as to compensate for a decrease in insulin action precedes disease onset
DNA in eukaryotes is packed into chromatin. The basic component of chromatin is the nucleosome consisting of DNA wrapped around a histone octamer. Inside the cell nucleus, chromatin is folded into higher-order structures through various mechanisms, including repositioning of nucleosomes along the DNA, packing of nucleosomes into more condensed 3-dimensional configurations, looping of chromatin fibres, and tethering of chromosomal regions to nuclear structures. In such a particular context, the transition from a repressed compacted chromatin to a rather extended fiber is necessary for transcription. The chromatin opening includes three events, the initial factor getting access to nucleosome DNA, local chromatin opening mediated by activator/coactivator, and transcription associated with extensive chromatin opening. Chromatin dynamics, which is DNA sequence dependent, and also occurs in condensed fiber, provides the opportunity for activators binding to DNA. Coactivators recruited by the activator open the chromatin locally. However, it appears that genes adopt distinct chromatin opening mechanisms according to whether the gene is induced expression, developmental and tissue-specific expression, or constitutive expression. In contrast to transcription initiation-related local chromatin opening, large scale of chromatin opening is associated with a functional enhancer as well as high transcription rate.
The role of chromatin in the pathogenesis of diseases has attracted broad interests from the clinicians. Cis-elements of chromatin DNA helps defining the functional segments within the genome, which provide indispensable evidences to bio-informatics, and to the linkage between genomics and proteomics. The assembly of chromatin from multiple bio-active molecules displays new functions on gene activity.

Martin Eastwood
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