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Epigenetics and stem cell development

Distal enhancers have emerged as key regulatory non coding structures in the mammalian genome that support gene expression over long distances. We have identified well over 130,000 new enhancer regions in several different cell types in the mouse genome. We have shown that these enhancer networks are active in a cell state dependent manner and control cellular identity. Furthermore we provided evidence that enhancers can be divided between inactive, active and poised configurations based on specific histone modifications providing insight into the limitations of a cells ability to respond to environmental cues. The enhancer network is reset to a pluripotent state during reprogramming of adult cell types into induced pluripotent stem cells and we can identify transcription factors involved in this process by interrogating genomic elements at the location of these enhancers. Similarly our lab is now attempting to use these networks to identify transcription factors that can facilitate trans-differentiation for the purpose of regenerative medicine.
Several diseases are known to be caused by mutations in non coding enhancer elements such as hirschsprung’s disease, thalassemias, preaxial polydactyly and lymphoma. These discoveries not only have established enhancers as potential disease causing structures in the genome when mutated, but also explain the tissue specific manifestation of such phenotypes. Many diseases of unknown origin might be supported by dysfunctional distal enhancers. Furthermore several hundreds of genome wide association studies have linked disease susceptibility to large areas (~200kb) in the genome many of which contain no coding elements. Indeed several nucleotide polymorphisms found to be involved in altered disease susceptibility were shown to alter an enhancer element in a gene desert. Our lab is currently attempting to identify disease associated non coding elements using reprogrammed stem cells from patient material.

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