Lsh, a guardian of heterochromatinEpigenetic modifications determine chromatin structure and thus control processes such as transcription, recombination or DNA repair. Epigenetic chromatin changes consist largely of posttranslational histone tail modifications and methylation of cytosine residues. A disturbance of epigenetic patterns plays a role in human inherited diseases (such as the RETT or ICF syndromes) and is thought to play a role in cancer development.To understand more about epigenesis our lab uses Lsh-/- mice as a genetic tool to dissect some of the pathways that shape chromatin. Using the Lsh model, we hope to gain more insights into the role of chromatin during normal development and tumorigenesis. Our lab has previously identified and characterized Lsh as a major epigenetic regulator in mice. Lsh (lymphoid specific helicase) is a member of the SNF2 chromatin remodeling family. Lsh is predominantly found in lymphoid tissues in the adult animal, but it is ubiquitously expressed during embryogenesis. Lsh is a component of pericentromeric heterochromatin and Lsh deficiency results in a greatly perturbed heterochromatin organization. Lsh regulates DNA methylation pattern which are a major hallmark of heterochromatin. Altered DNA methylation in turn changes histone acetylation and methylation levels. As a consequence of perturbed heterochromatin structure upon Lsh deletion we observed de-repression of endogenous retroviral elements suggesting an important role for Lsh in silencing of parasitic elements in the genome. Overexpression of genes (including the oncogene PU.1) has also been observed in erythroleukemia that develop spontaneously in the absence of Lsh. Thus Lsh may preserve genome integrity and genomic hypomehylation upon Lsh deletion may promote tumor development via de-repression of genes. We are currently testing the role of Lsh inhibition in tumor development. These studies should provide insights in a number of basic biologic processes that involve epigenetic modifications such as transcription, imprinting, mitosis and cellular transformation.
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