Lsh, a guardian of heterochromatin Epigenetic modifications comprising DNA methylation and histone modifications are crucial for organization of the genome into active chromatin (euchromatin) and repressed chromatin (heterochromatin). The functional organization of chromatin is important for regulation of transcription, cellular differentiation, imprinting and normal mitosis. Our group studies the role of epigenetic modifications that control chromatin structure in particular DNA methylation during normal embryonic development and during cancer development. The current focus of our studies is to understand the molecular mechanisms and biological role of Lsh. Lsh (lymphoid specific helicase) is a chromatin remodeling protein that our group has previously identified, cloned and characterized. Lsh is predominantly found in lymphoid tissues in the adult animal, but it is ubiquitously expressed during embryogenesis. Lsh is a crucial factor for normal embryonic development since targeted deletion of Lsh leads to death of the newborn animal. Lsh is a component of pericentromeric heterochromatin and Lsh deficiency results in a greatly perturbed heterochromatin organization with loss of DNA methylation and altered histone tail acetylation and methylation. As a functional consequence of perturbed pericentromeric heterochromatin we observe aberrant reactivation of 'parasitic' elements (such as endogenous retroviral elements) and abnormal mitosis with amplified centrosomes and genomic instability. Thus Lsh is a major epigenetic regulator that controls DNA methylation patterns and is crucial for normal heterochromatin structure and function. We are currently testing the role of Lsh and genomic demethylation in tumor progression. 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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