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 Chromatin Regulation in Development and Disease
Professor Susan Strome, MCD Biology The currently booming field of "epigenetics" includes investigations of how chromatin-level regulation controls gene expression and development. The Strome lab uses the nematode worm C. elegans to investigate the roles of covalent histone modifications in specifying the ON and OFF states of genes, and in guiding cells to adopt correct fates and undergo correct developmental programs.(Keywords: chromosome biology, epigenetics, developmental biology, C. elegans, gene experession, stem cell biology, RNA molecular biology)
Using the nematode worm C. elegans as a powerful model system, the Strome lab is investigating the roles of histone-modifying enzymes whose homologs in mammals play key roles in development and disease. Like mammalian Polycomb Repressive Complex 2 (PRC2), the C. elegans MES-2/3/6 complex methylates Lys27 on the tail of histone H3 and participates in repressing gene expression. Like mammalian NSD1 protein, C. elegans MES-4 methylates Lys36 of histone H3 and also participates in regulating gene expression. Strome's group is elucidating the patterns of MES protein binding and methylation at the gene level using chromatin immunopreicipation (ChIP) approaches, and investigating how MES-2/3/6 and MES-4 regulate each other's distribution and action. MES-4 Illustrates Strome Lab's Findings and Current Questions
MES-4 shows the remarkable property of selectively binding to the autosomes. How is MES-4 selectively recruited to autosomes or excluded from the X chromosomes? Part of the answer is by MES-2/3/6. MES-2/3/6 histone methylation action is concentrated on the Xs, where it may somehow "repel" MES-4. MES-4 serves an essential role, as removing MES-4 function causes germ cells to die. At the gene expression level, removing MES-4 function causes genes on the X chromosome to be up-regulated. Strome's group is testing models for how an autosomally concentrated chromatin regulator participates in silencing genes on the X chromosomes. MES-4 may serve an important role in specifying a "germline state" of chromatin. This view comes from findings that show that the loss of synMuv B chromatin regulators cause larvae to die, and concomitant loss of MES-4 restores viability. synMuv larval death is thought to be due to somatic cells adopting germline fates; loss of MES-4 may impair the germline fate option, allowing normal somatic development. Srome's studies of C. elegans MES-4 and MES-2/3/6 will provide valuable insights into chromatin regulation by mammalian NSD1 and PRC2. Both mammalian regulators are involved in maintaining stem cell pluripotency and are associated with cancers, and are prime targets for analysis in model systems. |
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