Transcriptional Silencing Of ?-globin Gene Expression By H4K20 Poly-methylation And Epigenetic Promotion Of Lung Cancer Cells Proliferation By H3S10 Phosphorylation

Epigenetics is defir as the inheritable changes in gene expression with no alterations is DNA sequences.Epigenetic events are important in all aspects of biology,including hemoglobinopathies and tumor progression.In this study,we focused on investigating how H4K20 methylation regulates the expression of?-globin and how H3S10 phosphorylation regulats lung cancer cell aberrant proliferation.?-globin is an important component of hemoglobins,which play essential roles in oxygen transport.The severe hemoglobinopathies,?-thalassemia and Sickle Cell Disease(SCD)together represent the most common single gene disorders,which draw an intense interest to study the globin gene expression regulations.Research efforts to establish therapeutic strategies to treat?-thalassemia and SCD have been hinderd by our imeomplete understanding of the developmental regulation of human ?-like globin gene expression.Increased embryonic globin(?-globin)gene expression has been reported to ameliorate the severity of ?-thalassemia and SCD in mice.Therefore,elucidating the molecular mechanism of ?-globin gene silencing is of biologic and clinical importance.In the first section,we showed the mechanism by which H4K20 poly-methylation mediated regulation of ?-globin gene expression,providing potential therapeutic targets for ?-thalassemia and SCD.We showed that a histone lysine methyltransferase,SUV4-20hl,Plays a critical role in silencing ?-globin gene expression in both K562 cells and primary erythroid progenitor cells.?-globin gene expression could be modulated coordinately by SUV4-20hl-dependnet histone modification and DNA methylation.We also showed that methylation of histone H4 lysine 20(H4K20me2/3)interacts with histone H3 lysine 9 methylation(H3K9me2/3).SUV4-20h2,another H4K20 methyltransferase,recruites HPlyto coordinately repress the expression of?-globin.We identified SUV4-20h family proteins as novel epigenetic suppressors of ?-globin gene expression,involving DNA methylthransferase and HPly,which provides a potential therapeutic strategy for treating of ?-thalassemia and SCD.Lung cancer is one of the leading causes of cancer death worldwide.Although much effort has been centered on probing the pathogenesis of disease,the molecular mechanisms underlying the process are still largely unknown.One key feature of lung cancer is genome instability,which generates the genetic diversity that expedites tumor acquisition,through sustained proliferation.AURKB plays a vital role in concert with many other proteins in controlling chromosome conformation and segregation during mitosis.AURKB kinase is expressed at high levels in lung tumors and the expression level has been associated with increased genetic instability and poor clinical outcome.In the second section,we showed that AURKB phosphorylates histone H3510,which in turn regulates the expression of key genes to control cell cycle.We also indentified a novel AURKB inhibitor that performed efficiently both in vivo and in vitro,which could serve as a useful candidate tool to treat lung cancer.