Sirt1 To Acetylation Satb1 And Promote Epsilon - Globin Gene Expression

Higher Eukaryote develops hundreds of cell types from a single zygote. Despite of their shared genome DNA sequence, different cell types show unique gene expression profiles under exquisite epigenetic regulation. Gene subnuclear localization and chromatin higher-order structure organization have recently emerged as two new focuses of epigenetic study. The network structure of nuclear matrix, which consists of nuclear lamina and recruits PolⅡ and transcripational modulators to participate in gene transcription and regulation. MAR (matrix attachment region) binding proteins bridge the association of nuclear matrix and special chromatin region, and thus constitute a major regulator to the gene subnuclear localization and chromatin higher-order structure.The most studied MAR binding protein SATB1recuits components of chromatin remodeling complex and histone modifiers to act as an active chromatin organizer. Studies of SATB1knockout mice demonstrate S ATB1to be a key regulator of T cell differentiation through regulating the expression of many T cell specific genes. SATB1binds multiple MARs in cytokine gene locus and self-polymerized to form a "core base" structure in coordinating the expression of cytokine genes. Another work found that SATB1interacts with PML, the major component of PML bodies, and mediates the formation of dense loop structure plus tothe localization to PML nuclear body of MHC I gene cluster.β-globin globin gene cluster expressed in erythroid cells is a famous model in the studing of gene regulation for the switching on/off of its structural genes during erythroid differentiation and development. Previous work finds that SATB1could bind on specific MARs of the locus and regulate the expression of embryonic and fetal β-like globin (namely s-globin and y-globin) genes. Further exploration finds that SATB1gathers these distinct MAR elements to form an "Inter-MAR association" in its operation.Trans-factors themselves are subjected to tight control for their important roles in gene regulation. Among them posttranslational modifications provide a convenient and efficient means of quick response to the environmental and developmental signals. Whether they also contribute to the regulation of chromatin looping eventsremains unclear. Acetylation of SATB1has been previously noted to affect the transacting activity of the factor in T-cells. How this modification may change SATB1mediated higher-order chromatin organization in globin gene cluster and hence regulate globin gene expression will be of interest to know.In this study, we find that SATB1could interact with class Ⅲ protein deactylase SIRT1, and be deacetylated by SIRT1at K136and K175of its PDZ domain. SIRT1binds on SATB1binding MARs in B-globin gene cluster, and regulates ε-globin gene expression through promoting SATB1’s binding to the MARs and strengthening the inter-MAR association. We also show increased SIRT1protein level and its binding to MAR elements of globin cluster during Hemin induced K562differentiation. Interfering of SIRT1not only reduce the expression level of ε-globin gene inuninduced K562cells, but also impairs Hemin activated ε-globin gene expression. Together with our previous work showing decreased acetylation of SATB1and increased’inter-MAR association’upon Hemin induction of K562cells, we suggest that during Hemin induced K562cells erythroid differentiaton, SIRT1proteins accumulate, bind on SATB1associated MARs element to promote ε-globin gene expression through increasing DNA binding ability of SATB1and strengthening the "inter-MAR association"...