Project Grant R01HL174778

BCOR REGULATION OF VENOUS THROMBOEMBOLISM - PROJECT SUMMARY/ABSTRACT: VENOUS THROMBOEMBOLISM (VTE) IS A MAJOR CAUSE OF MORBIDITY AND MORTALITY. VTE IS CAUSED BY ACQUIRED AND GENETIC FACTORS, BUT THE GENETIC FACTORS THAT MODIFY THE RISK FOR VTE ARE NOT FULLY UNDERSTOOD. COAGULATION FACTORS PLAY A MAJOR ROLE IN VTE, BUT THE REGULATION OF COAGULATION FACTOR EXPRESSION IN THE LIVER IS NOT WELL CHARACTERIZED. OUR LONG-TERM GOAL IS TO DISSECT THE TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS THAT REGULATE HEPATOCYTE EXPRESSION OF COAGULATION FACTORS. OUR STRATEGY IS TO USE GENOME WIDE ASSOCIATION STUDIES (GWAS) TO IDENTIFY NOVEL CANDIDATE GENES THAT ARE LINKED TO VTE RISK. A RECENT GWAS IDENTIFIED THE BCL6 CO-REPRESSOR (BCOR) LOCUS AS A RISK FOR VTE IN HUMANS. THE OBJECTIVE OF THIS GRANT IS TO CHARACTERIZE THE ROLE OF BCOR IN EPIGENETIC REGULATION OF FACTOR VII AND THROMBOSIS. OUR PRELIMINARY DATA SHOW THAT (1) BCOR CONTROLS FACTOR VII EXPRESSION IN CELLS AND MICE, AND (2) BCOR ASSOCIATES WITH TWO EPIGENETIC MODULES: THE POLYCOMB REPRESSOR COMPLEX (PRC1.1), AND THE ADA2A-CONTAINING COMPLEX (ATAC). OUR CENTRAL HYPOTHESIS IS THAT BCOR SUPPRESSES FACTOR VII EXPRESSION THROUGH THE EPIGENETIC REGULATORS PRC1.1 AND ATAC. OUR RATIONALE IS THAT IDENTIFICATION OF EPIGENETIC PATHWAYS THAT CONTROL COAGULATION MAY LEAD TO NEW SPECIFIC THERAPIES TO PREVENT OR TREAT VTE. OUR SPECIFIC AIMS WILL TEST THE FOLLOWING HYPOTHESES: (1) BCOR SUPPRESSES FACTOR VII EXPRESSION IN HEPATOCYTES BY CONTROLLING THE EPIGENETIC MODULES PRC1.1 AND ATAC. (2) THE GENETIC VARIANT IN THE BCOR LOCUS LINKED TO VTE RISK DECREASES BCOR EXPRESSION BY CONTROLLING TEAD1 BINDING TO THE BCOR ENHANCER (WHERE TEAD1 IS A TEA DOMAIN FAMILY MEMBER SUPPRESSOR PROTEIN). (3) INHIBITION OF HEPATIC BCOR EXPRESSION INCREASES FACTOR VII LEVELS AND INCREASES COAGULATION AND THROMBOSIS IN VIVO. UPON CONCLUSION OF THIS PROJECT, WE WILL UNDERSTAND HOW HUMAN GENETIC VARIANTS IN THE BOCR LOCUS CONTRIBUTES TO RISK OF VTE. THE SIGNIFICANCE OF OUR STUDIES IS THAT WE WILL ESTABLISH EPIGENETIC REGULATION AS A PATHWAY TO CONTROL FACTOR VII LEVELS, POSSIBLY LEADING TO NOVEL THERAPIES FOR VTE BY TARGETING SPECIFIC EPIGENETIC PATHWAYS. THE INNOVATION OF OUR STUDIES IS: (A) BCOR HAS NOT BEEN PREVIOUSLY LINKED TO VTE; (B) BCOR HAS NOT BEEN SHOWN TO INTERACT WITH THE ATAC EPIGENETIC COMPLEX; (C) EPIGENETIC REGULATION OF LIVER PRODUCTION OF COAGULATION FACTORS IS NOT WELL CHARACTERIZED. IN SUMMARY: HUMAN GENETICS SUGGESTS BCOR MODULATES THE RISK OF VTE, OUR ANIMAL MODEL SHOWS THAT BCOR IN THE LIVER AFFECTS PLASMA FACTOR VII LEVELS AND COAGULATION IN VIVO, OUR CELL STUDIES SHOW THAT BCOR ASSOCIATES WITH EPIGENETIC REGULATORS AND MODULATES EXPRESSION OF FACTOR VII IN VITRO. WE NOW PROPOSE TO STUDY THE EPIGENETIC MECHANISMS BY WHICH BCOR IN THE LIVER REGULATES COAGULATION.