GENOME-WIDE DISCOVERY AND ANNOTATION OF HUMAN ENHANCERS RELEVANT TO DEVELOPMENT AND DISEASE

Abstract

ENHANCERS ARE KEY DETERMINANTS OF CELL-SPECIFIC GENE EXPRESSION DURING DEVELOPMENT AND DISEASE, AND THEIR GENOME-WIDE IDENTIFICATION AND ANNOTATION ARE CRUCIAL FOR A COMPLETE UNDERSTANDING OF GENOME REGULATION. HERE WE EMPLOYED NEXT-GENERATION SEQUENCING-BASED METHODS FOR THE DISCOVERY AND ANNOTATION OF ENHANCERS UTILIZED BY THE HUMAN ENDODERM, THROUGH TRANSCRIPTOME AND HISTONE MODIFICATION PROFILING. SEQUENCE AND INTEGRATIVE ANALYSES REVEALED MULTIPLE TFS BOUND AT ENDODERM ENHANCERS, INCLUDING EOMES AND NODAL SIGNALLING EFFECTORS, AND THE COORDINATION BETWEEN THESE TFS FOR ENHANCER ACTIVATION. THESE EARLY ENHANCER SIGNATURES ALLOWED A COMPREHENSIVE INVESTIGATION OF ENHANCER POISING STATE. WE FURTHER IDENTIFIED ENHANCERS UTILIZED DURING ANTERIOR-POSTERIOR ENDODERM PATTERNING, WHICH DROVE REGION-SPECIFIC EXPRESSION IN ZEBRAFISH EMBRYOS AND MAY ACCOUNT FOR COMMON DISEASE RISK AFFECTING ENDODERM ORGANS. LASTLY, WE INVESTIGATED CHROMATIN CONFORMATION IN HUMAN CELLS TO STUDY HOW ENHANCERS A