Multi-omics Integration Analysis Of Transcription Factor Regulation And Epigenetic Modification During Lineage Formation

In 2003,with the completion of the Human Genome Project,people opened the door to analyze genome sequences.Recently,with the development of sequencing technology,massive high-throughput data such as gene expression,DNA methylation,histone modification,DNA high sensitivity loci and other sequencing data emerged.Large-scale scientific projects including ENCODE project,ROADMAP project,modENCODE project provide people a wide range of research platform,but how to extract useful data from this massive data and make a biological explanation is still not an easy problem to address.Previous studies have shown that preimplantation embryos undergoes a siries of intense reprogramming events,which not only induce the start of gene transcription but also shape the pluripotency of ESCs.However,the mechanism of reprogramming is unknown and we are still not clear the key factors duiring this process.To deal with this problem,we analyzed the dynamic changes of transcription factors regulation and epigenetic modification of accessible chromatin in preimplantation embryos,and then we discussed the key factors of cell fate during development process.We found that more accessible chromatin tend to locate in the coding genome as preimplantation embryos development and accessible chromatin is highly enriched in inner cell masses(ICMs),which is defined as the first cell fate decision in the mammal embryo,additionally,accessible chromatin of ICM is shortest and the closest to the gene transcription start site(TSS).Furthermore,we scanned and identified transcription factor binding sites(TFBS)of accessible chromatin,and found a specification feature of TFBS by cluster analysis.Then,we shaped the dynamic changes of epigenetic regulation with histone modification data,and finally conjectured a mode of cell fate decision.Our preivous work showed that transcritption factors regulation and epigenetic modifications play important roles in the reprogramming of preimplantation embryos.We next discussed how these factors act in the process from ESCs to differentiated cells.Although transcription factors are important protein molecule that regulates the expression of genes,transcription factor binding sites(TFBSs)are only a few base pairs in the genome.However,more than 90% of TFBSs occupied only less than 2% of the whole genome.Recent studies have found these TFBSs high-occupancy target regions in Caenorhabditis elegans,Drosophila melanogaster,and humans and defined as HOT regions.For example,In C.elegans,22 different TFs were used to identify 304 HOT regions bound to 15 or more TFs.The broad presence of these regions in metazoan genomes suggests that they might reflect a general property of regulatory genomes.However,how hundreds of TFs coordinate clustered binding to regulatory DNA to form HOT regions across cell types and tissues is still unclear,in addition,the effects of these regions on human diseases and cancer remain unknown.Here we characterized and validated HOT regions in embryonic stem cells and produced a catalogue of HOT regions in a broad range of human cell types.We found that HOT regions are associated with genes that control and define the developmental processes of the respective cells and tissue types.We also showed evidence of the developmental persistence of HOT regions at primitive enhancers and demonstrate unique signatures of HOT regions that distinguish them from typical enhancers and super-enhancers.Finally,we performed a analysis to show the dynamical regulation of HOT regions upon H1 differentiation.To better understand the effects of HOT regions on human diseases and cancer,we performed a comprehensive analysis of the genetic variants in HOT regions.We observed that GWAS variants that map to HOT regions undergo a substantial net decrease and illustrate development-specific localisation during haematopoiesis.Additionally,genetic risk variants are disproportionally enriched in HOT regions compared with LOT(low-occupancy target)regions in both disease-relevant and cancer cells.Importantly,this enrichment is biased toward disease-or cancer-specific cell types.Furthermore,we observed that cancer cells generally acquire cancer-specific HOT regions at oncogenes through diverse mechanisms of cancer pathogenesis.To understand the important roles of transcription factors regulation and epigenetic modifications in the development of cell lineage,we performed an integrated analysis of transcription factors regulation and epigenetic modification during mammal pre-implantation embryos development and cell differentiation and tissue development processes.The study focused on the dynamic changes of the development of cell lineage and the regulation of genomic noncoding regions,not only adding a new content to the understanding of genomic noncoding regions but also discussing the determinants of cell fate.