title: Functional annotation of HOT regions in the human genome: implications for human disease and cancer.
abstract: Advances in genome-wide association studies (GWAS) and large-scale sequencing studies have resulted in an impressive and growing list of disease- and trait-associated genetic variants. Most studies have emphasised the discovery of genetic variation in coding sequences, however, the noncoding regulatory effects responsible for human disease and cancer biology have been substantially understudied. To better characterise the cis-regulatory effects of noncoding variation, we performed a comprehensive analysis of the genetic variants in HOT (high-occupancy target) regions, which are considered to be one of the most intriguing findings of recent large-scale sequencing studies. 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. Collectively, our findings demonstrate the key roles of HOT regions in human disease and cancer and represent a critical step toward further understanding disease biology, diagnosis, and therapy.
authors.affiliation: Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Hebing
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ren
authors.affiliation: Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Shengqi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Bo
authors.affiliation: Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Shu
mesh_terms: D045744:Cell Line, Tumor; D004194:Disease / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D058977:Molecular Sequence Annotation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009857:Oncogenes / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors