HPV-CCDC106 integration alters local chromosome architecture and hijacks an enhancer by three-dimensional genome structure remodeling in cervical cancer

Integration of human papillomavirus(HPV)DNA into the human genome is a reputed key driver of cervical cancer.However,the effects of HPV integration on chromatin structural organization and gene expression are largely unknown.We studied a cohort of 61 samples and identified an integration hot spot in the CCDC106 gene on chromosome 19.We then selected fresh cancer tissue that contained the unique integration loci at CCDC106 with no HPV episomal DNA and performed whole-genome,RNA,chromatin immunoprecipitation and high-throughput chromosome conformation capture(Hi-C)sequencing to identify the mechanisms of HPV integration in cervical carcinogenesis.Molecular analyses indicated that chromosome 19 exhibited significant genomic variation and differential expression densities,with correlation found between three-dimensional(3D)structural change and gene expression.Importantly,HPV integration divided one topologically associated domain(TAD)into two smaller TADs and hijacked an enhancer from PEG3 to CCDC106,with a decrease in PEG3 expression and an increase in CCDC106 expression.This expression dysregulation was further confirmed using 10 samples from our cohort,which exhibited the same HPV-CCDC106 integration.In summary,we found that HPV-CCDC106 integration altered local chromosome architecture and hijacked an enhancer via 3D genome structure remodeling.Thus,this study provides insight into the 3D structural mechanism underlying HPV integration in cervical carcinogenesis.

Amino acid variation analysis of surface spike glycoprotein at 614 in SARS-CoV-2 strains

As severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continues to disperse globally with worrisome speed,identifying amino acid variations in the virus could help to understand the characteristics of it.Here,we studied 489 SARS-CoV-2 genomes obtained from 32 countries from the Nextstrain database and performed phylogenetic tree analysis by clade,country,and genotype of the surface spike glycoprotein(S protein)at site 614.We found that virus strains from China's Mainland were mostly distributed in Clade B and Clade undefined in the phylogenetic tree,with very few found in Clade A.In contrast,Clades A2(one case)and A2a(112 cases)predominantly contained strains from European regions.Moreover,Clades A2 and A2a differed significantly from those of China's Mainland in age of infected population(P Z 0.0071,mean age 40.24 to 46.66),although such differences did not exist between the US and China's Mainland.Further analysis demonstrated that the variation of the Sprotein at site 614(QHD43416.1:p.614D>G)was a characteristic of stains in Clades A2 and A2a.Importantly,this variation was predicted to have neutral or benign effects on the function of the S protein.In addition,global quality estimates and 3D protein structures tended to be different between the two S proteins.In summary,we identified different genomic epidemiology among SARS-CoV-2 strains in different clades,especially in an amino acid variation of the S protein at 614,revealing potential viral genome divergence in SARS-CoV-2 strains.