Study On Three-dimensional Genome Regulation And Radiobiology In Esophageal Squamous Cell Carcinom

Esophageal squamous cell carcinoma is a digestive system tumor with a high incidence in China,and radiotherapy plays an important role in the treatment process.However,radiotherapy resistance is still common in esophageal squamous cell carcinoma,and there is still a lack of effective prediction methods.In order to explore the general determinants of tumor radiosensitivity,we invested a lot of energy in evaluating the existing radiobiological evidence to find stable radiosensitivity parameters.We found that the iSF2 dataset we constructed can well characterize the inherent differences in radiosensitivity of tumor cell lines based on the extensive collections of literature SF2 data.On this basis,our results show that the radiosensitivity of tumor cell lines is positively correlated with the sensitivity of most anticancer drugs,suggesting that tumor cells have similar sensitivity determinants under different screening pressures.Based on the feature correlation multi-omics fusion algorithm developed by us,we found that different tumor types have different radiosensitivity-related features,which can be divided into two types:type A and type B.Esophageal squamous cell carcinoma belongs to type B,and its radiotherapy resistance is positively correlated with the total number of mutations,RNA transcription activity,histone modification pathways,and DNA damage repair.We then explored it more deeply with a radioresistant cell line model of esophageal squamous cell carcinoma.Under long-term radiation screening,the esophageal squamous cell lines underwent stable changes in genome,transcriptome and epigenetic regulation;resistant cell lines acquired new somatic mutations,and had more active chromatin modification and transcriptional status.This inspired us to further pay attention to the influence of three-dimensional chromatin conformation on radiosensitivity.Through the in situ Hi-C library,a high-resolution three-dimensional genome map of normal esophageal epithelial cell lines and tumor cell lines was constructed for the first time.The three-dimensional chromatin profile was highly correlated with other omics features,indicating that chromatin conformation regulates transcriptional metabolism in the nucleus,and esophageal squamous cell lines underwent significant chromatin conformational transformation compared with normal esophageal epithelial cells.The three-dimensional genomic state is closely related to radiosensitivity.The chromatin of radiation-resistant strains has reduced short-distance interactions and increased long-distance interactions.Transcriptional changes.To further explain this altered chromatin state,we focused on the PRC2 protein complex associated with the heterochromatin state.Through multi-omics analysis,we found that the level of PRC2 was lower in resistant cell lines,and knockdown and overexpression experiments proved that PRC2 can regulate radiotherapy sensitivity.Further analysis proved that PRC2 negatively regulated the expression of TP53INP1;in resistant cell lines,the activity of TP53INP1 increased due to the release of the inhibition of PRC2,which led to an increase in the resistance of cells to radiation.The core components of PRC2 and H3K27me3 can be used as markers to predict radiosensitivity of esophageal squamous cell carcinoma.In order to obtain the clinical evidence that esophageal squamous cell carcinoma genes affect its phenotypic characteristics,we constructed ESCC-META,an integrated esophageal squamous cell carcinoma genome cohort including 1930 patients,and obtained many research results with translational value on this basis.We found that mutations in histone modification-related genes are prominent features of the ESCC genome.Due to the interaction between genomic features and tumor treatment patterns,mutations in many important genes have different prognostic significance in early versus advanced tumors.Based on the genetic characteristics of esophageal squamous cell carcinoma,we constructed an 8-gene mutation score model,and validated it in an independent test data.As a continuously updated open-source high-quality data set,ESCC-META provides a translational bridge for basic and clinical research on esophageal squamous cell carcinoma.