Since Banerji et al. first described an enhancer dement in SV40 genome in 1981, similar enhancer sequences have been discovered in many other viral genomes and eukaryotic cells. It is not dear, however, whether there ...Since Banerji et al. first described an enhancer dement in SV40 genome in 1981, similar enhancer sequences have been discovered in many other viral genomes and eukaryotic cells. It is not dear, however, whether there is also a similar transcription-controlling element in prokaryotic cells. In 1985 Hou et al. and Wu et al. surprisingly found展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is notorious for its aggressive progression and dismal prognosis,with chromatin accessibility dynamics emerging as pivotal yet poorly understood drivers.AIM To dissect how multi...BACKGROUND Hepatocellular carcinoma(HCC)is notorious for its aggressive progression and dismal prognosis,with chromatin accessibility dynamics emerging as pivotal yet poorly understood drivers.AIM To dissect how multilayered chromatin regulation sustains oncogenic transcription and tumor-stroma crosstalk in HCC,we combined multiomics single cell analysis.METHODS We integrated single-cell RNA sequencing and paired single-cell assay for transposase-accessible chromatin with sequencing data of HCC samples,complemented by bulk RNA sequencing validation across The Cancer Genome Atlas,Liver Cancer Institute,and GSE25907 cohorts.Cell type-specific chromatin architectures were resolved via ArchR,with regulatory hubs identified through peak-to-gene linkages and coaccessibility networks.Functional validation employed A485-mediated histone 3 lysine 27 acetylation suppression and small interfering RNA targeting DGAT1.RESULTS Malignant hepatocytes exhibited expanded chromatin accessibility profiles,characterized by increased numbers of accessible peaks and larger physical regions despite reduced peak intensity.Enhancer-like peaks enriched in malignant regulation,forming long-range hubs.Eighteen enhancer-like peak-related genes showed tumor-specific overexpression and diagnostic accuracy,correlating with poor prognosis.Intercellular coaccessibility analysis revealed tumor-stroma symbiosis via shared chromatin states.Pharmacological histone 3 lysine 27 acetylation inhibition paradoxically downregulated DGAT1,the hub gene most strongly regulated by chromatin accessibility.DGAT1 knockdown suppressed cell proliferation.CONCLUSION Multilayered chromatin reprogramming sustains HCC progression through tumor-stroma crosstalk and DGAT1-related oncogenic transcription,defining targetable epigenetic vulnerabilities.展开更多
基金This work was supported by the,National Committee for High Technology of Bioscience(102-18-46).
文摘Since Banerji et al. first described an enhancer dement in SV40 genome in 1981, similar enhancer sequences have been discovered in many other viral genomes and eukaryotic cells. It is not dear, however, whether there is also a similar transcription-controlling element in prokaryotic cells. In 1985 Hou et al. and Wu et al. surprisingly found
基金Supported by the Science and Technology Planning Project of Guangzhou,No.2024A03J0102the Natural Science Foundation of Guangdong Province for Distinguished Young Scholar,No.2022B1515020024+1 种基金National Natural Science Foundation of China,No.82070574the Key Research and Development Program of Guangzhou,No.2023B03J1298.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is notorious for its aggressive progression and dismal prognosis,with chromatin accessibility dynamics emerging as pivotal yet poorly understood drivers.AIM To dissect how multilayered chromatin regulation sustains oncogenic transcription and tumor-stroma crosstalk in HCC,we combined multiomics single cell analysis.METHODS We integrated single-cell RNA sequencing and paired single-cell assay for transposase-accessible chromatin with sequencing data of HCC samples,complemented by bulk RNA sequencing validation across The Cancer Genome Atlas,Liver Cancer Institute,and GSE25907 cohorts.Cell type-specific chromatin architectures were resolved via ArchR,with regulatory hubs identified through peak-to-gene linkages and coaccessibility networks.Functional validation employed A485-mediated histone 3 lysine 27 acetylation suppression and small interfering RNA targeting DGAT1.RESULTS Malignant hepatocytes exhibited expanded chromatin accessibility profiles,characterized by increased numbers of accessible peaks and larger physical regions despite reduced peak intensity.Enhancer-like peaks enriched in malignant regulation,forming long-range hubs.Eighteen enhancer-like peak-related genes showed tumor-specific overexpression and diagnostic accuracy,correlating with poor prognosis.Intercellular coaccessibility analysis revealed tumor-stroma symbiosis via shared chromatin states.Pharmacological histone 3 lysine 27 acetylation inhibition paradoxically downregulated DGAT1,the hub gene most strongly regulated by chromatin accessibility.DGAT1 knockdown suppressed cell proliferation.CONCLUSION Multilayered chromatin reprogramming sustains HCC progression through tumor-stroma crosstalk and DGAT1-related oncogenic transcription,defining targetable epigenetic vulnerabilities.
