Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers

Ando, Mizuo; Saito, Yuki; Xu, Guiyin; Bui, Nam Q.; Medetgul-Ernar, Kate; Pu, Minya; Fisch, Kathleen; Ren, Shuling; Sakai, Akihiro; Fukusumi, Takahito; Liu, Chao; Haft, Sunny; Pang, John; Mark, Adam; Gaykalova, Daria A.; Guo, Theresa; Favorov, Alexander V.; Yegnasubramanian, Srinivasan; Fertig, Elana J.; Ha, Patrick K.; Tamayo, Pablo; Yamasoba, Tatsuya; Ideker, Trey; Messer, Karen; Califano, Joseph A.

doi:10.1038/s41467-019-09937-w

Cited by 73 publications

(58 citation statements)

References 65 publications

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“…H3K9me3 and DNA methylation leading to depression of a collection of genes [28,29]. The changes in histone modi cation precede the alterations in DNA methylation [30,31].…”

Section: Discussionmentioning

confidence: 99%

SUV39H1-DNMT3A-mediated epigenetic regulation of Tim-3 and galectin-9 in the cervical cancer

Zhang

Tian

Zhao

et al. 2020

Preprint

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Background: Methylation of histone 3 at lysine 9 (H3K9) and DNA methylation are epigenetic marks correlated with genes silencing. The tumor microenvironment significantly influences therapeutic responses and clinical outcomes. The epigenetic-regulation mechanism of the costimulatory factors Tim-3 and galectin-9 in cervical cancer remains unknown. Methods: The methylation status of HAVCR2 and LGALS9 were detected by MS-PCR in cervical cancer tissues and cell lines. The underlying molecular mechanism of SUV39H1-DNMT3A-Tim-3/galectin-9 regulation was elucidated using cervical cancer cell lines containing siRNA or/and over-expression system. Confirmation of the regulation of DNMT3A by SUV39H1 used ChIP-qPCR.Results: SUV39H1 up-regulates H3K9me3 expression at the DNMT3A promoter region, which in turn induced expression of DNMT3A in cervical cancer. In addition, the mechanistic studies indicate that DNMT3A mediates the epigenetic modulation of the HAVCR2 and LGALS9 genes by directly binding to their promoter regions in vitro. Moreover, in an in vivo assay, the expression profile of SUV39H1 up-regulates the level of H3K9me3 at the DNMT3A promoter region was found to correlate with Tim-3 and galectin-9 cellular expression level. Conclusion: These results indicate that SUV39H1-DNMT3A is a crucial Tim-3 and galectin-9 regulatory axis in cervical cancer.

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“…H3K9me3 and DNA methylation leading to depression of a collection of genes [28,29]. The changes in histone modi cation precede the alterations in DNA methylation [30,31].…”

Section: Discussionmentioning

confidence: 99%

SUV39H1-DNMT3A-mediated epigenetic regulation of Tim-3 and galectin-9 in the cervical cancer

Zhang

Tian

Zhao

et al. 2020

Preprint

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“…To validate the obtained results from the TCGA database, the Gene Expression Omnibus (GEO) data repository, with GSE112026 [ 30 ] and GSE65858 [ 31 ] sets for HNSCC samples, was used. The PRINS expression was compared between normal vs. HPV+ using GSE112026 for 25 and 47 samples, respectively.…”

Section: Methodsmentioning

confidence: 99%

PRINS lncRNA Is a New Biomarker Candidate for HPV Infection and Prognosis of Head and Neck Squamous Cell Carcinomas

et al. 2020

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Numerous studies have shown that human papillomavirus (HPV) infection is one of the important risk factors for head and neck squamous cell carcinoma (HNSCC) progression and affects the expression of multiple genes, which might serve as new biomarkers. This study examines the effects of HPV infection on long non-coding RNA (lncRNA) expression and the immune system, particularly PRINS (Psoriasis susceptibility-related RNA Gene Induced by Stress). The Cancer Genome Atlas (TCGA) expression data for lncRNA genes and clinical data were analyzed by GraphPad Prism 5/7. The expressions of PRINS, CDKN2B-AS1, TTTY14, TTTY15, MEG3, and H19 were significantly different in HPV-positive and HPV-negative patients. HPV-positive patients with high PRINS expression demonstrated significantly better overall survival (OS) and disease-free survival (DFS). HPV-positive patients with high PRINS expression showed changes in gene expression associated with immune and antiviral responses. A majority of HPV-positive patients with high PRINS expression demonstrated a high number of immune cells within tumors. PRINS expression was significantly associated with HPV-infection HNSCC tumors. Validation of these results using data set from Gene Expression Omnibus (GEO) indicated that PRINS is upregulated in HPV active infections and in “atypical 1 (IR)” HNSCC clusters, negatively influencing patients’ overall survival. Patients with high PRINS expression display different immunological profiles than those with low expression levels. For instance, they have active HPV infection status or are clustered in the “atypical 1 (IR)” subtype of HNSCC which influences both viral infection and patients’ survival. It is likely that PRINS could be used as a potential biomarker for HNSCC patients, but its role is dual. On the one hand, it stimulates patients’ immune response, while on the other it can be favorable in virus replication.

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“…TF binding can be both negatively or positively influenced by DNA methylation [58,59]. DNA methylation of gene TSS associates negatively with gene expression [60], whereas methylation of CpGs located within gene body can also associate with active gene expression [61]. To investigate the potential relationship between DNA methylation alterations and gene expression in SSc, we searched for possible meQTLs (methylation-expression quantitative trait loci).…”

Section: Dna Methylation Changes Establish Short-and Longdistance Relmentioning

confidence: 99%

Epigenomics and transcriptomics of systemic sclerosis CD4+ T cells reveal long-range dysregulation of key inflammatory pathways mediated by disease-associated susceptibility loci

Ortiz-Fernández

Andrés-León

et al. 2020

Genome Med

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Background Systemic sclerosis (SSc) is a genetically complex autoimmune disease mediated by the interplay between genetic and epigenetic factors in a multitude of immune cells, with CD4+ T lymphocytes as one of the principle drivers of pathogenesis. Methods DNA samples exacted from CD4+ T cells of 48 SSc patients and 16 healthy controls were hybridized on MethylationEPIC BeadChip array. In parallel, gene expression was interrogated by hybridizing total RNA on Clariom™ S array. Downstream bioinformatics analyses were performed to identify correlating differentially methylated CpG positions (DMPs) and differentially expressed genes (DEGs), which were then confirmed utilizing previously published promoter capture Hi-C (PCHi-C) data. Results We identified 9112 and 3929 DMPs and DEGs, respectively. These DMPs and DEGs are enriched in functional categories related to inflammation and T cell biology. Furthermore, correlation analysis identified 17,500 possible DMP-DEG interaction pairs within a window of 5 Mb, and utilizing PCHi-C data, we observed that 212 CD4+ T cell-specific pairs of DMP-DEG also formed part of three-dimensional promoter-enhancer networks, potentially involving CTCF. Finally, combining PCHi-C data with SSc GWAS data, we identified four important SSc-associated susceptibility loci, TNIP1 (rs3792783), GSDMB (rs9303277), IL12RB1 (rs2305743), and CSK (rs1378942), that could potentially interact with DMP-DEG pairs cg17239269-ANXA6, cg19458020-CCR7, cg10808810-JUND, and cg11062629-ULK3, respectively. Conclusion Our study unveils a potential link between genetic, epigenetic, and transcriptional deregulation in CD4+ T cells of SSc patients, providing a novel integrated view of molecular components driving SSc pathogenesis.

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Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers

Cited by 73 publications

References 65 publications

SUV39H1-DNMT3A-mediated epigenetic regulation of Tim-3 and galectin-9 in the cervical cancer

SUV39H1-DNMT3A-mediated epigenetic regulation of Tim-3 and galectin-9 in the cervical cancer

PRINS lncRNA Is a New Biomarker Candidate for HPV Infection and Prognosis of Head and Neck Squamous Cell Carcinomas

Epigenomics and transcriptomics of systemic sclerosis CD4+ T cells reveal long-range dysregulation of key inflammatory pathways mediated by disease-associated susceptibility loci

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