Dataset Information

Epigenomic profiling of myelofibrosis reveals widespread DNA methylation changes in enhancer elements and ZFP36L1 as a potential tumor suppressor gene that is epigenetically regulated.

ABSTRACT: In this study we interrogated the DNA methylome of myelofibrosis patients using high-density DNA methylation arrays. We detected 35,215 differentially methylated CpG, corresponding to 10,253 genes, between myelofibrosis patients and healthy controls. These changes were present both in primary and secondary myelofibrosis, which showed no differences between them. Remarkably, most differentially methylated CpG were located outside gene promoter regions and showed significant association with enhancer regions. This aberrant enhancer hypermethylation was negatively correlated with the expression of 27 genes in the myelofibrosis cohort. Of these, we focused on the ZFP36L1 gene and validated its decreased expression and enhancer DNA hypermethylation in an independent cohort of patients and myeloid cell-lines. In vitro reporter assay and 5'-azacitidine treatment confirmed the functional relevance of hyper-methylation of ZFP36L1 enhancer. Furthermore, in vitro rescue of ZFP36L1 expression had an impact on cell proliferation and induced apoptosis in SET-2 cell line indicating a possible role of ZFP36L1 as a tumor suppressor gene in myelofibrosis. Collectively, we describe the DNA methylation profile of myelofibrosis, identifying extensive changes in enhancer elements and revealing ZFP36L1 as a novel candidate tumor suppressor gene.

SUBMITTER: Martinez-Calle N

PROVIDER: S-EPMC6669145 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Epigenomic profiling of myelofibrosis reveals widespread DNA methylation changes in enhancer elements and <i>ZFP36L1</i> as a potential tumor suppressor gene that is epigenetically regulated.

Martínez-Calle Nicolás N Pascual Marien M Ordoñez Raquel R Enériz Edurne San José ESJ Kulis Marta M Miranda Estíbaliz E Guruceaga Elisabeth E Segura Víctor V Larráyoz María José MJ Bellosillo Beatriz B Calasanz María José MJ Besses Carles C Rifón José J Martín-Subero José I JI Agirre Xabier X Prosper Felipe F

Haematologica 20190117 8

In this study we interrogated the DNA methylome of myelofibrosis patients using high-density DNA methylation arrays. We detected 35,215 differentially methylated CpG, corresponding to 10,253 genes, between myelofibrosis patients and healthy controls. These changes were present both in primary and secondary myelofibrosis, which showed no differences between them. Remarkably, most differentially methylated CpG were located outside gene promoter regions and showed significant association with enhan ...[more]

PMID: 30655376

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Project description:Gastric cancer is the second leading cause of cancer death and remains a major clinical challenge due to poor prognosis and limited treatment options. Therefore, the basic mechanisms underlying gastric tumorigenesis deserve investigation. Although regulation of the galactoside-binding lectin galectin-7 in cancer has been studied, its role in tumor formation and progression remains controversial. In this study, we investigated galectin-7 expression and its role in gastric cancer. Immunohistochemical staining using a tissue microarray of gastric cancer patients revealed significantly low expression levels of galectin-7 in malignant tissues compared with matched normal tissues, and decreased expression of galectin-7 in malignant tissues was associated with advanced TMN stage disease (p=0.034). Importantly, low expression of galectin-7 in normal tissues was associated with a poor survival rate (p=0.0561). Over-expression of galectin-7 in AGS gastric adenocarcinoma cells suppressed cell proliferation, migration, and invasion, whereas ablation of galectin-7 in KATO III gastric carcinoma cells reversed these properties. AGS cells that overexpressed galectin-7 could not form gastric tumors in xenografted mice. More than 70% hypermethylation was observed in 7 of 9 gastric cancer cell lines tested and 5-aza-cytidine treatment lowered galectin-7 expression by reducing methylation in 24 cancer cell lines from five different organ origins. We analyzed CpG islands in the galectin-7 genomic region and detected hypermethylation at +1566bp of exon 2, the predicted p53 binding region. DNA hypermethylation of this region was also detected in gastric cancer tissues from 20 patients. Taken together, our data indicate that galectin-7 has a tumor suppressive function, and that the gene is epigenetically modified by DNA methylation and significantly down-regulated in gastric cancer. Further study of galectin-7 regulation may lead to improved gastric cancer diagnosis and therapy.

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Dataset Information

Epigenomic profiling of myelofibrosis reveals widespread DNA methylation changes in enhancer elements and ZFP36L1 as a potential tumor suppressor gene that is epigenetically regulated.

Publications

Epigenomic profiling of myelofibrosis reveals widespread DNA methylation changes in enhancer elements and <i>ZFP36L1</i> as a potential tumor suppressor gene that is epigenetically regulated.

Similar Datasets

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