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Methylation Heterogeneity within Human non-functional Pancreatic neuroendocrine tumors (PanNETs)

ABSTRACT: DNA CpG methylation profiling of PanNETs patients samples were performed to understand genotype to phenotype corrlelations , novel molecular subtypes and cell of origins The most commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. Little is known about the cells-of-origin for non-functional neuroendocrine tumors. Here, we genotyped 64 PanNETs for mutations in ATRX, DAXX, and MEN1 and found 37 tumors (58%) carry mutations in these three genes (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis on 33 randomly selected cases to reveal two distinct subgroups with one group consisting entirely of A-D-M mutant PanNETs. Two biomarkers differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX gene expression and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha cells (pval < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117852 | GEO | 2018/10/01

REPOSITORIES: GEO

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Project description:In mammals, DNA methylation is essential for protecting repetitive sequences from aberrant transcription, translocation, and homologous recombination. However, DNA hypomethylation occurs during specific developmental stages (e.g. preimplantation embryos) and in certain cell types (e.g., primordial germ cells). The absence of dysregulated repetitive elements in these cells suggests the existence of alternative mechanisms that prevent genome instability triggered by DNA hypomethylation. In this report, we seek to elucidate the factors that play a critical role in ensuring genome stability by focusing on DAXX and ATRX, two proteins that have been linked to transcriptional control and epigenetic regulation. We carried out ChIP-seq and RNA-seq analyses to compare the genome-wide binding and transcriptome profiles of DAXX and ATRX in mouse ES (mES) cells triple knocked out for the three mammalian DNA methyltransferases (DNMTs) (TKO cells) to those in wildtype mES cells. Our data indicate that DAXX and ATRX are distinct in their chromatin-binding profiles and highly co-enriched at tandem repetitive elements. Global DNA hypomethylation, as was the case in TKO cells, further promoted the recruitment of the DAXX/ATRX complex to tandem repeat sequences including IAP (intracisternal A‐particle) retrotransposons and telomeres. Inhibition of DAXX or ATRX in cells with hypomethylated genomes (e.g., TKO cells, mES cells cultured in ground-state conditions, and preimplantation embryos) increased aberrant transcriptional de-repression of repeat elements and dysfunction at telomeres. Furthermore, we provide evidence that DAXX/ATRX-dependent silencing may occur through DAXX’s interaction with SUV39H1 and increased H3K9me3 on repetitive sequences. Our study suggests that DAXX and ATRX are important for safeguarding the genome, particularly in silencing repetitive elements in the absence of DNA methylation. We tested the hypothesis that the DAXX/ATRX complex participates in protecting repetitive elements in the absence of DNA methylation. To this end, we investigated genome-wide chromatin targeting of DAXX and ATRX in wildtype mES cells, and in mES cells that exhibit extensive loss of DNA methylation due to homozygous knockout of all three DNA.

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Methylation Heterogeneity within Human non-functional Pancreatic neuroendocrine tumors (PanNETs)

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