TET Upregulation Leads to 5-Hydroxymethylation Enrichment in Hepatoblastoma.

Maria Prates Rivas,Luiz Carlos Caires-Júnior,Ana Cristina Victorino Krepischi,Monica Cypriano,Ernesto Goulart,Kayque Alves Telles-Silva,Silvia Regina Caminada De Toledo,Cecilia Maria Lima Da Costa,Gustavo Ribeiro Fernandes,Talita Ferreira Marques Aguiar,Isabela Werneck Da Cunha,Dirce Maria Carraro,Carla Rosenberg

doi:10.3389/fgene.2019.00553

Abstract

Hepatoblastoma is an embryonal liver tumor carrying few genetic alterations. We previously disclosed in hepatoblastomas a genome-wide methylation dysfunction, characterized by hypermethylation at specific CpG islands, in addition to a low-level hypomethylation pattern in non-repetitive intergenic sequences, in comparison to non-tumoral liver tissues, shedding light into a crucial role for epigenetic dysregulation in this type of cancer. To explore the underlying mechanisms possibly related to aberrant epigenetic modifications, we evaluated the expression profile of a set of genes engaged in the epigenetic machinery related to DNA methylation (DNMT1, DNMT3A, DNMT3B, DNMT3L, UHRF1, TET1, TET2, and TET3), as well as the 5-hydroxymethylcytosine (5hmC) global level. We observed in hepatoblastomas a general disrupted expression of these genes from the epigenetic machinery, mainly UHRF1, TET1, and TET2 upregulation, in association with an enrichment of 5hmC content. Our findings support a model of active demethylation by TETs in hepatoblastoma, probably during early stages of liver development, which in combination with UHRF1 overexpression would lead to DNA hypomethylation and an increase in overall 5hmC content. Furthermore, our data suggest that decreased 5hmC content might be associated with poor survival rate, highlighting a pivotal role of epigenetics in hepatoblastoma development and progression.

Highlights

Pediatric tumors are inherently different from tumors that develop in adults (Maris and Denny, 2002) since they are supposedly derived from defects of cell differentiation and organogenesis (Anderson, 2006)
The hydroxymethylation process was evaluated by assessing the expression level of the three TET genes, and all of them were found to be significantly upregulated in hepatoblastomas as compared to non-tumoral liver tissue (Figure 2A): TET1, TET2, and TET3
Except for the UHRF1 gene (Beck et al, 2018), here we disclosed for the first time dysregulated expression of genes from the DNA methylation machinery that could be related to the detected epigenetic disturbance, such as upregulation of DNMT3A, DNMT1, UHRF1, and the TET family of genes

Summary

Introduction

Pediatric tumors are inherently different from tumors that develop in adults (Maris and Denny, 2002) since they are supposedly derived from defects of cell differentiation and organogenesis (Anderson, 2006). A more comprehensive background takes into account the dysregulation of epigenetic mechanisms (Sandoval and Esteller, 2012), considering the interplay between genetic and epigenetic factors as a key element for tumor development (Soo You and Jones, 2012). Well-known DNA methylation disturbances include repression of tumor suppressor genes by promoter hypermethylation, and hypomethylation at repetitive sequences, leading to genomic instability (Łuczak and Jagodzinski, 2006; Rodrigues-Paredez and Esteller, 2011)

Methods

Results

Conclusion