Differential DNA Methylation in Prostate Tumors from Puerto Rican Men

In 2020, approximately 191,930 new prostate cancer (PCa) cases are estimated in the United States (US). Hispanic/Latinos (H/L) are the second largest racial/ethnic group in the US. This study aims to assess methylation patterns between aggressive and indolent PCa including DNA repair genes along with ancestry proportions. Prostate tumors classified as aggressive (n = 11) and indolent (n = 13) on the basis of the Gleason score were collected. Tumor and adjacent normal tissue were annotated on H&E (Haemotoxylin and Eosin) slides and extracted by macro-dissection. Methylation patterns were assessed using the Illumina 850K DNA methylation platform. Raw data were processed using the Bioconductor package. Global ancestry proportions were estimated using ADMIXTURE (k = 3). One hundred eight genes including AOX1 were differentially methylated in tumor samples. Regarding the PCa aggressiveness, six hypermethylated genes (RREB1, FAM71F2, JMJD1C, COL5A3, RAE1, and GABRQ) and 11 hypomethylated genes (COL9A2, FAM179A, SLC17A2, PDE10A, PLEKHS1, TNNI2, OR51A4, RNF169, SPNS2, ADAMTSL5, and CYP4F12) were identified. Two significant differentially methylated DNA repair genes, JMJD1C and RNF169, were found. Ancestry proportion results for African, European, and Indigenous American were 24.1%, 64.2%, and 11.7%, respectively. The identification of DNA methylation patterns related to PCa in H/L men along with specific patterns related to aggressiveness and DNA repair constitutes a pivotal effort for the understanding of PCa in this population.

Download Full-text

The influence of polymorphisms of xenobiotic-metabolizing and DNA repair genes in DNA damage, telomere length and global DNA methylation evaluated in open-cast coal mining workers

Ecotoxicology and Environmental Safety ◽

10.1016/j.ecoenv.2019.109975 ◽

2020 ◽

Vol 189 ◽

pp. 109975 ◽

Cited By ~ 2

Author(s):

Melissa Rosa de Souza ◽

Paula Rohr ◽

Vivian Francília Silva Kahl ◽

Kátia Kvitko ◽

Mónica Cappetta ◽

...

Keyword(s):

Dna Methylation ◽

Dna Damage ◽

Dna Repair ◽

Telomere Length ◽

Coal Mining ◽

Global Dna Methylation ◽

Dna Repair Genes ◽

Repair Genes ◽

Open Cast

Download Full-text

Dysregulation of DNA Methylation and Epigenetic Clocks in Prostate Cancer among Puerto Rican Men

Biomolecules ◽

10.3390/biom12010002 ◽

2021 ◽

Vol 12 (1) ◽

pp. 2

Author(s):

Anders Berglund ◽

Jaime Matta ◽

Jarline Encarnación-Medina ◽

Carmen Ortiz-Sanchéz ◽

Julie Dutil ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Methylation ◽

Stem Cell ◽

The United States ◽

Epigenetic Clock ◽

Normal Tissues ◽

Differentially Methylated Genes ◽

Stem Cell Divisions ◽

Methylation Patterns ◽

Ancestry Proportions

In 2021, approximately 248,530 new prostate cancer (PCa) cases are estimated in the United States. Hispanic/Latinos (H/L) are the second largest racial/ethnic group in the US. The objective of this study was to assess DNA methylation patterns between aggressive and indolent PCa along with ancestry proportions in 49 H/L men from Puerto Rico (PR). Prostate tumors were classified as aggressive (n = 17) and indolent (n = 32) based on the Gleason score. Genomic DNA samples were extracted by macro-dissection. DNA methylation patterns were assessed using the Illumina EPIC DNA methylation platform. We used ADMIXTURE to estimate global ancestry proportions. We identified 892 differentially methylated genes in prostate tumor tissues as compared with normal tissues. Based on an epigenetic clock model, we observed that the total number of stem cell divisions (TNSC) and stem cell division rate (SCDR) were significantly higher in tumor than adjacent normal tissues. Regarding PCa aggressiveness, 141 differentially methylated genes were identified. Ancestry proportions of PR men were estimated as African, European, and Indigenous American; these were 24.1%, 64.2%, and 11.7%, respectively. The identification of DNA methylation profiles associated with risk and aggressiveness of PCa in PR H/L men will shed light on potential mechanisms contributing to PCa disparities in PR population.

Download Full-text

TET1 Modulates H4K16 Acetylation by Interacting with hMOF to Regulate Expression of DNA Repair Genes and Oncogenic Transformation

10.1101/024844 ◽

2015 ◽

Author(s):

Jianing Zhong ◽

Xianfeng Li ◽

Wanshi Cai ◽

Yan Wang ◽

Shanshan Dong ◽

...

Keyword(s):

Dna Methylation ◽

Dna Repair ◽

Embryonic Stem ◽

Genomic Analysis ◽

Dna Demethylation ◽

Dna Repair Genes ◽

Histone H4 ◽

Dna Double Strand Breaks ◽

Independent Manner ◽

Repair Genes

The Ten Eleven Translocation 1 (TET1) protein is a DNA demethylase that regulates gene expression through alteration of DNA methylation. Recent studies have demonstrated that TET1 could modulate transcriptional expression independent of its DNA demethylation activity; however, the detailed mechanisms underlying TET1’s role in such transcriptional regulation remain not well understood. Here, we uncovered that Tet1 formed a chromatin complex with histone acetyltransferase Mof and scaffold protein Sin3a in mouse embryonic stem cells by integrative genomic analysis using publicly available ChIP-seq data sets. Specifically, the TET1/SIN3A/hMOF complex mediates acetylation of histone H4 at lysine 16, via facilitating the binding of hMOF on chromatin, to regulate expression of important DNA repair genes in DNA double strand breaks, including TP53BP1, RAD50, RAD51, and BRCA1, for homologous recombination and non-homologous end joining repairs. Under hydrogen peroxide-induced DNA damage, dissociation of TET1 and hMOF from chromatin, concurrent with increased binding of SIRT1 on chromatin, led to hypo-acetylation of H4K16, reduced expression of these DNA repair genes, and DNA repair defects in a DNA methylation independent manner. A similar epigenetic dynamic alteration was also observed in H-RASV12 oncogenic-transformed cells, supporting the notion that suppression of TET1 downregulates DNA repair genes through modifying H4K16ac, instead of its demethylation function, and therefore contribute to tumorigenesis. Taken together, our results suggested a mechanistic link between a novel TET1 complex and H4K16ac, DNA repair genes expression, and genomic instability.

Download Full-text

Role of the DNA repair genes H2AX and HMGB1 in human fat distribution and lipid profiles

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000831 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000831

Author(s):

Kerstin Rohde ◽

Torunn Rønningen ◽

Lars la Cour Poulsen ◽

Maria Keller ◽

Matthias Blüher ◽

...

Keyword(s):

Dna Methylation ◽

Dna Repair ◽

Density Lipoprotein ◽

Fat Distribution ◽

Lipoprotein Cholesterol ◽

Mrna Levels ◽

Dna Repair Genes ◽

Specific Regulation ◽

Repair Genes

IntroductionRegional fat distribution strongly relates to metabolic comorbidities. We identified the DNA repair genes H2AX and HMGB1 to be differentially expressed between human subcutaneous (SAT) and omental visceral adipose tissue (OVAT) depots. As increased DNA damage is linked to metabolic disease, we here sought to analyze whether depot-specific H2AX and HMGB1 expression is related to anthropometric and metabolic profiles of obesity. We further tested for different H2AX mRNA regulatory mechanisms by analyzing promoter DNA methylation and genotyped rs7350 in the H2AX locus.Research design and methodsGene expression (OVAT n=48; SAT n=55) and DNA promoter methylation data (OVAT and SAT n=77) were extracted from an existing dataset as described elsewhere. Genotype data for the 3’untranslated region (3’UTR) H2AX variant rs7350 were generated by using the TaqMan genotyping system in 243 subjects of the same cohort. Statistical analyses were done using SPSS statistics software 24 and GraphPad Prism 6.ResultsWe identified H2AX being higher (p=0.002) and HMGB1 being less expressed (p=0.0001) in OVAT compared with SAT. Further, we observed positive interdepot correlations of OVAT and SAT for both HMGB1 (p=1×10–6) and H2AX mRNA levels (p=0.024). Depot-specific associations were observed for both genes’ methylation levels with either high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides and/or with OVAT/SAT-ratio (all p<0.05). A significantly lower level of total cholesterol in minor A-Allele carriers of rs7350 compared with AG and GG carriers (p=0.001) was observed. Additionally, subjects carrying the A-allele showed lower SAT HMGB1 expression level (p=0.030).ConclusionOur results suggest a fat depot-specific regulation of H2AX and HMGB1 potentially mediated by both DNA methylation and genetic variation. Rs7350, DNA methylation and/or mRNA levels of H2AX and HMGB1 are related to lipid parameters. Further studies are warranted to evaluate the functional role of the DNA repair genes H2AX and HMGB1 in obesity and fat distribution.

Download Full-text