DNA Damage Response Pathways meet Endocrine Systems

Editorial

27 January 2023

Editorial: DNA damage response pathways meet endocrine systems

Haim Werner

and

Leonard Girnita

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0 citations

Editors

Haim Werner

Tel Aviv University

Leonard Girnita

Karolinska Institutet (KI)

Impact

Original Research

10 October 2022

Integrative analysis reveals novel associations between DNA methylation and the serum metabolome of adolescents with type 2 diabetes: A cross-sectional study

Prasoon Agarwal

, 11 more and

Vernon W. Dolinsky

Objective: Rates of type 2 diabetes (T2D) among adolescents are on the rise. Epigenetic changes could be associated with the metabolic alterations in adolescents with T2D.

Methods: We performed a cross sectional integrated analysis of DNA methylation data from peripheral blood mononuclear cells with serum metabolomic data from First Nation adolescents with T2D and controls participating in the Improving Renal Complications in Adolescents with type 2 diabetes through Research (iCARE) cohort study, to explore the molecular changes in adolescents with T2D.

Results: Our analysis showed that 43 serum metabolites and 36 differentially methylated regions (DMR) were associated with T2D. Several DMRs were located near the transcriptional start site of genes with established roles in metabolic disease and associated with altered serum metabolites (e.g. glucose, leucine, and gamma-glutamylisoleucine). These included the free fatty acid receptor-1 (FFAR1), upstream transcription factor-2 (USF2), and tumor necrosis factor-related protein-9 (C1QTNF9), among others.

Conclusions: We identified DMRs and metabolites that merit further investigation to determine their significance in controlling gene expression and metabolism which could define T2D risk in adolescents.

4,298 views

11 citations

(A) Heatmap showing the DNA methylation pattern between CIMP (high-methylation) and nCIMP(low-methylation) using DNA methylation M-values. Kaplan-Meier curves between two epigenetic phenotypes regarding (B) OS (Overall survival) and (C) PFS (Progression free survival).

Original Research

24 October 2022

Characterization of the CpG island methylator phenotype subclass in papillary thyroid carcinoma

Pengfei Gu

, 8 more and

Ming Gao

3,237 views

4 citations

Original Research

31 May 2022

Novel Targeting of DNA Methyltransferase Activity Inhibits Ewing Sarcoma Cell Proliferation and Enhances Tumor Cell Sensitivity to DNA Damaging Drugs by Activating the DNA Damage Response

Camilla Cristalli

, 12 more and

Katia Scotlandi

DNA methylation is an important component of the epigenetic machinery that regulates the malignancy of Ewing sarcoma (EWS), the second most common primary bone tumor in children and adolescents. Coordination of DNA methylation and DNA replication is critical for maintaining epigenetic programming and the DNMT1 enzyme has been demonstrated to have an important role in both maintaining the epigenome and controlling cell cycle. Here, we showed that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 induces a specific depletion of DNMT1 and affects EWS tumor proliferation through a mechanism that is independent on DNA methylation. Depletion of DNMT1 causes perturbation of the cell cycle, with an accumulation of cells in the G1 phase, and DNA damage, as revealed by the induction of γH2AX foci. These effects elicited activation of p53-dependent signaling and apoptosis in p53wt cells, while in p53 mutated cells, persistent micronuclei and increased DNA instability was observed. Treatment with MC3343 potentiates the efficacy of DNA damaging agents such as doxorubicin and PARP-inhibitors (PARPi). This effect correlates with increased DNA damage and synergistic tumor cytotoxicity, supporting the use of the DNMTi MC3343 as an adjuvant agent in treating EWS.

3,880 views

10 citations

Original Research

04 August 2022

A comparison of DP-TOF Mass Spectroscopy (MS) and Next Generation Sequencing (NGS) methods for detecting molecular mutations in thyroid nodules fine needle aspiration biopsies

Xiao-qin Qian

, 10 more and

Fei-ju Xu

2,859 views

1 citations

Original Research

14 March 2022

Integrative Analysis of DNA Methylation and Gene Expression Identified Follicular Thyroid Cancer-Specific Diagnostic Biomarkers

Yunjin Yao

, 10 more and

Xiaoming Lou

The diagnosis of follicular thyroid carcinoma (FTC) prior surgical resection remains a challenge, as routine screening methods, such as ultrasound or even FNAB, could not diagnose FTC preoperatively. Here, we performed an integrative analysis of DNA methylation and RNA array data from our own cohort (14 Follicular thyroid carcinoma vs 16 Benign thyroid lesion) to identify thyroid cancer-specific DNA methylation markers. We first identified differentially methylated and expressed genes and examined their correlations. Candidate DNA methylation sites were selected and further verified in validation set. Among all candidate methylation sites, cg06928209 was the most promising site as a molecular marker for early diagnosis, with a sensitivity of 90%, a specificity of 80% and an AUC of 0.77. Overall, our study demonstrates the potential use of methylation markers in FTC diagnosis and may boost the development of new epigenetic therapies.

3,677 views

11 citations

Original Research

27 May 2022

The Effect of Sperm DNA Fragmentation on In Vitro Fertilization Outcomes for Women With Polycystic Ovary Syndrome

Huan Wang

, 6 more and

Qingling Yang

2,157 views

4 citations

Original Research

23 November 2021

Decreased DNA Repair Ability: A Mechanism for Low Early Embryonic Development Potential of Oocytes From Overweight Patients After Fertilization in IVF Cycles

Hui Li

, 6 more and

Qingling Yang

Background: Whether female BMI impacts the DNA repair ability in the oocytes after fertilization has not been investigated. The aim of this study is to assess the early embryo quality and reproductive outcomes of oocytes from overweight women when fertilized with sperm with varying degrees of DNA fragmentation.

Methods: A total number of 1,612 patients undergoing fresh autologous in vitro fertilization (IVF) cycles was included. These patients were divided into two groups according to maternal body mass index (BMI): normal weight group (18.5–24.9 kg/m²; n=1187; 73.64%) and overweight group (≥25 kg/m²; n=425; 26.36%). Each group was then subdivided into two groups by sperm DNA fragmentation index (DFI): low fragmentation group (<20% DFI, LF) and high fragmentation group (≥20% DFI, HF). Laboratory and clinical outcomes were compared between subgroups.

Results: For the normal-weight group, there was no statistical significance in embryo quality and reproductive outcomes between the LF and HF groups. But in the overweight group, significantly lower fertilization rate (LF: 64%; HF: 59%; p=0.011), blastocyst development rate (LF: 57%; HF: 44%; p=0.001), as well as high-quality blastocyst rate (LF: 32%; HF: 22%; p=0.034) were found in the HF group, despite the similar pregnancy rates (LF: 56%; HF: 60%; p=0.630).

Conclusions: Decreased DNA repair activity in oocytes may be a possible mechanism for the low early development potential of embryos from overweight patients in in vitro fertilization cycles.

2,242 views

7 citations