Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of chronic kidney disease with Polycystin (PKD) 1 and 2 gene mutation. However, the intra-familial variability in symptoms further suggests a non-Mendelian contribution to the disease. Our goal was to find a marker to track the epigenetic changes common to rapidly progressing forms of the disease. The risk of ADPKD increases with age, and aging shortens the telomere length (TL). Telomeres are a nucleoprotein structure composed mainly of three complexes, shelterin, CST and RNA-containing telomere repeat(TERRA), which protects the ends of chromosomes from degradation and fusion, and plays a role in maintaining cellular stability and in the repair of telomeric damage. TERRAs are transcribed from telomeric regions and a part of them is engaged in a DNA/RNA hybrid (R-loop) at each chromosome end. We tracked TL and TERRA levels in blood samples of 78 patients and 20 healthy control. Our study demonstrates that TL was shortened and TERRA expression levels in the DNA-attached fraction increased in autosomal dominant polycystic kidney patients with mutations in PKD1 and PKD2 compared to the control group. Moreover, it was observed that the expression of TERRA engaged in the R-loop was higher and the length of telomeres shorter in patients with ADPKD who showed rapid disease progression. Intrafamilial variation in TL and TERRA levels with the same mutation would indicate reliable epigenetic potential biomarkers in disease monitoring.

A wide range of diseases result from environmental effects, and the levels of many native transcripts are altered. The alteration of non-coding RNAs (ncRNAs) and transmission of the variation to the next generation is increasingly recognized as a marker of disease. However, the determining signals and mechanisms of RNA-induced heritability remain unclear. We performed functional tests with four different genotypes of mice maintained on a high-fat diet to trace the transfer of the obesity/diabetes phenotype to the next generation in order to detect common signals. Two founders of four mouse lines (B6/D2 hybrid and Dnmt2^{−/−C57BL/6}) resist and do not change their phenotype while their sperm RNAs after microinjection into fertilized mouse eggs transfer the newly acquired phenotypes in a susceptible inbred line (C57BL/6 or Balb/c). Unexpectedly, in the same line of experiments, sperm RNA from animals raised on a normal diet when mixed with the sperm RNA from animals raised on a diet high in fat or synthetic miR-19b (inducer of obesity) affects or prevents the development of obesity and diabetes. However, it remains unclear what happens to ncRNA signaling under diet. With a comprehensive new analysis of the transcripts maintained as an RNA/DNA hybrid in sperm, we suggest that a fraction of the RNAs are stably attached to the genome. Thus, we propose that changes in the dynamics of ncRNA retention on DNA by factors such as transcriptional variations or lack of adequate methylation could serve as molecular markers to trace these epigenetics events.

Purpose: Traumatic Brain Injury (TBI) poses a significant global health burden, with Mild TBI (mTBI) being the most prevalent form. TBI triggers activation of the hypothalamic–pituitary–adrenal (HPA) axis, which in turn affects the hypothalamic-pituitary–gonadal (HPG) axis regulating oogenesis and spermatogenesis. In this study, we investigated the impact of mTBI on sperm genome integrity using a repetitive mTBI (r-mTBI) mouse model. Methods: We assessed sperm telomere length (TL), free TERRA (fTERRA), and DNA/RNA hybrid TERRA (hTERRA) levels, alongside transcriptional changes in genes involved in TERRA regulation and DNA damage response. Results: Our findings reveal that a single mTBI event leads to a significant reduction in sperm TL during the acute phase, followed by an increase in TL during the chronic phase of r-mTBI, reminiscent of aging-associated changes. Moreover, we observed alterations in the transcription levels of Rad51, Exo1, Rb1, RNaseH1, and RNaseH2 genes, particularly in association with fTERRA and hTERRA levels, following mTBI. Conclusion: Understanding the potential non-Mendelian effects of TBI holds promise for elucidating TBI pathogenesis, mechanisms of TBI-induced diseases, and conditions of unknown etiology. Given the risks associated with repeated TBI exposure, especially in sports like football and boxing, consideration of potential paternal transmission of effects to offspring is crucial.

Objective: Breast cancer is a heterogeneous disease comprising distinct molecular subtypes, including estrogen receptor-positive (ER+) breast cancer and triple-negative breast cancer (TNBC). MicroRNAs (miRNAs) regulate post-transcriptional gene expression and play important roles in cancer progression by functioning as oncogenic or tumor-suppressive molecules. Forkhead box M1 (FOXM1) is an oncogenic transcription factor that is frequently upregulated in aggressive breast cancers, particularly TNBC, and is associated with proliferation, invasion, metastasis, therapy resistance, and poor prognosis. Materials and Methods: Clinically relevant miRNAs associated with survival in patients with ER+ and ER− breast cancer were identified using publicly available datasets. The expression levels of miR-34a-5p, miR-873-5p, miR-193b-5p, miR-330-5p, miR-10b-5p, miR-155-5p, and miR-484 were evaluated in MDA-MB-231 TNBC cells and MCF-7 ER+ breast cancer cells following FOXM1 knockdown. Results: FOXM1 knockdown was associated with increased expression of several tumor-suppressive miRNAs, including miR-34a-5p, miR-873-5p, miR-193b-5p, miR-330-5p, miR-10b-5p, and miR-484, in MDA-MB-231 cells. In contrast, most of these miRNAs were not markedly altered in MCF-7 cells, except for miR-10b-5p, whose expression decreased following FOXM1 knockdown. miR-155-5p expression remained largely unchanged in both cell lines. Conclusion: Our findings demonstrate that FOXM1 knockdown was associated with differential expression of clinically relevant miRNAs in the two breast cancer cell models examined. These findings suggest that FOXM1-associated alterations in miRNA expression may contribute to the aggressive phenotype of TNBC and warrant further mechanistic investigation.