BRCA1 mutation carriers face a high lifetime risk of developing breast cancer. Physical activity induces broad transcriptional changes and multiple studies have documented its beneficial effects across cancers. Since haploinsufficiency predisposes to breast cancer in these women, factors that increase BRCA1 levels may mitigate the effect of the mutation. Whether physical activity modulates BRCA1 expression, and whether lifestyle factors could benefit women with a mutation remains unclear. The objective of this study was to systematically evaluate whether physical activity or sedentary behavior affect BRCA1 mRNA expression. Activity levels were assessed in 50 female participants (14 BRCA1 mutation carriers and 36 non-carriers) using the GT3X Actigraph accelerometer, and BRCA1 mRNA expression was quantified from peripheral blood lymphocytes using the Nanostring nCounter Analysis System. There was a significant negative correlation between the longest sedentary bout and BRCA1 mRNA expression (ρ = ─ 0.32; P = 0.02). Women below the median for the longest sedentary bout had significantly higher BRCA1 mRNA levels compared to women above the median (161 vs. 132 counts; P = 0.04; one-sided Mann-Whitney U test). There was no significant relationship between mean Metabolic Equivalents of Task (MET) rate or mean sedentary time and BRCA1 mRNA expression (Spearman correlation P ≥ 0.75; P ≥ 0.14; Mann-Whitney U test). These findings suggest that prolonged periods of sedentary behavior are associated with significantly lower BRCA1 mRNA expression. Whether this translates into a potentially more harmful effect in BRCA1 mutation carriers warrants further investigation.

Werner syndrome (WS) is a premature aging disorder that mainly affects tissues derived from mesoderm. We have recently developed a novel human WS model using WRN-deficient human mesenchymal stem cells (MSCs). This model recapitulates many phenotypic features of WS. Based on a screen of a number of chemicals, here we found that Vitamin C exerts most efficient rescue for many features in premature aging as shown in WRN-deficient MSCs, including cell growth arrest, increased reactive oxygen species levels, telomere attrition, excessive secretion of inflammatory factors, as well as disorganization of nuclear lamina and heterochromatin. Moreover, Vitamin C restores in vivo viability of MSCs in a mouse model. RNA sequencing analysis indicates that Vitamin C alters the expression of a series of genes involved in chromatin condensation, cell cycle regulation, DNA replication, and DNA damage repair pathways in WRN-deficient MSCs. Our results identify Vitamin C as a rejuvenating factor for WS MSCs, which holds the potential of being applied as a novel type of treatment of WS.

Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by defined factors, which provide a powerful basis for personalized stem-cell based therapies. However, cellular reprogramming is an inefficient and metabolically demanding process commonly associated with obstacles that hamper further use of this technology. Spontaneous differentiation of iPS cells cultures represents a significant hurdle that hinder obtaining high quality iPS cells for further downstream experimentation. In this study, we found that a natural compound, vitamin C, augmented pluripotency in iPS cells and reduced unwanted spontaneous differentiation during iPS cells maintenance. Gene expression analysis showed that Vitamin C increased the expression of the histone demethylase JARID1A. Furthermore, through gain- and loss-of-function approaches, we show that JARID1A is a key effector in promoting pluripotency and reducing differentiation downstream of vitamin C. Our results therefore highlight a straightforward method for improving the pluripotency and quality of iPS cells; it also shows a possible role for H3K4me2/3 in cell fate determination and establishes a link between vitamin C and epigenetic regulation.