BRCA1, Hormone, and Tissue-Specific Tumor Suppression

Germline mutations of BRCA1 predispose women to breast and ovarian cancers. Elucidating molecular mechanism of tissue- and gender-specific phenomena in BRCA1-related tumors is a key to our understanding of BRCA1 function in tumor suppression. This review summarizes studies in recent years on the link between BRCA1 and estrogen/progesterone signaling pathways, as well as discusses various models underscoring a triangle relationship among BRCA1, estrogen and genome instability

Prediction of body fat increase from food addiction scale in school-aged children and adolescents: A longitudinal cross-lagged study

ObjectiveFood addiction (FA) is associated with a higher body mass index z-score (BMIZ) in children and adolescents; however, whether these two aspects evolve interdependently remains unknown. This study aimed to address this question using a cross-lagged study.MethodsWeight status, including BMIZ, fat content (FC), and visceral fat level (VFL), was determined in 880 children and adolescents (mean age = 14.02 years [range = 8.83–17.52 years]) at two-time points with an interval of 6 months. FA was characterized using the Chinese version of the dimensional Yale Food Addiction Scale for Children 2.0. Furthermore, FC and VFL were measured using direct segmental multi-frequency bioelectrical impedance analysis at each time point.ResultsHigher FA was associated with increased BMIZ, FC, and VFL (P < 0.05). FA at T0 could predict increased FC at T1 (P < 0.05). The characteristics of females, primary students, and living in urban areas may aggravate the adverse effect of FA on weight status over time and age, particularly the increased VFL in participants aged > 14 years.ConclusionChildren and adolescents with a high FA level were at risk for weight gain attributed to increased FC, and the adverse effect could be aggravated with time and age. Novel FA-targeting interventions may help mitigate the risk of getting obesity

Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development

Negative Elongation Factor Controls Energy Homeostasis in Cardiomyocytes

SummaryNegative elongation factor (NELF) is known to enforce promoter-proximal pausing of RNA polymerase II (Pol II), a pervasive phenomenon observed across multicellular genomes. However, the physiological impact of NELF on tissue homeostasis remains unclear. Here, we show that whole-body conditional deletion of the B subunit of NELF (NELF-B) in adult mice results in cardiomyopathy and impaired response to cardiac stress. Tissue-specific knockout of NELF-B confirms its cell-autonomous function in cardiomyocytes. NELF directly supports transcription of those genes encoding rate-limiting enzymes in fatty acid oxidation (FAO) and the tricarboxylic acid (TCA) cycle. NELF also shares extensively transcriptional target genes with peroxisome proliferator-activated receptor α (PPARα), a master regulator of energy metabolism in the myocardium. Mechanistically, NELF helps stabilize the transcription initiation complex at the metabolism-related genes. Our findings strongly indicate that NELF is part of the PPARα-mediated transcription regulatory network that maintains metabolic homeostasis in cardiomyocytes

Soil diazotrophic abundance, diversity, and community assembly mechanisms significantly differ between glacier riparian wetlands and their adjacent alpine meadows

Global warming can trigger dramatic glacier area shrinkage and change the flux of glacial runoff, leading to the expansion and subsequent retreat of riparian wetlands. This elicits the interconversion of riparian wetlands and their adjacent ecosystems (e.g., alpine meadows), probably significantly impacting ecosystem nitrogen input by changing soil diazotrophic communities. However, the soil diazotrophic community differences between glacial riparian wetlands and their adjacent ecosystems remain largely unexplored. Here, soils were collected from riparian wetlands and their adjacent alpine meadows at six locations from glacier foreland to lake mouth along a typical Tibetan glacial river in the Namtso watershed. The abundance and diversity of soil diazotrophs were determined by real-time PCR and amplicon sequencing based on nifH gene. The soil diazotrophic community assembly mechanisms were analyzed via iCAMP, a recently developed null model-based method. The results showed that compared with the riparian wetlands, the abundance and diversity of the diazotrophs in the alpine meadow soils significantly decreased. The soil diazotrophic community profiles also significantly differed between the riparian wetlands and alpine meadows. For example, compared with the alpine meadows, the relative abundance of chemoheterotrophic and sulfate-respiration diazotrophs was significantly higher in the riparian wetland soils. In contrast, the diazotrophs related to ureolysis, photoautotrophy, and denitrification were significantly enriched in the alpine meadow soils. The iCAMP analysis showed that the assembly of soil diazotrophic community was mainly controlled by drift and dispersal limitation. Compared with the riparian wetlands, the assembly of the alpine meadow soil diazotrophic community was more affected by dispersal limitation and homogeneous selection. These findings suggest that the conversion of riparian wetlands and alpine meadows can significantly alter soil diazotrophic community and probably the ecosystem nitrogen input mechanisms, highlighting the enormous effects of climate change on alpine ecosystems

Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 50 end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development

Unimodal productivity-biodiversity relationship along the gradient of multidimensional resources across Chinese grasslands

Resources can affect plant productivity and biodiversity simultaneously and thus are key drivers of their relationships in addition to plant-plant interactions. However, most previous studies only focused on a single resource while neglecting the nature of resource multidimensionality. Here we integrated four essential resources for plant growth into a single metric of resource diversity (RD) to investigate its effects on the productivity-biodiversity relationship (PBR) across Chinese grasslands. Results showed that habitats differing in RD have different PBRs − positive in low-resource habitats, but neutral in medium- and high-resource ones—while collectively, a weak positive PBR was observed. However, when excluding direct effects of RD on productivity and biodiversity, PBR in high-resource habitats became negative, which leads to a unimodal instead of a positive PBR along the RD gradient. By integrating resource effects and changing plant-plant interactions into a unified framework with the RD gradient, our work contributes to uncovering underlying mechanisms for inconsistent PBRs at large scales