Search

PGC1α protects against kidney injury by upregulating enzymes that enhance nicotinamide adenine dinucleotide (NAD) and driving local accumulation of the fatty acid breakdown product β-hydroxybutyrate, which leads to increased production of the renoprotective prostaglandin E2.

Multiple myeloma (MM) is characterized by a highly unstable genome, with aneuploidy observed in nearly all patients. The mechanism causing this karyotypic instability is largely unknown, but recent observations have correlated these abnormalities with dysfunctional DNA damage response. Here, we show that the NAD+-dependent deacetylase SIRT6 is highly expressed in MM cells, as an adaptive response to genomic stability, and that high SIRT6 levels are associated with adverse prognosis. Mechanistically, SIRT6 interacts with the transcription factor ELK1 and with the ERK signaling-related gene. By binding to their promoters and deacetylating H3K9 at these sites, SIRT6 downregulates the expression of mitogen-activated protein kinase (MAPK) pathway genes, MAPK signaling, and proliferation. In addition, inactivation of ERK2/p90RSK signaling triggered by high SIRT6 levels increases DNA repair via Chk1 and confers resistance to DNA damage. Using genetic and biochemical studies in vitro and in human MM xenograft models, we show that SIRT6 depletion both enhances proliferation and confers sensitization to DNA-damaging agents. Our findings therefore provide insights into the functional interplay between SIRT6 and DNA repair mechanisms, with implications for both tumorigenesis and the treatment of MM.

Multiple myeloma (MM) is characterized by a highly unstable genome, with aneuploidy observed in nearly all patients. The mechanism causing this karyotypic instability is largely unknown, but recent observations have correlated these abnormalities with dysfunctional DNA damage response. Here, we show that the NAD+-dependent deacetylase SIRT6 is highly expressed in MM cells, as an adaptive response to genomic stability, and that high SIRT6 levels are associated with adverse prognosis. Mechanistically, SIRT6 interacts with the transcription factor ELK1 and with the ERK signaling-related gene. By binding to their promoters and deacetylating H3K9 at these sites, SIRT6 downregulates the expression of mitogen-activated protein kinase (MAPK) pathway genes, MAPK signaling, and proliferation. In addition, inactivation of ERK2/p90RSK signaling triggered by high SIRT6 levels increases DNA repair via Chk1 and confers resistance to DNA damage. Using genetic and biochemical studies in vitro and in human MM xenograft models, we show that SIRT6 depletion both enhances proliferation and confers sensitization to DNA-damaging agents. Our findings therefore provide insights into the functional interplay between SIRT6 and DNA repair mechanisms, with implications for both tumorigenesis and the treatment of MM.

The relationship between the host and its microbiota is challenging to understand because both microbial communities and their environments are highly variable. We have developed a set of techniques based on population dynamics and information theory to address this challenge. These methods identify additional bacterial taxa associated with pediatric Crohn disease and can detect significant changes in microbial communities with fewer samples than previous statistical approaches required. We have also substantially improved the accuracy of the diagnosis based on the microbiota from stool samples, and we found that the ecological niche of a microbe predicts its role in Crohn disease. Bacteria typically residing in the lumen of healthy individuals decrease in disease, whereas bacteria typically residing on the mucosa of healthy individuals increase in disease. Our results also show that the associations with Crohn disease are evolutionarily conserved and provide a mutual information-based method to depict dysbiosis.

PI3K-stimulated induction of pentraxin-3 links innate immune signaling with the growth of basal-like breast cancer.