Epigenetic adaptation drives monocyte differentiation into microglia-like cells upon engraftment into the retina.

The identification of specific markers for microglia has been a long-standing challenge. Recently, markers such as P2ry12, TMEM119, and Fcrls have been proposed as microglia-specific and widely used to explore microglial functions within various central nervous system (CNS) contexts. The specificity of these markers was based on the assumption that circulating monocytes retain their distinct signatures even after infiltrating the CNS.

Subcellular one carbon metabolism in cancer, aging and epigenetics.

The crosstalk between metabolism and epigenetics is an emerging field that is gaining importance in different areas such as cancer and aging, where changes in metabolism significantly impacts the cellular epigenome, in turn dictating changes in chromatin as an adaptive mechanism to bring back metabolic homeostasis. A key metabolic pathway influencing an organism's epigenetic state is one-carbon metabolism (OCM), which includes the folate and methionine cycles. Together, these cycles generate S-adenosylmethionine (SAM), the universal methyl donor essential for DNA and histone methylation.

The glutathione S-transferase Gstt1 drives survival and dissemination in metastases.

Identifying the adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (pancreatic adenocarcinoma, PDA). A loss-of-function shRNA targeted screen in metastatic-derived cells identified Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for dissemination and metastasis, but dispensable for primary tumour growth. Gstt1 is expressed in latent disseminated tumour cells (DTCs), is retained within a subpopulation of slow-cycling cells within existing metastases, and its inhibition leads to complete regression of macrometastatic tumours.

Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells.

Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood.

NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer.

Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator, KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers; however, the role of this pathway in cancers with wild-type KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small cell lung cancer cell lines.

SIRT6 is a key regulator of mitochondrial function in the brain.

The SIRT6 deacetylase has been implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it has critical roles in the brain ranging from its development to neurodegeneration. Here, we combined transcriptomics and metabolomics approaches to characterize the functions of SIRT6 in mouse brains. Our analysis reveals that SIRT6 is a central regulator of mitochondrial activity in the brain.

Loss of epigenetic information as a cause of mammalian aging.

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation.

Sirtuin 6 inhibition protects against glucocorticoid-induced skeletal muscle atrophy by regulating IGF/PI3K/AKT signaling.

Chronic activation of stress hormones such as glucocorticoids leads to skeletal muscle wasting in mammals. However, the molecular events that mediate glucocorticoid-induced muscle wasting are not well understood. Here, we show that SIRT6, a chromatin-associated deacetylase indirectly regulates glucocorticoid-induced muscle wasting by modulating IGF/PI3K/AKT signaling.

DNA repair as a shared hallmark in cancer and ageing.

Increasing evidence demonstrates that DNA damage and genome instability play a crucial role in ageing. Mammalian cells have developed a wide range of complex and well-orchestrated DNA repair pathways to respond to and resolve many different types of DNA lesions that occur from exogenous and endogenous sources. Defects in these repair pathways lead to accelerated or premature ageing syndromes and increase the likelihood of cancer development.

Liquid biopsy reveals collateral tissue damage in cancer.

Cancer inflicts damage to surrounding normal tissues, which can culminate in fatal organ failure. Here, we demonstrate that cell death in organs affected by cancer can be detected by tissue-specific methylation patterns of circulating cell-free DNA (cfDNA). We detected elevated levels of hepatocyte-derived cfDNA in the plasma of patients with liver metastases originating from different primary tumors, compared with cancer patients without liver metastases.

Assessing kinetics and recruitment of DNA repair factors using high content screens.

Repair of genetic damage is coordinated in the context of chromatin, so cells dynamically modulate accessibility at DNA breaks for the recruitment of DNA damage response (DDR) factors. The identification of chromatin factors with roles in DDR has mostly relied on loss-of-function screens while lacking robust high-throughput systems to study DNA repair. In this study, we have developed two high-throughput systems that allow the study of DNA repair kinetics and the recruitment of factors to double-strand breaks in a 384-well plate format.

Long-term analysis of antibodies elicited by SPUTNIK V: A prospective cohort study in Tucumán, Argentina.

Background: Gam-COVID-Vac (SPUTNIK V) has been granted emergency use authorization in 70 nations and has been administered to millions worldwide. However, there are very few peer-reviewed studies describing its effects. Independent reports regarding safety and effectiveness could accelerate the final approval by the WHO.

Elevated Humoral Immune Response to SARS-CoV-2 at High Altitudes Revealed by an Anti-RBD "" ELISA.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a global pandemic with dramatic health and socioeconomic consequences. The Coronavirus Disease 2019 (COVID-19) challenges health systems to quickly respond by developing new diagnostic strategies that contribute to identify infected individuals, monitor infections, perform contact-tracing, and limit the spread of the virus. In this brief report, we developed a highly sensitive, specific, and precise "" ELISA to correctly discriminate previously SARS-CoV-2-infected and non-infected individuals and study population seroprevalence.

SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ.

Pathological lipid accumulation is often associated with enhanced uptake of free fatty acids via specific transporters in cardiomyocytes. Here, we identify SIRT6 as a critical transcriptional regulator of fatty acid transporters in cardiomyocytes. We find that SIRT6 deficiency enhances the expression of fatty acid transporters, leading to enhanced fatty acid uptake and lipid accumulation.

A unique subset of glycolytic tumour-propagating cells drives squamous cell carcinoma.

Head and neck squamous cell carcinoma (SCC) remains among the most aggressive human cancers. Tumour progression and aggressiveness in SCC are largely driven by tumour-propagating cells (TPCs). Aerobic glycolysis, also known as the Warburg effect, is a characteristic of many cancers; however, whether this adaptation is functionally important in SCC, and at which stage, remains poorly understood.

Nuclear metabolism and the regulation of the epigenome.

Cellular metabolism has emerged as a major biological node governing cellular behaviour. Metabolic pathways fuel cellular energy needs, providing basic chemical molecules to sustain cellular homeostasis, proliferation and function. Changes in nutrient consumption or availability therefore can result in complete reprogramming of cellular metabolism towards stabilizing core metabolite pools, such as ATP, S-adenosyl methionine, acetyl-CoA, NAD/NADP and α-ketoglutarate.

Resveratrol: Friend or Foe?

In this issue of Molecular Cell, Benslimane et al. (2020) perform a CRISPR-Cas9 chemogenomic screen, identifying a network of DNA replication and genome integrity genes with the nutraceutical compound Resveratrol and its analog Pterostilbene, linking these compounds to the induction of DNA replication stress in mammalian cells.

Sirt6 deletion in bone marrow-derived cells increases atherosclerosis - Central role of macrophage scavenger receptor 1.

Aims: Sirtuin 6 (Sirt6) is a NAD-dependent deacetylase that plays a key role in DNA repair, inflammation and lipid regulation. Sirt6-null mice show severe metabolic defects and accelerated aging. Macrophage-foam cell formation via scavenger receptors is a key step in atherogenesis.

Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1.

mTORC2 controls glucose and lipid metabolism, but the mechanisms are unclear. Here, we show that conditionally deleting the essential mTORC2 subunit Rictor in murine brown adipocytes inhibits de novo lipid synthesis, promotes lipid catabolism and thermogenesis, and protects against diet-induced obesity and hepatic steatosis. AKT kinases are the canonical mTORC2 substrates; however, deleting Rictor in brown adipocytes appears to drive lipid catabolism by promoting FoxO1 deacetylation independently of AKT, and in a pathway distinct from its positive role in anabolic lipid synthesis.