Papers by R. Mostoslavsky
Cold Spring Harbor Symposia on Quantitative Biology, 2011
Aberrant cholesterol/lipid homeostasis is linked to a number of diseases prevalent in the develop... more Aberrant cholesterol/lipid homeostasis is linked to a number of diseases prevalent in the developed world, including metabolic syndrome, type II diabetes, and cardiovascular disease. We have previously uncovered gene regulatory mechanisms of the sterol regulatory element-binding protein (SREBP) family of transcription factors, which control the expression of genes involved in cholesterol and lipid biosynthesis and uptake. Intriguingly, we recently discovered conserved microRNAs (miR-33a/b) embedded within intronic sequences of the human SREBF genes that act in a concerted manner with their host gene products to regulate cholesterol/lipid homeostasis. Indeed, miR-33a/b control the levels of ATP-binding cassette (ABC) transporter ABCA1, a cholesterol efflux pump critical for high-density lipoprotein (HDL) synthesis and reverse cholesterol transport from peripheral tissues. Importantly, antisense inhibition of miR-33 in mice results in elevated HDL and decreased atherosclerosis. Interestingly, miR-33a/b also act in the fatty acid/lipid homeostasis pathway by controlling the fatty acid boxidation genes carnitine O-octanoyltransferase (CROT), hydroxyacyl-coenzyme A-dehydrogenase (HADHB), and carnitine palmitoyltransferase 1A (CPT1A), as well as the energy sensor AMP-activated protein kinase (AMPKa1), the NAD þdependent sirtuin SIRT6, and the insulin signaling intermediate IRS2, key regulators of glucose and lipid metabolism. These results have revealed a highly integrated microRNA (miRNA)-host gene circuit governing cholesterol/lipid metabolism and energy homeostasis in mammals that may have important therapeutic implications for the treatment of cardiometabolic disorders.
Introductory Review on Sirtuins in Biology, Aging, and Disease, 2018
Abstract Sirtuins (SIRT) are highly conserved proteins first described as nicotinamide adenine di... more Abstract Sirtuins (SIRT) are highly conserved proteins first described as nicotinamide adenine dinucleotide (NAD+)-dependent type III histone deacetylases. They are the mammalian homologs of the SIR2 gene found in yeast. Seven homologs (SIRT1–7) have been described, all sharing an NAD+ binding catalytic domain comprising 275 amino acids and variable N and C termini. This difference in their terminal domains dictates distant roles and cellular localization of the members of the sirtuin family. In this review, we will focus on the chromatin deacetylase SIRT6, a multitasking protein with various roles in metabolism, development, DNA repair, and cancer. We will provide current knowledge in the context of its structure, enzymatic activity, and regulation. We will discuss its role in genomic stability and DNA repair, metabolism, and development. Finally, we will review SIRT6’s involvement in several diseases.
Chromatin Regulation and Dynamics, 2017
Abstract Chromatin modifications are established through the usage of chemical moieties attached ... more Abstract Chromatin modifications are established through the usage of chemical moieties attached to DNA and histones. In particular two of those modifications, acetylation and methylation, are obtained through direct utilization of intermediate metabolites (acetyl-CoA and S-adenosylmethionine), establishing an intimate crosstalk between metabolism and epigenetics. Although neglected for many years, recent advances have demonstrated that cellular metabolism, and more specifically changes in nutrient availability, directly influence epigenetic adaptations by means of histone modifications and DNA methylation. In this chapter, we will review the current literature linking metabolism to epigenetics, both in the context of normal physiology as well as the imbalance of such cross talk in disease.
We hypothesized that in individuals with previous SARS-CoV-2 infection, the first vaccine dose wo... more We hypothesized that in individuals with previous SARS-CoV-2 infection, the first vaccine dose would work as a booster, eliciting a faster and more intense immune response. We herein describe antibody responses to the first and second doses of Gam-COVID-Vac (SPUTNIK V) vaccine in health personnel of Tucumán, Argentina, with previous COVID-19 and compared it with uninfected personnel. Individuals with anti-SARS-CoV-2 titers at baseline showed significantly higher responses to the first dose than people with no prior history of disease (p <0.0001), with titers higher to those registered after the second dose in the control group, representing a clear secondary antibody response. This suggests that a single dose of SPUTNIK V for people with previous SARS-CoV-2 infection could contribute to a better use of available doses.One-Sentence SummaryFirst vaccine dose in subjects with prior COVID19 elicits a higher antibody response than two doses in uninfected individuals
Nature Genetics, 2000
A subset of mammalian genes is monoallelically expressed in a parent-of-origin manner. These gene... more A subset of mammalian genes is monoallelically expressed in a parent-of-origin manner. These genes are subject to an imprinting process that epigenetically marks alleles according to their parental origin during gametogenesis. Imprinted genes can be organized in clusters as exemplified by the 2-Mb domain on human chromosome 15q11-q13 and its mouse orthologue on chromosome 7c (ref. 1). Loss of this 2-Mb domain on the paternal or maternal allele results in two neurogenetic disorders, Prader-Willi syndrome (PWS) or Angelman syndrome (AS), respectively. Microdeletions on the paternal allele share a 4.3-kb short region of overlap (SRO), which includes the SNRPN promoter/exon1, cause PWS and silence paternally expressed genes. Microdeletions on the maternal allele share a 0.88-kb SRO located 35 kb upstream to the SNRPN promoter, cause AS and alleviate repression of genes on the maternal allele. Individuals carrying both AS and PWS deletions on the paternal allele show a PWS phenotype and genotype. These observations suggest that cis elements within the AS-SRO and PWS-SRO constitute an imprinting box that regulates the entire domain on both chromosomes. Here we show that a minitransgene composed of a 200-bp Snrpn promoter/exon1 and a 1-kb sequence located approximately 35 kb upstream to the SNRPN promoter confer imprinting as judged by differential methylation, parent-of-origin-specific transcription and asynchronous replication.
Atherosclerosis, 2016
Reference EPFL-CONF-225204View record in Web of Science Record created on 2017-01-24, modified on... more Reference EPFL-CONF-225204View record in Web of Science Record created on 2017-01-24, modified on 2017-05-12
Cancer discovery, 2014
Dietary composition has an important role in shaping the gut microbiota. In turn, changes in the ... more Dietary composition has an important role in shaping the gut microbiota. In turn, changes in the diet directly impinge on bacterial metabolites present in the intestinal lumen. Whether such metabolites play a role in intestinal cancer has been a topic of hot debate. In this issue of Cancer Discovery, Donohoe and colleagues show that dietary fiber protects against colorectal carcinoma in a microbiota-dependent manner. Furthermore, fiber-derived butyrate acts as a histone deacetylase inhibitor, inhibiting cell proliferation and inducing apoptosis in colorectal cancer cells experiencing the Warburg effect.
Cancer Discovery, 2013
Mitochondrial metabolism infl uences histone and DNA modifi cations by retrograde signaling and a... more Mitochondrial metabolism infl uences histone and DNA modifi cations by retrograde signaling and activation of transcriptional programs. Considering the high number of putative sites for acetylation and methylation in chromatin, we propose in this perspective article that epigenetic modifi cations might impinge on cellular metabolism by affecting the pool of acetyl-CoA and S -adenosylmethionine. Cancer Discov; 3(5); 497-501. ©2013 AACR.
Cell, 2006
Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, flies, and... more Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, flies, and worms. Mammals have seven Sir2 homologs (SIRT1-7). We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADPribosylate and downregulate glutamate dehydrogenase (GDH) activity. GDH is known to promote the metabolism of glutamate and glutamine, generating ATP, which promotes insulin secretion. Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acidstimulated insulin secretion. A similar effect is observed in pancreatic b cells from mice deficient in SIRT4 or on the dietary regimen of calorie restriction (CR). Furthermore, GDH from SIRT4deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation. These results indicate that SIRT4 functions in b cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR.
Uploads
Papers by R. Mostoslavsky