Aging-Dependent Demethylation of Regulatory Elements Correlates with Chromatin State and Improved β Cell Function.

Abstract:

:Aging is driven by changes of the epigenetic state that are only partially understood. We performed a comprehensive epigenomic analysis of the pancreatic β cell, key player in glucose homeostasis, in adolescent and very old mice. We observe a global methylation drift resulting in an overall more leveled methylome in old β cells. Importantly, we discover targeted changes in the methylation status of β cell proliferation and function genes that go against the global methylation drift, are specific to β cells, and correlate with repression of the proliferation program and activation of metabolic regulators. These targeted alterations are associated with specific chromatin marks and transcription factor occupancy in young β cells. Strikingly, we find β cell function improved in aged mice, as predicted by the changes in methylome and transcriptome. Thus, aging of terminally differentiated cells in mammals is not always coupled to functional decline.

journal_name

Cell Metab

journal_title

Cell metabolism

authors

Avrahami D,Li C,Zhang J,Schug J,Avrahami R,Rao S,Stadler MB,Burger L,Schübeler D,Glaser B,Kaestner KH

doi

10.1016/j.cmet.2015.07.025

subject

Has Abstract

pub_date

2015-10-06 00:00:00

pages

619-32

issue

4

eissn

1550-4131

issn

1932-7420

pii

S1550-4131(15)00388-5

journal_volume

22

pub_type

杂志文章
  • AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control.

    abstract::The AMPK (AMP-activated protein kinase) and TOR (target-of-rapamycin) pathways are interlinked, opposing signaling pathways involved in sensing availability of nutrients and energy and regulation of cell growth. AMPK (Yin, or the "dark side") is switched on by lack of energy or nutrients and inhibits cell growth, whil...

    journal_title:Cell metabolism

    pub_type: 杂志文章,评审

    doi:10.1016/j.cmet.2020.01.015

    authors: González A,Hall MN,Lin SC,Hardie DG

    更新日期:2020-03-03 00:00:00

  • ATF4-Induced Metabolic Reprograming Is a Synthetic Vulnerability of the p62-Deficient Tumor Stroma.

    abstract::Tumors undergo nutrient stress and need to reprogram their metabolism to survive. The stroma may play a critical role in this process by providing nutrients to support the epithelial compartment of the tumor. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation by the di...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2017.09.001

    authors: Linares JF,Cordes T,Duran A,Reina-Campos M,Valencia T,Ahn CS,Castilla EA,Moscat J,Metallo CM,Diaz-Meco MT

    更新日期:2017-12-05 00:00:00

  • A noncanonical, GSK3-independent pathway controls postprandial hepatic glycogen deposition.

    abstract::Insulin rapidly suppresses hepatic glucose production and slowly decreases expression of genes encoding gluconeogenic proteins. In this study, we show that an immediate effect of insulin is to redirect newly synthesized glucose-6-phosphate to glycogen without changing the rate of gluconeogenesis. This process requires...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2013.06.001

    authors: Wan M,Leavens KF,Hunter RW,Koren S,von Wilamowitz-Moellendorff A,Lu M,Satapati S,Chu Q,Sakamoto K,Burgess SC,Birnbaum MJ

    更新日期:2013-07-02 00:00:00

  • Di-methylation of CD147-K234 Promotes the Progression of NSCLC by Enhancing Lactate Export.

    abstract::CD147 is a tumor-associated glycoprotein that regulates cell metabolism. However, CD147 methylation and its subsequent role in cancer cell metabolism remain unclear. Here, we detect CD147 di-methylation in 16 non-small-cell lung cancer (NSCLC) tissues using liquid chromatography-tandem mass spectrometry. CD147 is di-m...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2020.12.010

    authors: Wang K,Huang W,Chen R,Lin P,Zhang T,Ni YF,Li H,Wu J,Sun XX,Geng JJ,Zhu YM,Nan G,Zhang W,Chen X,Zhu P,Bian H,Chen ZN

    更新日期:2021-01-05 00:00:00

  • Differential Metabolic Reprogramming by Zika Virus Promotes Cell Death in Human versus Mosquito Cells.

    abstract::Zika virus is a pathogen that poses serious consequences, including congenital microcephaly. Although many viruses reprogram host cell metabolism, whether Zika virus alters cellular metabolism and the functional consequences of Zika-induced metabolic changes remain unknown. Here, we show that Zika virus infection diff...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2019.01.024

    authors: Thaker SK,Chapa T,Garcia G Jr,Gong D,Schmid EW,Arumugaswami V,Sun R,Christofk HR

    更新日期:2019-05-07 00:00:00

  • NAD+ Metabolism and Signaling.

    abstract::We caught up with some of the leading researchers in the NAD+ metabolism and signaling field as they gathered in Dublin for the 2019 FASEB Science Research Conference. Here they share their excitement from the rich history of NAD+ biology dating back over 100 years ago to a future of translation benefiting human healt...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2019.06.013

    authors:

    更新日期:2019-07-02 00:00:00

  • JAK/STAT3-Regulated Fatty Acid β-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance.

    abstract::Cancer stem cells (CSCs) are critical for cancer progression and chemoresistance. How lipid metabolism regulates CSCs and chemoresistance remains elusive. Here, we demonstrate that JAK/STAT3 regulates lipid metabolism, which promotes breast CSCs (BCSCs) and cancer chemoresistance. Inhibiting JAK/STAT3 blocks BCSC self...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2017.11.001

    authors: Wang T,Fahrmann JF,Lee H,Li YJ,Tripathi SC,Yue C,Zhang C,Lifshitz V,Song J,Yuan Y,Somlo G,Jandial R,Ann D,Hanash S,Jove R,Yu H

    更新日期:2018-01-09 00:00:00

  • Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan.

    abstract::Healthy aging depends on removal of damaged cellular material that is in part mediated by autophagy. The nutritional status of cells affects both aging and autophagy through as-yet-elusive metabolic circuitries. Here, we show that nucleocytosolic acetyl-coenzyme A (AcCoA) production is a metabolic repressor of autopha...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2014.02.010

    authors: Eisenberg T,Schroeder S,Andryushkova A,Pendl T,Küttner V,Bhukel A,Mariño G,Pietrocola F,Harger A,Zimmermann A,Moustafa T,Sprenger A,Jany E,Büttner S,Carmona-Gutierrez D,Ruckenstuhl C,Ring J,Reichelt W,Schimmel K,Lee

    更新日期:2014-03-04 00:00:00

  • MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2.

    abstract::Repression of mitochondrial respiration represents an evolutionarily ancient cellular adaptation to hypoxia and profoundly influences cell survival and function; however, the underlying molecular mechanisms are incompletely understood. Primarily utilizing pulmonary arterial endothelial cells as a representative hypoxi...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2009.08.015

    authors: Chan SY,Zhang YY,Hemann C,Mahoney CE,Zweier JL,Loscalzo J

    更新日期:2009-10-01 00:00:00

  • TRPM channels mediate zinc homeostasis and cellular growth during Drosophila larval development.

    abstract::TRPM channels have emerged as key mediators of diverse physiological functions. However, the ionic permeability relevant to physiological function in vivo remains unclear for most members. We report that the single Drosophila TRPM gene (dTRPM) generates a conductance permeable to divalent cations, especially Zn(2+) an...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2010.08.012

    authors: Georgiev P,Okkenhaug H,Drews A,Wright D,Lambert S,Flick M,Carta V,Martel C,Oberwinkler J,Raghu P

    更新日期:2010-10-06 00:00:00

  • Molecular control of systemic bile acid homeostasis by the liver glucocorticoid receptor.

    abstract::Systemic bile acid (BA) homeostasis is a critical determinant of dietary fat digestion, enterohepatic function, and postprandial thermogenesis. However, major checkpoints for the dynamics and the molecular regulation of BA homeostasis remain unknown. Here we show that hypothalamic-pituitary-adrenal (HPA) axis impairme...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2011.04.010

    authors: Rose AJ,Berriel Díaz M,Reimann A,Klement J,Walcher T,Krones-Herzig A,Strobel O,Werner J,Peters A,Kleyman A,Tuckermann JP,Vegiopoulos A,Herzig S

    更新日期:2011-07-06 00:00:00

  • The oscillating miRNA 959-964 cluster impacts Drosophila feeding time and other circadian outputs.

    abstract::We sequenced Drosophila head RNA to identify a small set of miRNAs that undergo robust circadian cycling. We concentrated on a cluster of six miRNAs, mir-959-964, all of which peak at about ZT12 or lights off. The cluster pri-miRNA is transcribed under bona fide circadian transcriptional control, and all six mature mi...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2012.10.002

    authors: Vodala S,Pescatore S,Rodriguez J,Buescher M,Chen YW,Weng R,Cohen SM,Rosbash M

    更新日期:2012-11-07 00:00:00

  • Central role of Mic10 in the mitochondrial contact site and cristae organizing system.

    abstract::The mitochondrial contact site and cristae organizing system (MICOS) is a conserved multi-subunit complex crucial for maintaining the characteristic architecture of mitochondria. Studies with deletion mutants identified Mic10 and Mic60 as core subunits of MICOS. Mic60 has been studied in detail; however, topogenesis a...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2015.04.007

    authors: Bohnert M,Zerbes RM,Davies KM,Mühleip AW,Rampelt H,Horvath SE,Boenke T,Kram A,Perschil I,Veenhuis M,Kühlbrandt W,van der Klei IJ,Pfanner N,van der Laan M

    更新日期:2015-05-05 00:00:00

  • The IRE1alpha-XBP1 pathway of the unfolded protein response is required for adipogenesis.

    abstract::Signaling cascades during adipogenesis culminate in the expression of two essential adipogenic factors, PPARgamma and C/EBPalpha. Here we demonstrate that the IRE1alpha-XBP1 pathway, the most conserved branch of the unfolded protein response (UPR), is indispensable for adipogenesis. Indeed, XBP1-deficient mouse embryo...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2009.04.009

    authors: Sha H,He Y,Chen H,Wang C,Zenno A,Shi H,Yang X,Zhang X,Qi L

    更新日期:2009-06-01 00:00:00

  • Pro- versus Anti-inflammatory Actions of HDLs in Innate Immunity.

    abstract::High-density lipoproteins (HDLs) can inhibit inflammatory cytokine expression on innate immune cells, but sometimes they promote cytokine production as suggested in a recent article in Cell Metabolism by van der Vorst et al. (2017). Kopecky et al. point out that the origin, handling, and storage conditions of HDL prep...

    journal_title:Cell metabolism

    pub_type: 信件

    doi:10.1016/j.cmet.2017.04.007

    authors: Kopecky C,Michlits G,Säemann MD,Weichhart T

    更新日期:2017-07-05 00:00:00

  • Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin.

    abstract::Current evidence suggests that hypothalamic fatty acid metabolism may play a role in regulating food intake; however, confirmation that it is a physiologically relevant regulatory system of feeding is still incomplete. Here, we use pharmacological and genetic approaches to demonstrate that the physiological orexigenic...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2008.03.006

    authors: López M,Lage R,Saha AK,Pérez-Tilve D,Vázquez MJ,Varela L,Sangiao-Alvarellos S,Tovar S,Raghay K,Rodríguez-Cuenca S,Deoliveira RM,Castañeda T,Datta R,Dong JZ,Culler M,Sleeman MW,Alvarez CV,Gallego R,Lelliott CJ,Carlin

    更新日期:2008-05-01 00:00:00

  • Mitochondrial medicine: a metabolic perspective on the pathology of oxidative phosphorylation disorders.

    abstract::The final steps in the production of adenosine triphosphate (ATP) in mitochondria are executed by a series of multisubunit complexes and electron carriers, which together constitute the oxidative phosphorylation (OXPHOS) system. OXPHOS is under dual genetic control, with communication between the nuclear and mitochond...

    journal_title:Cell metabolism

    pub_type: 杂志文章,评审

    doi:10.1016/j.cmet.2005.12.001

    authors: Smeitink JA,Zeviani M,Turnbull DM,Jacobs HT

    更新日期:2006-01-01 00:00:00

  • Mapping out starvation responses.

    abstract::What are the pathways that underlie the coordinated responses of an organism to well-fed and food-deprived states? A report in this issue of Cell Metabolism suggests that starvation functions via a muscarinic acetylcholine receptor to activate MAP kinase signaling in the pharyngeal muscle of C. elegans (You et al., 20...

    journal_title:Cell metabolism

    pub_type: 评论,杂志文章

    doi:10.1016/j.cmet.2006.03.002

    authors: Ashrafi K

    更新日期:2006-04-01 00:00:00

  • A macrophage sterol-responsive network linked to atherogenesis.

    abstract::Cholesteryl ester accumulation by macrophages is a critical early event in atherogenesis. To test the hypothesis that sterol loading promotes foam cell formation and vascular disease by perturbing a network of interacting proteins, we used a global approach to identify proteins that are differentially expressed when m...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2010.01.003

    authors: Becker L,Gharib SA,Irwin AD,Wijsman E,Vaisar T,Oram JF,Heinecke JW

    更新日期:2010-02-03 00:00:00

  • Dysfunctional families: Clostridium scindens and secondary bile acids inhibit the growth of Clostridium difficile.

    abstract::C. difficile infection is a deadly disease that is influenced by the microbiome. In a recent article in Nature, Buffie et al. (2014) demonstrate that the ability of C. scindens to synthesize secondary bile acids is crucial to providing resistance to C. difficile infection. ...

    journal_title:Cell metabolism

    pub_type: 评论,杂志文章

    doi:10.1016/j.cmet.2014.12.016

    authors: Greathouse KL,Harris CC,Bultman SJ

    更新日期:2015-01-06 00:00:00

  • Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells.

    abstract::Because MYC plays a causal role in many human cancers, including those with hypoxic and nutrient-poor tumor microenvironments, we have determined the metabolic responses of a MYC-inducible human Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, using stable isotope-re...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2011.12.009

    authors: Le A,Lane AN,Hamaker M,Bose S,Gouw A,Barbi J,Tsukamoto T,Rojas CJ,Slusher BS,Zhang H,Zimmerman LJ,Liebler DC,Slebos RJ,Lorkiewicz PK,Higashi RM,Fan TW,Dang CV

    更新日期:2012-01-04 00:00:00

  • Palatability Can Drive Feeding Independent of AgRP Neurons.

    abstract::Feeding behavior is exquisitely regulated by homeostatic and hedonic neural substrates that integrate energy demand as well as the reinforcing and rewarding aspects of food. Understanding the net contribution of homeostatic and reward-driven feeding has become critical because of the ubiquitous source of energy-dense ...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2015.07.011

    authors: Denis RG,Joly-Amado A,Webber E,Langlet F,Schaeffer M,Padilla SL,Cansell C,Dehouck B,Castel J,Delbès AS,Martinez S,Lacombe A,Rouch C,Kassis N,Fehrentz JA,Martinez J,Verdié P,Hnasko TS,Palmiter RD,Krashes MJ,Güler A

    更新日期:2015-10-06 00:00:00

  • Lipid Metabolism Gets in a JAML during Kidney Disease.

    abstract::It is still unclear if the ability of key regulators of actin cytoskeletal remodeling to influence lipid metabolism contributes to kidney injury. In this issue of Cell Metabolism, Fu et al. (2020) show that junctional adhesion molecule-like (JAML) is a novel mediator of glomerular disease progression while suggesting ...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2020.11.002

    authors: Fornoni A,Merscher S

    更新日期:2020-12-01 00:00:00

  • Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN.

    abstract::Neuropepetide Y (NPY) is best known for its powerful stimulation of food intake and its effects on reducing energy expenditure. However, the pathways involved and the regulatory mechanisms behind this are not well understood. Here we demonstrate that NPY derived from the arcuate nucleus (Arc) is critical for the contr...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2013.01.006

    authors: Shi YC,Lau J,Lin Z,Zhang H,Zhai L,Sperk G,Heilbronn R,Mietzsch M,Weger S,Huang XF,Enriquez RF,Baldock PA,Zhang L,Sainsbury A,Herzog H,Lin S

    更新日期:2013-02-05 00:00:00

  • Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle.

    abstract::Skeletal and cardiac muscle depend on high turnover of ATP made by mitochondria in order to contract efficiently. The transcriptional coactivator PGC-1alpha has been shown to function as a major regulator of mitochondrial biogenesis and respiration in both skeletal and cardiac muscle, but this has been based only on g...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2005.03.002

    authors: Arany Z,He H,Lin J,Hoyer K,Handschin C,Toka O,Ahmad F,Matsui T,Chin S,Wu PH,Rybkin II,Shelton JM,Manieri M,Cinti S,Schoen FJ,Bassel-Duby R,Rosenzweig A,Ingwall JS,Spiegelman BM

    更新日期:2005-04-01 00:00:00

  • Calcitonin Receptor Neurons in the Mouse Nucleus Tractus Solitarius Control Energy Balance via the Non-aversive Suppression of Feeding.

    abstract::To understand hindbrain pathways involved in the control of food intake, we examined roles for calcitonin receptor (CALCR)-containing neurons in the NTS. Ablation of NTS Calcr abrogated the long-term suppression of food intake, but not aversive responses, by CALCR agonists. Similarly, activating CalcrNTS neurons decre...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2019.12.012

    authors: Cheng W,Gonzalez I,Pan W,Tsang AH,Adams J,Ndoka E,Gordian D,Khoury B,Roelofs K,Evers SS,MacKinnon A,Wu S,Frikke-Schmidt H,Flak JN,Trevaskis JL,Rhodes CJ,Fukada SI,Seeley RJ,Sandoval DA,Olson DP,Blouet C,Myers MG

    更新日期:2020-02-04 00:00:00

  • Dynamics of an Aging Genome.

    abstract::The genetic mechanisms mediating longevity and maximum lifespan of the human species are likely different than those explaining differences in life expectancy and healthspan across individuals. Both of these perspectives are important and can be separated and explored using genomic data. ...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2016.06.002

    authors: Telenti A,Perkins BA,Venter JC

    更新日期:2016-06-14 00:00:00

  • mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc.

    abstract::Aerobic glycolysis (the Warburg effect) is a core hallmark of cancer, but the molecular mechanisms underlying it remain unclear. Here, we identify an unexpected central role for mTORC2 in cancer metabolic reprogramming where it controls glycolytic metabolism by ultimately regulating the cellular level of c-Myc. We sho...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2013.09.013

    authors: Masui K,Tanaka K,Akhavan D,Babic I,Gini B,Matsutani T,Iwanami A,Liu F,Villa GR,Gu Y,Campos C,Zhu S,Yang H,Yong WH,Cloughesy TF,Mellinghoff IK,Cavenee WK,Shaw RJ,Mischel PS

    更新日期:2013-11-05 00:00:00

  • Getting a "Hold" on NPC2.

    abstract::Lipoprotein cholesterol is mobilized from lysosomes by actions of the NPC1 and NPC2 proteins. In this issue of Cell Metabolism, Harrison et al. report on identification of an NPC2-interacting protein, the Nogo-B receptor, that regulates NPC2 protein levels. NPC2 stabilization may represent a novel mechanism through wh...

    journal_title:Cell metabolism

    pub_type: 评论,杂志文章

    doi:10.1016/j.cmet.2009.08.006

    authors: Ory DS

    更新日期:2009-09-01 00:00:00

  • Toward a Molecular Definition of Leucine-Dependent mTORC1 Activation.

    abstract::The mechanistic target of rapamycin complex 1 (mTORC1) coordinates nutrient availability with cell growth. Recent reports by Sabatini and coworkers (Saxton et al., 2016; Wolfson et al., 2016) characterize a cytoplasmic amino acid receptor that couples the binding of leucine to the activation of mTORC1. ...

    journal_title:Cell metabolism

    pub_type: 杂志文章

    doi:10.1016/j.cmet.2016.02.012

    authors: Abraham RT

    更新日期:2016-03-08 00:00:00