1 2301 109 EPIGENETIC REGULATION OF BEIGE ADIPOCYTE FATE BY HISTONE METHYLATION. ADIPOSE TISSUE HARBORS PLASTICITY TO ADAPT TO ENVIRONMENTAL THERMAL CHANGES. WHILE BROWN ADIPOCYTE IS A THERMOGENIC CELL WHICH PRODUCES HEAT ACUTELY IN RESPONSE TO COLD STIMULI, BEIGE (OR BRITE) ADIPOCYTE IS AN INDUCIBLE FORM OF THERMOGENIC ADIPOCYTES WHICH EMERGES IN THE WHITE ADIPOSE DEPOTS IN RESPONSE TO CHRONIC COLD EXPOSURE. SUCH ADAPTABILITY OF ADIPOCYTES IS REGULATED BY EPIGENETIC MECHANISMS. AMONG THEM, HISTONE METHYLATION IS CHEMICALLY STABLE AND THUS IS AN APPROPRIATE EPIGENETIC MARK FOR MEDIATING CELLULAR MEMORY TO INDUCE AND MAINTAIN THE BEIGE ADIPOCYTE CHARACTERISTICS. THE ENZYMES THAT CATALYZE THE METHYLATION OR DEMETHYLATION OF H3K27 AND H3K9 REGULATE BROWN ADIPOCYTE BIOGENESIS THROUGH THEIR CATALYTIC ACTIVITY-DEPENDENT AND -INDEPENDENT MECHANISMS. RESOLVING THE BIVALENCY OF H3K4ME3 AND H3K27ME3 AS WELL AS "OPENING" THE CHROMATIN STRUCTURE BY DEMETHYLATION OF H3K9 BOTH MEDIATE BEIGE ADIPOGENESIS. IN ADDITION, IT IS RECENTLY REPORTED THAT MAINTENANCE OF BEIGE ADIPOCYTE, BEIGE-TO-WHITE TRANSITION, AND CELLULAR MEMORY OF PRIOR COLD EXPOSURE IN BEIGE ADIPOCYTE ARE ALSO REGULATED BY HISTONE METHYLATION. A FURTHER UNDERSTANDING OF THE EPIGENETIC MECHANISM OF BEIGE ADIPOCYTE BIOGENESIS WOULD UNRAVEL THE MECHANISM OF THE CELLULAR MEMORY OF ENVIRONMENTAL STIMULI AND PROVIDE A NOVEL THERAPEUTICS FOR THE METABOLIC DISORDERS SUCH AS OBESITY AND DIABETES THAT ARE INFLUENCED BY ENVIRONMENTAL FACTORS. 2019 2 4022 29 LSD1 FOR THE TARGETED REGULATION OF ADIPOSE TISSUE. WHITE AND THERMAL (BROWN AND BEIGE) ADIPOSE TISSUE ENERGY STORAGE AND OXIDATIVE REGULATION PATHWAYS PLAY A CENTRAL ROLE IN MAINTAINING THE ENERGY BALANCE THROUGHOUT THE BODY, AND THE DYSREGULATION OF THESE PATHWAYS IS CLOSELY RELATED TO GLUCOSE AND LIPID METABOLISM DISORDERS AND ADIPOSE TISSUE DYSFUNCTION, INCLUDING OBESITY, CHRONIC INFLAMMATION, INSULIN RESISTANCE, MITOCHONDRIAL DYSFUNCTION, AND FIBROSIS. RECENT EPIGENETIC STUDIES HAVE IDENTIFIED THE NOVEL REGULATORY ELEMENT LSD1, WHICH CONTROLS THE ABOVE PARAMETERS, AND HAVE PROVIDED NEW MECHANISTIC POSSIBILITIES FOR RE-ENCODING THE FATE AND FUNCTION OF ADIPOCYTES. IN THIS REVIEW, WE OUTLINE THE CURRENT ADVANCES IN ADIPOCYTE METABOLISM IN PHYSIOLOGY AND DISEASE AND DISCUSS POSSIBLE STRATEGIES FOR LSD1 TO ALTER THE PHENOTYPE OF ADIPOSE TISSUE AND THUS INFLUENCE ENERGY UTILIZATION TO IMPROVE METABOLIC HEALTH. 2022 3 2298 26 EPIGENETIC REGULATION OF ADIPOGENESIS. PURPOSE OF REVIEW: EPIGENETIC REGULATION PLAYS AN ESSENTIAL ROLE IN CELL DIFFERENTIATION, BY ALLOWING THE ESTABLISHMENT AND MAINTENANCE OF THE GENE-EXPRESSION PATTERN OF THE MATURE CELL TYPE. BECAUSE OF ITS IMPORTANCE IN CHRONIC DISEASES, ADIPOGENESIS IS ONE OF THE BEST-STUDIED DIFFERENTIATION PROCESSES. THE HORMONAL AND TRANSCRIPTIONAL CASCADES GOVERNING THE DIFFERENTIATION OF THE ADIPOCYTES ARE WELL KNOWN, BUT THE ROLE OF EPIGENETIC MECHANISMS IS ONLY STARTING TO EMERGE. IN THIS REVIEW, WE INTEND TO SUMMARIZE THE RECENTLY DESCRIBED EPIGENETIC EVENTS THAT PARTICIPATE IN ADIPOGENESIS AND THEIR CONNECTIONS WITH THE MAIN FACTORS THAT CONSTITUTE THE CLASSICAL TRANSCRIPTIONAL CASCADE. RECENT FINDINGS: THE ADVENT OF HIGH-THROUGHPUT TECHNOLOGIES HAS MADE POSSIBLE THE EXHAUSTIVE ANALYSIS OF THE EPIGENETIC PHENOMENONS TAKING PLACE DURING ADIPOGENESIS. THE COOPERATIVE RECRUITMENT OF CCAAT/ENHANCER-BINDING PROTEIN (C/EBPBETA) AND OTHER EARLY PROADIPOGENIC TRANSCRIPTION FACTORS TO TRANSCRIPTION FACTOR HOTSPOTS SHORTLY AFTER INDUCTION OF ADIPOGENESIS IS REQUIRED TO ESTABLISH A TRANSIENT EPIGENOMIC STATE THAT THEN INFORMS THE RECRUITMENT OF THE LATER ADIPOGENIC TRANSCRIPTION FACTORS PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPARGAMMA) AND C/EBPALPHA TO THEIR TARGET GENES. SUMMARY: EPIGENETIC MARKS AND CHROMATIN-MODIFYING PROTEINS CONTRIBUTE TO ADIPOGENESIS AND, THROUGH REGULATION OF THE PHENOTYPIC MAINTENANCE OF THE MATURE ADIPOCYTES, TO THE CONTROL OF METABOLISM. 2012 4 2002 25 EPIGENETIC AND POST-TRANSCRIPTIONAL REPRESSION SUPPORT METABOLIC SUPPRESSION IN CHRONICALLY HYPOXIC GOLDFISH. GOLDFISH ENTER A HYPOMETABOLIC STATE TO SURVIVE CHRONIC HYPOXIA. WE RECENTLY DESCRIBED TISSUE-SPECIFIC CONTRIBUTIONS OF MEMBRANE LIPID COMPOSITION REMODELING AND MITOCHONDRIAL FUNCTION TO METABOLIC SUPPRESSION ACROSS DIFFERENT GOLDFISH TISSUES. HOWEVER, THE MOLECULAR AND ESPECIALLY EPIGENETIC FOUNDATIONS OF HYPOXIA TOLERANCE IN GOLDFISH UNDER METABOLIC SUPPRESSION ARE NOT WELL UNDERSTOOD. HERE WE SHOW THAT COMPONENTS OF THE MOLECULAR OXYGEN-SENSING MACHINERY ARE ROBUSTLY ACTIVATED ACROSS TISSUES IRRESPECTIVE OF HYPOXIA DURATION. INDUCTION OF GENE EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION TURNOVER AND MICRORNA BIOGENESIS SUGGEST A ROLE FOR EPIGENETIC TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL SUPPRESSION OF GENE EXPRESSION IN THE HYPOXIA-ACCLIMATED BRAIN. CONVERSELY, MECHANISTIC TARGET OF RAPAMYCIN-DEPENDENT TRANSLATIONAL MACHINERY ACTIVITY IS NOT REDUCED IN LIVER AND WHITE MUSCLE, SUGGESTING THIS PATHWAY DOES NOT CONTRIBUTE TO LOWERING CELLULAR ENERGY EXPENDITURE. FINALLY, MOLECULAR EVIDENCE SUPPORTS PREVIOUSLY REPORTED CHRONIC HYPOXIA-DEPENDENT CHANGES IN MEMBRANE CHOLESTEROL, LIPID METABOLISM AND MITOCHONDRIAL FUNCTION VIA CHANGES IN TRANSCRIPTS INVOLVED IN CHOLESTEROL BIOSYNTHESIS, BETA-OXIDATION, AND MITOCHONDRIAL FUSION IN MULTIPLE TISSUES. OVERALL, THIS STUDY SHOWS THAT CHRONIC HYPOXIA ROBUSTLY INDUCES EXPRESSION OF OXYGEN-SENSING MACHINERY ACROSS TISSUES, INDUCES REPRESSIVE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL EPIGENETIC MARKS ESPECIALLY IN THE CHRONIC HYPOXIA-ACCLIMATED BRAIN AND SUPPORTS A ROLE FOR MEMBRANE REMODELING AND MITOCHONDRIAL FUNCTION AND DYNAMICS IN PROMOTING METABOLIC SUPPRESSION. 2022 5 4992 24 PEELING THE ONION: ANOTHER LAYER IN THE REGULATION OF INSULIN SECRETION. INSULIN SECRETION BY PANCREATIC BETA CELLS IS A DYNAMIC AND HIGHLY REGULATED PROCESS DUE TO THE CENTRAL IMPORTANCE OF INSULIN IN ENABLING EFFICIENT UTILIZATION AND STORAGE OF GLUCOSE. MULTIPLE REGULATORY LAYERS ENABLE BETA CELLS TO ADAPT TO ACUTE CHANGES IN NUTRIENT AVAILABILITY AS WELL AS CHRONIC CHANGES IN METABOLIC DEMAND. WHILE EPIGENETIC FACTORS HAVE BEEN WELL ESTABLISHED AS REGULATORS OF CHRONIC BETA CELL ADAPTATIONS TO INSULIN RESISTANCE, THEIR ROLE IN ACUTE ADAPTATIONS IN RESPONSE TO NUTRIENT STIMULATION HAS BEEN RELATIVELY UNEXPLORED. IN THIS ISSUE OF THE JCI, WORTHAM ET AL. REPORT THAT SHORT-TERM DYNAMIC CHANGES IN HISTONE MODIFICATIONS REGULATED INSULIN SECRETION AND ACUTE BETA CELL ADAPTATIONS IN RESPONSE TO FASTING AND FEEDING CYCLES. THESE FINDINGS HIGHLIGHT THE IMPORTANCE OF INVESTIGATING WHETHER OTHER EPIGENETIC MECHANISMS MAY CONTRIBUTE TO ACUTE PHYSIOLOGIC ADAPTATIONS IN BETA CELLS. 2023 6 2336 32 EPIGENETIC REGULATION OF INFLAMMATORY FACTORS IN ADIPOSE TISSUE. OBESITY IS A STRONG RISK FACTOR FOR INSULIN RESISTANCE. CHRONIC LOW-GRADE TISSUE INFLAMMATION AND SYSTEMIC INFLAMMATION HAVE BEEN PROPOSED AS MAJOR MECHANISMS THAT PROMOTE INSULIN RESISTANCE IN OBESITY. ADIPOSE TISSUE HAS BEEN RECOGNIZED AS A NEXUS BETWEEN INFLAMMATION AND METABOLISM, BUT HOW EXACTLY INFLAMMATORY GENE EXPRESSION IS ORCHESTRATED DURING THE DEVELOPMENT OF OBESITY IS NOT WELL UNDERSTOOD. EPIGENETIC MODIFICATIONS ARE DEFINED AS HERITABLE CHANGES IN GENE EXPRESSION AND CELLULAR FUNCTION WITHOUT CHANGES TO THE ORIGINAL DNA SEQUENCE. THE MAJOR EPIGENETIC MECHANISMS INCLUDE DNA METHYLATION, HISTONE MODIFICATION, NONCODING RNAS, NUCLEOPOSITIONING/REMODELING AND CHROMATIN REORGANIZATION. EPIGENETIC MECHANISMS PROVIDE A CRITICAL LAYER OF GENE REGULATION IN RESPONSE TO ENVIRONMENTAL CHANGES. ACCUMULATING EVIDENCE SUPPORTS THAT EPIGENETICS PLAYS A LARGE ROLE IN THE REGULATION OF INFLAMMATORY GENES IN ADIPOCYTES AND ADIPOSE-RESIDENT IMMUNE CELL TYPES. THIS REVIEW FOCUSES ON THE ASSOCIATION BETWEEN ADIPOSE TISSUE INFLAMMATION IN OBESITY AND MAJOR EPIGENETIC MODIFICATIONS. 2021 7 6203 27 THE INFLUENCE OF EPIGENETIC MODIFICATIONS ON METABOLIC CHANGES IN WHITE ADIPOSE TISSUE AND LIVER AND THEIR POTENTIAL IMPACT IN EXERCISE. BACKGROUND: EPIGENETIC MARKS ARE RESPONSIVE TO A WIDE VARIETY OF ENVIRONMENTAL STIMULI AND SERVE AS IMPORTANT MEDIATORS FOR GENE TRANSCRIPTION. A NUMBER OF CHROMATIN MODIFYING ENZYMES ORCHESTRATE EPIGENETIC RESPONSES TO ENVIRONMENTAL STIMULI, WITH A GROWING BODY OF RESEARCH EXAMINING HOW CHANGES IN METABOLIC SUBSTRATES OR CO-FACTORS ALTER EPIGENETIC MODIFICATIONS. SCOPE OF REVIEW: HERE, WE PROVIDE A SYSTEMATIC REVIEW OF EXISTING EVIDENCE OF METABOLISM-RELATED EPIGENETIC CHANGES IN WHITE ADIPOSE TISSUE (WAT) AND THE LIVER AND GENERATE SECONDARY HYPOTHESES ON HOW EXERCISE MAY IMPACT METABOLISM-RELATED EPIGENETIC MARKS IN THESE TISSUES. MAJOR CONCLUSIONS: EPIGENETIC CHANGES CONTRIBUTE TO THE COMPLEX TRANSCRIPTIONAL RESPONSES ASSOCIATED WITH WAT LIPOLYSIS, HEPATIC DE NOVO LIPOGENESIS, AND HEPATIC GLUCONEOGENESIS. WHILE THESE METABOLIC RESPONSES MAY HYPOTHETICALLY BE ALTERED WITH ACUTE AND CHRONIC EXERCISE, DIRECT TESTING IS NEEDED. 2021 8 6291 25 THE POTENTIAL TO FIGHT OBESITY WITH ADIPOGENESIS MODULATING COMPOUNDS. OBESITY IS AN INCREASINGLY SEVERE PUBLIC HEALTH PROBLEM, WHICH BRINGS HUGE SOCIAL AND ECONOMIC BURDENS. INCREASED BODY ADIPOSITY IN OBESITY IS NOT ONLY TIGHTLY ASSOCIATED WITH TYPE 2 DIABETES, BUT ALSO SIGNIFICANTLY INCREASES THE RISKS OF OTHER CHRONIC DISEASES INCLUDING CARDIOVASCULAR DISEASES, FATTY LIVER DISEASES AND CANCERS. ADIPOGENESIS DESCRIBES THE PROCESS OF THE DIFFERENTIATION AND MATURATION OF ADIPOCYTES, WHICH ACCUMULATE IN DISTRIBUTED ADIPOSE TISSUE AT VARIOUS SITES IN THE BODY. THE MAJOR FUNCTIONS OF WHITE ADIPOCYTES ARE TO STORE ENERGY AS FAT DURING PERIODS WHEN ENERGY INTAKE EXCEEDS EXPENDITURE AND TO MOBILIZE THIS STORED FUEL WHEN ENERGY EXPENDITURE EXCEEDS INTAKE. BROWN/BEIGE ADIPOCYTES CONTRIBUTE TO NON-SHIVERING THERMOGENESIS UPON COLD EXPOSURE AND ADRENERGIC STIMULATION, AND THEREBY PROMOTE ENERGY CONSUMPTION. THE IMBALANCE OF ENERGY INTAKE AND EXPENDITURE CAUSES OBESITY. RECENT INTEREST IN EPIGENETICS AND SIGNALING PATHWAYS HAS UTILIZED SMALL MOLECULE TOOLS AIMED AT MODIFYING OBESITY-SPECIFIC GENE EXPRESSION. IN THIS REVIEW, WE DISCUSS COMPOUNDS WITH ADIPOGENESIS-RELATED SIGNALING PATHWAYS AND EPIGENETIC MODULATING PROPERTIES THAT HAVE BEEN IDENTIFIED AS POTENTIAL THERAPEUTIC AGENTS WHICH CAST SOME LIGHT ON THE FUTURE TREATMENT OF OBESITY. 2022 9 3403 26 HOW EPIGENETIC MODIFICATIONS DRIVE THE EXPRESSION AND MEDIATE THE ACTION OF PGC-1ALPHA IN THE REGULATION OF METABOLISM. EPIGENETIC CHANGES ARE A HALLMARK OF SHORT- AND LONG-TERM TRANSCRIPTIONAL REGULATION, AND HENCE INSTRUMENTAL IN THE CONTROL OF CELLULAR IDENTITY AND PLASTICITY. EPIGENETIC MECHANISMS LEADING TO CHANGES IN CHROMATIN STRUCTURE, ACCESSIBILITY FOR RECRUITMENT OF TRANSCRIPTIONAL COMPLEXES, AND INTERACTION OF ENHANCERS AND PROMOTERS ALL CONTRIBUTE TO ACUTE AND CHRONIC ADAPTATIONS OF CELLS, TISSUES AND ORGANS TO INTERNAL AND EXTERNAL PERTURBATIONS. SIMILARLY, THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA (PGC-1ALPHA) IS ACTIVATED BY STIMULI THAT ALTER THE CELLULAR ENERGETIC DEMAND, AND SUBSEQUENTLY CONTROLS COMPLEX TRANSCRIPTIONAL NETWORKS RESPONSIBLE FOR CELLULAR PLASTICITY. IT THUS IS OF NO SURPRISE THAT PGC-1ALPHA IS UNDER THE CONTROL OF EPIGENETIC MECHANISMS, AND CONSTITUTES A MEDIATOR OF EPIGENETIC CHANGES IN VARIOUS TISSUES AND CONTEXTS. IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE LINK BETWEEN EPIGENETICS AND PGC-1ALPHA IN HEALTH AND DISEASE. 2019 10 2332 27 EPIGENETIC REGULATION OF INFLAMMATION IN INSULIN RESISTANCE. EPIGENETICS FOCUSES ON THE STUDY OF CHANGES IN GENE EXPRESSION BASED ON MODIFICATIONS THAT DO NOT INTERFERE WITH THE DNA SEQUENCE, SUCH AS DNA METHYLATION, POST-TRANSLATIONAL HISTONE MODIFICATION, AND NON-CODING RNA. EPIGENETIC CHANGES REGULATE THE EXPRESSION OF MANY GENES, INCLUDING INFLAMMATORY ONES. CHRONIC INFLAMMATION IS OFTEN ACCOMPANIED BY INSULIN RESISTANCE (IR), WHICH IS CHARACTERISTIC OF INTER ALIA TYPE 2 DIABETES. RECENTLY, IT HAS BEEN REPORTED THAT ALTERED EPIGENETIC SIGNATURE IN THE PROMOTER REGIONS OF INFLAMMATORY GENES MAY CONTRIBUTE TO THE DEVELOPMENT OF IR. THEREFORE, THE AIM OF THIS REVIEW IS TO PRESENT THE CURRENT STATE OF KNOWLEDGE REGARDING THE EPIGENETIC REGULATION OF INFLAMMATION IN IR. IT INCLUDES ORIGINAL PAPERS PUBLISHED FROM 2014 TO 2022. IT APPEARS THAT HYPOMETHYLATION OF THE SOCS3 GENE INCREASES THE RISK OF IR, WHILE THE ALTERATION OF H3K4ME IN THE NF-KB PROMOTER PROMOTES CHANGES IN INFLAMMATORY PHENOTYPE. FINALLY, IN HYPERGLYCEMIC STATES ASSOCIATED WITH IR, ALTERED LEVELS OF H3K4/K9M3 AND H3K9/K14AC RESULT IN INCREASED EXPRESSION OF THE INFLAMMATORY CYTOKINE IL-6. IN ADDITION, NUMEROUS MIRNAS HAVE BEEN IDENTIFIED THAT MAY BECOME A TARGET IN THE FIGHT AGAINST DISEASES RELATED TO INFLAMMATION AND IR. FUTURE STUDIES SHOULD EXAMINE THE EPIGENETIC MODIFICATIONS OF IR INFLAMMATORY MARKERS ASSOCIATED WITH ENVIRONMENTAL FACTORS. 2022 11 701 20 BROWN FAT DNMT3B DEFICIENCY AMELIORATES OBESITY IN FEMALE MICE. OBESITY RESULTS FROM A CHRONIC ENERGY IMBALANCE DUE TO ENERGY INTAKE EXCEEDING ENERGY EXPENDITURE. ACTIVATION OF BROWN FAT THERMOGENESIS HAS BEEN SHOWN TO COMBAT OBESITY. EPIGENETIC REGULATION, INCLUDING DNA METHYLATION, HAS EMERGED AS A KEY REGULATOR OF BROWN FAT THERMOGENIC FUNCTION. HERE WE AIMED TO STUDY THE ROLE OF DNMT3B, A DNA METHYLTRANSFERASE INVOLVED IN DE NOVO DNA METHYLATION, IN THE REGULATION OF BROWN FAT THERMOGENESIS AND OBESITY. WE FOUND THAT THE SPECIFIC DELETION OF DNMT3B IN BROWN FAT PROMOTES THE THERMOGENIC AND MITOCHONDRIAL PROGRAM IN BROWN FAT, ENHANCES ENERGY EXPENDITURE, AND DECREASES ADIPOSITY IN FEMALE MICE FED A REGULAR CHOW DIET. WITH A LEAN PHENOTYPE, THE FEMALE KNOCKOUT MICE ALSO EXHIBIT INCREASED INSULIN SENSITIVITY. IN ADDITION, DNMT3B DEFICIENCY IN BROWN FAT ALSO PREVENTS DIET-INDUCED OBESITY AND INSULIN RESISTANCE IN FEMALE MICE. INTERESTINGLY, OUR RNA-SEQ ANALYSIS REVEALED AN UPREGULATION OF THE PI3K-AKT PATHWAY IN THE BROWN FAT OF FEMALE DNMT3B KNOCKOUT MICE. HOWEVER, MALE DNMT3B KNOCKOUT MICE HAVE NO CHANGE IN THEIR BODY WEIGHT, SUGGESTING THE EXISTENCE OF SEXUAL DIMORPHISM IN THE BROWN FAT DNMT3B KNOCKOUT MODEL. OUR DATA DEMONSTRATE THAT DNMT3B PLAYS AN IMPORTANT ROLE IN THE REGULATION OF BROWN FAT FUNCTION, ENERGY METABOLISM AND OBESITY IN FEMALE MICE. 2021 12 4103 25 MECHANICAL CUES REGULATE HISTONE MODIFICATIONS AND CELL BEHAVIOR. CHANGE OF BIOPHYSICAL FACTORS IN TISSUE MICROENVIRONMENT IS AN IMPORTANT STEP IN A CHRONIC DISEASE DEVELOPMENT PROCESS. A MECHANICAL AND BIOCHEMICAL FACTOR FROM CELL LIVING MICRONICHE CAN REGULATE CELL EPIGENETIC DECORATION AND, THEREFORE, FURTHER INDUCE CHANGE OF GENE EXPRESSION. IN THIS REVIEW, WE WILL EMPHASIZE THE MECHANISM THAT BIOPHYSICAL MICROENVIRONMENT MANIPULATES CELL BEHAVIOR INCLUDING GENE EXPRESSION AND PROTEIN DECORATION, THROUGH MODIFYING HISTONE AMINO ACID RESIDUE MODIFICATION. THE INFLUENCE GIVEN BY DIFFERENT MECHANICAL FORCES, INCLUDING MECHANICAL STRETCH, SUBSTRATE SURFACE STIFFNESS, AND SHEAR STRESS, ON CELL FATE AND BEHAVIOR DURING CHRONIC DISEASE DEVELOPMENT INCLUDING TUMORIGENESIS WILL ALSO BE TEASED OUT. OVERALL, THE RECENT WORK SUMMARIZED IN THIS REVIEW CULMINATES ON THE HYPOTHESIS THAT A MECHANICAL FACTOR STIMULATES THE MODIFICATION ON HISTONE WHICH COULD FACILITATE DISEASE DETECTION AND POTENTIAL THERAPEUTIC TARGET. 2022 13 6129 29 THE EPIGENETIC REGULATION OF PODOCYTE FUNCTION IN DIABETES. CHRONIC HYPERGLYCEMIA EARLY IN THE COURSE OF DIABETES CONFERS A SUSTAINED INCREASE IN THE RISK OF COMPLICATIONS DEVELOPMENT. IN RECENT YEARS, EFFORTS TO UNDERSTAND THE MOLECULAR BASIS FOR THIS "METABOLIC MEMORY" HAVE FOCUSED ON EPIGENETIC MECHANISMS AS A MEANS BY WHICH TRANSIENT HIGH GLUCOSE CAN CAUSE PERSISTENT AND PROPAGATED CHANGES IN CELL FUNCTION. FOR INSTANCE, IN VASCULAR ENDOTHELIAL CELLS, SMOOTH MUSCLE CELLS AND PERIPHERAL BLOOD CELLS, TEMPORARY EXPOSURE TO HIGH GLUCOSE CAUSES CHANGES IN EPIGENETIC MARKS THAT PROMOTE A SHIFT TOWARDS A PRO-INFLAMMATORY PHENOTYPE. HOWEVER, THE INFLUENCE OF EPIGENETIC PROCESSES IN COMPLICATIONS DEVELOPMENT EXTENDS BEYOND THEIR CONTRIBUTION TO METABOLIC MEMORY. PODOCYTES, FOR EXAMPLE, ARE TERMINALLY DIFFERENTIATED CELLS OF THE RENAL GLOMERULUS WHOSE INJURY IS A MAJOR CONTRIBUTOR TO THE PATHOGENESIS OF NEPHROPATHY. OVER RECENT MONTHS, SEVERAL REPORTS HAVE EMERGED DESCRIBING THE ESSENTIAL ACTIONS OF HISTONE-MODIFYING ENZYMES AND DNA METHYLATION PATTERNS (THE TWO PRINCIPAL EPIGENETIC MECHANISMS) IN MAINTAINING PODOCYTE INTEGRITY, ESPECIALLY UNDER DIABETIC CONDITIONS. HERE, WE REVIEW THE KNOWN AND POTENTIAL ROLE OF EPIGENETIC PROCESSES WITHIN PODOCYTES, FOCUSING ON THE EVIDENCE LINKING THESE PROCESSES TO OXIDATIVE STRESS, CROSSTALK WITH TUBULE CELLS, AUTOPHAGY AND SLIT-PORE PROTEIN EXPRESSION. WHETHER PODOCYTES THEMSELVES EXHIBIT A METABOLIC MEMORY AWAITS TO BE SEEN. 2015 14 773 28 CELL AND MOLECULAR MECHANISMS BEHIND DIET-INDUCED HYPOTHALAMIC INFLAMMATION AND OBESITY. DIET-INDUCED OBESITY (DIO) IS ASSOCIATED WITH CHRONIC, LOW-GRADE INFLAMMATION IN THE HYPOTHALAMUS, A KEY REGULATOR OF ENERGY HOMEOSTASIS. CURRENT STUDIES HAVE REVEALED THE INVOLVEMENT OF DIFFERENT CELL TYPES, AS WELL AS CELL AND MOLECULAR MECHANISMS, THAT CONTRIBUTE TO DIET-INDUCED HYPOTHALAMIC INFLAMMATION (DIHI) AND DIO. SUBSEQUENT TO THE DISCOVERY THAT HIGH-FAT DIET AND SATURATED FATTY ACIDS INCREASE THE EXPRESSION OF HYPOTHALAMIC CYTOKINES PRIOR TO WEIGHT GAIN, RESEARCH HAS FOCUSED ON UNDERSTANDING THE CELLULAR AND MOLECULAR MECHANISMS UNDERLYING THESE CHANGES, IN ADDITION TO THE ROLE OF INFLAMMATION IN THE PATHOGENESIS OF OBESITY. RECENT STUDIES HAVE PROPOSED THAT THE INHIBITION OF PRO-INFLAMMATORY PATHWAYS IN MICROGLIA AND ASTROCYTES IS SUFFICIENT TO PROTECT AGAINST DIHI AND PREVENT OBESITY. IN ADDITION, IMPAIRMENT OF INTRACELLULAR AND EPIGENETIC MECHANISMS, SUCH AS HYPOTHALAMIC AUTOPHAGY AND CHANGES IN THE METHYLATION PATTERN OF CERTAIN GENES, HAVE BEEN IMPLICATED IN SUSCEPTIBILITY TO DIHI AND DIO. INTERESTINGLY, A SEXUAL DIMORPHISM HAS BEEN FOUND DURING DIO IN HYPOTHALAMIC INFLAMMATION, GLIAL ACTIVATION AND METABOLIC DISEASES, AND RECENT DATA SUPPORT AN IMPORTANT ROLE OF SEX STEROIDS IN DIHI. THESE NEW EXCITING FINDINGS UNCOVER NOVEL OBESITY PATHOGENIC MECHANISMS AND PROVIDE TARGETS TO DEVELOP THERAPEUTIC APPROACHES. 2018 15 6886 27 [ROLE OF EPIGENETIC MODIFICATION IN HIGHER BRAIN DYSFUNCTION AND AGING]. EPIGENETIC MECHANISMS TYPICALLY INVOLVE HERITABLE ALTERATIONS IN CHROMATIN STRUCTURE, WHICH, IN TURN, REGULATE GENE EXPRESSION. FUNDAMENTAL INSIGHTS ABOUT EPIGENETIC HERITABILITY HAVE COME FROM STUDIES OF CELL DIVISION AND DEVELOPMENT. HOWEVER, THERE IS INCREASING EVIDENCE THAT THE REGULATION OF CHROMATIN STRUCTURE THROUGH HISTONE MODIFICATIONS AND DNA METHYLATION MIGHT MEDIATE THE EXPRESSION OF KEY GENES INVOLVED IN ACQUIRED CHRONIC DISORDERS. THIS IDEA IS FASCINATING BECAUSE SIMILAR MECHANISMS ARE USED FOR TRIGGERING AND STORING LONG-TERM MEMORIES AT THE CELLULAR LEVEL DURING, FOR EXAMPLE, HIGHER-BRAIN DYSFUNCTION, STRESS DISEASE, DRUG DEPENDENCE, AGING, AND CHRONIC PAIN. THIS REVIEW WILL EXPLORE THE MOST CURRENT ISSUES IN THE FIELD OF EPIGENETICS, WITH A FOCUS ON NEXT LEVELS OF TRANSCRIPTIONAL MECHANISMS UNDERLYING AGING, ENRICHED ENVIRONMENT AND DRUG ADDICTION. EPIGENETIC MECHANISMS, WHICH ARE KEY CELLULAR AND MOLECULAR PROCESSES THAT INTEGRATE DIVERSE ENVIRONMENTAL STIMULI TO EXERT POTENT AND OFTEN LONG-LASTING CHANGES IN GENE EXPRESSION THROUGH THE REGULATION OF CHROMATIN STRUCTURE, CONTRIBUTE TO TRANSCRIPTIONAL AND BEHAVIORAL CHANGES. 2012 16 2499 25 EPIGENETICS AND EXERCISE. EPIGENETICS CAN BE DEFINED AS 'THE STRUCTURAL ADAPTATION OF CHROMOSOMAL REGIONS SO AS TO REGISTER, SIGNAL, OR PERPETUATE ALTERED ACTIVITY STATES.' INCREASED TRANSCRIPTION OF KEY REGULATORY, METABOLIC, AND MYOGENIC GENES IS AN EARLY RESPONSE TO EXERCISE AND IS IMPORTANT IN MEDIATING SUBSEQUENT ADAPTATIONS IN SKELETAL MUSCLE. DNA HYPOMETHYLATION AND HISTONE HYPERACETYLATION ARE EMERGING AS IMPORTANT CRUCIAL EVENTS FOR INCREASED TRANSCRIPTION. THE COMPLEX INTERACTIONS BETWEEN MULTIPLE EPIGENETIC MODIFICATIONS AND THEIR REGULATION BY METABOLIC CHANGES AND SIGNALING EVENTS DURING EXERCISE, WITH IMPLICATIONS FOR ENHANCED UNDERSTANDING OF THE ACUTE AND CHRONIC ADAPTATIONS TO EXERCISE, ARE QUESTIONS FOR FURTHER INVESTIGATION. 2019 17 5130 30 POSTTRANSCRIPTIONAL GENE REGULATION: NOVEL PATHWAYS FOR GLUCOCORTICOIDS' ANTI-INFLAMMATORY ACTION. POSTTRANSCRIPTIONAL GENE REGULATION (PTR) IS A FUNDAMENTAL BIOLOGICAL PROCESS THAT INTEGRATES WITH THE MASTER TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION, IN WAYS THAT ONLY IN THE LAST DECADE HAVE BEEN INCREASINGLY UNDERSTOOD [1, 2]. WHILE EPIGENETIC AND TRANSCRIPTIONAL EVENTS SHAPE CELL RESPONSE QUALITATIVELY, DECIDING THE PATTERN OF GENE EXPRESSION TO 'SWITCH ON OR OFF' IN RESPONSE TO ENDOGENOUS OR ENVIRONMENTAL TRIGGERS, THE KEY TASK OF PTR IS TO ACT AS A 'RHEOSTAT' AND RAPIDLY ADAPT THE CELLULAR RESPONSE BY PROVIDING THE APPROPRIATE AMPLITUDE AND TIMING TO THE PROTEIN EXPRESSION PATTERNS [3, 4]. THE PIVOTAL ROLE OF THIS MECHANISM COMES TO THE FOREFRONT IN INFLAMMATORY AND IMMUNE RESPONSE, WHERE THE CHANGES IN AMPLITUDE AND DURATION IN THE EXPRESSION OF DANGEROUS AND PROTECTIVE GENES ARE IN DELICATE BALANCE, AND ARE CRITICAL IN DETERMINING EITHER THE SUCCESSFUL RESOLUTION OF THE IMMUNE RESPONSE OR ITS CHRONIC OVEREXPRESSION [5]. THIS BRIEF REVIEW INTRODUCES MEMBERS OF THE MAIN CLASSES OF MOLECULES MEDIATING THE CYTOPLASMIC ARM OF GENE REGULATION, NAMELY RNA-BINDING PROTEINS AND MICRO-RNA (MIRNA), AND SUMMARIZES EXPERIMENTAL DATA THAT UNDERSCORE THE ROLE OF THESE MOLECULES IN THE PATHOPHYSIOLOGY OF CHRONIC INFLAMMATION, AS WELL AS THEIR PROMISING VALUE AS MECHANISMS CONVEYING THE ANTI-INFLAMMATORY EFFECT OF SYNTHETIC GLUCOCORTICOIDS. 2012 18 5878 26 SYNERGISTIC EFFECTS OF HYPERANDROGENEMIA AND OBESOGENIC WESTERN-STYLE DIET ON TRANSCRIPTION AND DNA METHYLATION IN VISCERAL ADIPOSE TISSUE OF NONHUMAN PRIMATES. POLYCYSTIC OVARY SYNDROME (PCOS) IS A MAJOR REPRODUCTIVE DISORDER THAT IS RESPONSIBLE FOR 80% OF ANOVULATORY INFERTILITY AND THAT IS ASSOCIATED WITH HYPERANDROGENEMIA, INCREASED RISK OF OBESITY, AND WHITE ADIPOSE TISSUE (WAT) DYSFUNCTION. WE HAVE PREVIOUSLY DEMONSTRATED THAT THE COMBINATION OF CHRONIC TESTOSTERONE (T) TREATMENT AND AN OBESOGENIC WESTERN-STYLE DIET (WSD) EXERTS SYNERGISTIC FUNCTIONAL EFFECTS ON WAT, LEADING TO INCREASED LIPID ACCUMULATION IN VISCERAL ADIPOCYTES BY AN UNKNOWN MECHANISM. IN THIS STUDY, WE EXAMINED THE WHOLE-GENOME TRANSCRIPTIONAL RESPONSE IN VISCERAL WAT TO T AND WSD, ALONE AND IN COMBINATION. WE OBSERVED A SYNERGISTIC EFFECT OF T AND WSD ON GENE EXPRESSION, RESULTING IN UPREGULATION OF LIPID STORAGE GENES CONCOMITANT WITH ADIPOCYTE HYPERTROPHY. BECAUSE DNA METHYLATION IS KNOWN TO BE ASSOCIATED WITH BODY FAT DISTRIBUTION AND THE ETIOLOGY OF PCOS, WE CONDUCTED WHOLE-GENOME DNA METHYLATION ANALYSIS OF VISCERAL WAT. WHILE ONLY A FRACTION OF DIFFERENTIALLY EXPRESSED GENES ALSO EXHIBITED DIFFERENTIAL DNA METHYLATION, IN SILICO ANALYSIS SHOWED THAT DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED IN TRANSCRIPTION FACTOR BINDING MOTIFS, SUGGESTING A POTENTIAL GENE REGULATORY ROLE FOR THESE REGIONS. IN SUMMARY, THIS STUDY DEMONSTRATES THAT HYPERANDROGENEMIA ALONE DOES NOT INDUCE GLOBAL TRANSCRIPTIONAL AND EPIGENETIC RESPONSE IN YOUNG FEMALE MACAQUES UNLESS COMBINED WITH AN OBESOGENIC DIET. 2019 19 1900 25 ENERGY SENSING PATHWAYS: BRIDGING TYPE 2 DIABETES AND COLORECTAL CANCER? THE RECENTLY RAPID INCREASE OF OBESITY AND TYPE 2 DIABETES MELLITUS HAS CAUSED GREAT BURDEN TO OUR SOCIETY. A POSITIVE ASSOCIATION BETWEEN TYPE 2 DIABETES AND RISK OF COLORECTAL CANCER HAS BEEN REPORTED BY INCREASING EPIDEMIOLOGICAL STUDIES. THE MOLECULAR MECHANISM OF THIS CONNECTION REMAINS ELUSIVE. HOWEVER, TYPE 2 DIABETES MAY RESULT IN ABNORMAL CARBOHYDRATE AND LIPID METABOLISM, HIGH LEVELS OF CIRCULATING INSULIN, INSULIN GROWTH FACTOR-1, AND ADIPOCYTOKINES, AS WELL AS CHRONIC INFLAMMATION. ALL THESE FACTORS COULD LEAD TO THE ALTERATION OF ENERGY SENSING PATHWAYS SUCH AS THE AMP ACTIVATED KINASE (PRKA), MECHANISTIC (MAMMALIAN) TARGET OF RAPAMYCIN (MTOR), SIRT1, AND AUTOPHAGY SIGNALING PATHWAYS. THE RESULTED IMPAIRED SIRT1 AND AUTOPHAGY SIGNALING PATHWAY COULD INCREASE THE RISK OF GENE MUTATION AND CANCER GENESIS BY DECREASING GENETIC STABILITY AND DNA MISMATCH REPAIR. THE DYSREGULATED MTOR AND PRKA PATHWAY COULD REMODEL CELL METABOLISM DURING THE GROWTH AND METASTASIS OF CANCER IN ORDER FOR THE CANCER CELL TO SURVIVE THE UNFAVORABLE MICROENVIRONMENT SUCH AS HYPOXIA AND LOW BLOOD SUPPLY. MOREOVER, THESE PATHWAYS MAY BE COUPLING METABOLIC AND EPIGENETIC ALTERATIONS THAT ARE CENTRAL TO ONCOGENIC TRANSFORMATION. FURTHER RESEARCHES INCLUDING MOLECULAR PATHOLOGIC EPIDEMIOLOGIC STUDIES ARE WARRANTED TO BETTER ADDRESS THE PRECISE LINKS BETWEEN THESE TWO IMPORTANT DISEASES. 2017 20 5410 30 REGULATION OF ADAPTIVE IMMUNE CELLS BY SIRTUINS. IT IS NOW WELL-ESTABLISHED THAT THE PATHWAYS THAT CONTROL LYMPHOCYTE METABOLISM AND FUNCTION ARE INTIMATELY LINKED, AND CHANGES IN LYMPHOCYTE METABOLISM CAN INFLUENCE AND DIRECT CELLULAR FUNCTION. INTERESTINGLY, A NUMBER OF RECENT ADVANCES INDICATE THAT LYMPHOCYTE IDENTITY AND METABOLISM IS PARTIALLY CONTROLLED VIA EPIGENETIC REGULATION. EPIGENETIC MECHANISMS, SUCH AS CHANGES IN DNA METHYLATION OR HISTONE ACETYLATION, HAVE BEEN FOUND TO ALTER IMMUNE FUNCTION AND PLAY A ROLE IN NUMEROUS CHRONIC DISEASE STATES. THERE ARE SEVERAL ENZYMES THAT CAN MEDIATE EPIGENETIC CHANGES; OF PARTICULAR INTEREST ARE SIRTUINS, PROTEIN DEACETYLASES THAT MEDIATE ADAPTIVE RESPONSES TO A VARIETY OF STRESSES (INCLUDING CALORIE RESTRICTION AND METABOLIC STRESS) AND ARE NOW UNDERSTOOD TO PLAY A SIGNIFICANT ROLE IN IMMUNITY. THIS REVIEW WILL FOCUS ON RECENT ADVANCES IN THE UNDERSTANDING OF HOW SIRTUINS AFFECT THE ADAPTIVE IMMUNE SYSTEM. THESE PATHWAYS ARE OF SIGNIFICANT INTEREST AS THERAPEUTIC TARGETS FOR THE TREATMENT OF AUTOIMMUNITY, CANCER, AND TRANSPLANT TOLERANCE. 2019