1 5285 136 PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) IN THE BRAIN AND RELEVANCE FOR NEUROPSYCHIATRIC DISORDERS. PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) HAS LONG BEEN STUDIED IN THE LIVER DUE TO ITS REGULATION OF PLASMA LOW-DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C) AND ITS CAUSAL ROLE IN FAMILIAL HYPERCHOLESTEROLEMIA. ALTHOUGH PCSK9 WAS FIRST DISCOVERED IN CEREBELLAR NEURONS UNDERGOING APOPTOSIS, ITS FUNCTION IN THE CENTRAL NERVOUS SYSTEM (CNS) IS LESS CLEAR. PCSK9 HAS BEEN SHOWN TO BE INVOLVED IN NEURONAL DIFFERENTIATION, LDL RECEPTOR FAMILY METABOLISM, APOPTOSIS, AND INFLAMMATION IN THE BRAIN, BUT IN VITRO AND IN VIVO STUDIES OFFER CONTRADICTORY FINDINGS. PCSK9 EXPRESSION IN THE ADULT BRAIN IS LOW BUT IS HIGHLY UPREGULATED DURING DISEASE STATES. CEREBRAL SPINAL FLUID (CSF) PCSK9 CONCENTRATIONS ARE CORRELATED WITH NEURAL TUBE DEFECTS AND NEURODEGENERATIVE DISEASES IN HUMAN PATIENTS. EPIGENETIC STUDIES REVEAL THAT CHRONIC ALCOHOL USE MAY MODULATE METHYLATION OF THE PCSK9 GENE AND GENETIC STUDIES SHOW THAT PATIENTS WITH GAIN-OF-FUNCTION PCSK9 VARIANTS HAVE HIGHER LDL-C AND AN INCREASED RISK OF ISCHEMIC STROKE. EARLY SAFETY STUDIES OF THE PCSK9 INHIBITORS EVOLOCUMAB AND ALIROCUMAB, USED TO TREAT HYPERCHOLESTEROLEMIA, HINTED THAT PCSK9 INHIBITION MAY NEGATIVELY IMPACT COGNITION BUT MORE RECENT, LONGER-TERM CLINICAL TRIALS FOUND NO ADVERSE NEUROCOGNITIVE EVENTS. THE PURPOSE OF THIS REVIEW IS TO ELUCIDATE THE ROLE OF PCSK9 IN THE BRAIN, PARTICULARLY ITS ROLE IN DISEASE PATHOGENESIS. 2020 2 4257 36 METHYLOMIC PROFILING AND REPLICATION IMPLICATES DEREGULATION OF PCSK9 IN ALCOHOL USE DISORDER. ALCOHOL USE DISORDER (AUD) IS A COMMON AND CHRONIC DISORDER WITH SUBSTANTIAL EFFECTS ON PERSONAL AND PUBLIC HEALTH. THE UNDERLYING PATHOPHYSIOLOGY IS POORLY UNDERSTOOD BUT STRONG EVIDENCE SUGGESTS SIGNIFICANT ROLES OF BOTH GENETIC AND EPIGENETIC COMPONENTS. GIVEN THAT ALCOHOL AFFECTS MANY ORGAN SYSTEMS, WE PERFORMED A CROSS-TISSUE AND CROSS-PHENOTYPIC ANALYSIS OF GENOME-WIDE METHYLOMIC VARIATION IN AUD USING SAMPLES FROM 3 DISCOVERY, 4 REPLICATION, AND 2 TRANSLATIONAL COHORTS. WE IDENTIFIED A DIFFERENTIALLY METHYLATED REGION IN THE PROMOTER OF THE PROPROTEIN CONVERTASE SUBTILISIN/KEXIN 9 (PCSK9) GENE THAT WAS ASSOCIATED WITH DISEASE PHENOTYPES. BIOLOGICAL VALIDATION SHOWED THAT PCSK9 PROMOTER METHYLATION IS CONSERVED ACROSS TISSUES AND POSITIVELY CORRELATED WITH EXPRESSION. REPLICATION IN AUD DATASETS CONFIRMED PCSK9 HYPOMETHYLATION AND A TRANSLATIONAL MOUSE MODEL OF AUD SHOWED THAT ALCOHOL EXPOSURE LEADS TO PCSK9 DOWNREGULATION. PCSK9 IS PRIMARILY EXPRESSED IN THE LIVER AND REGULATES LOW-DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C). OUR FINDING OF ALCOHOL-INDUCED EPIGENETIC REGULATION OF PCSK9 REPRESENTS ONE OF THE UNDERLYING MECHANISMS BETWEEN THE WELL-KNOWN EFFECTS OF ALCOHOL ON LIPID METABOLISM AND CARDIOVASCULAR RISK, WITH LIGHT ALCOHOL USE GENERALLY BEING PROTECTIVE WHILE CHRONIC HEAVY USE HAS DETRIMENTAL HEALTH OUTCOMES. 2018 3 4989 39 PCSK9 IS INCREASED IN CEREBROSPINAL FLUID OF INDIVIDUALS WITH ALCOHOL USE DISORDER. BACKGROUND: RECENT STUDIES HAVE SHOWN THAT ALCOHOL USE AFFECTS THE REGULATION AND EXPRESSION OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN 9 (PCSK9). WHILE A MAJOR ROLE OF PCSK9 IN HEPATIC FUNCTION AND LIPID REGULATION HAS BEEN CLEARLY ESTABLISHED, OTHER PLEIOTROPIC EFFECTS REMAIN POORLY UNDERSTOOD. EXISTING RESEARCH SUGGESTS A POSITIVE ASSOCIATION BETWEEN PCSK9 EXPRESSION IN THE BRAIN AND PSYCHOPATHOLOGY, WITH INCREASED LEVELS OF PCSK9 IN THE CEREBROSPINAL FLUID (CSF) OF INDIVIDUALS WITH DEMENTIA AND EPIGENETIC MODIFICATIONS OF PCSK9 ASSOCIATED WITH ALCOHOL USE DISORDER (AUD). IN THIS STUDY, WE HYPOTHESIZED THAT CHRONIC ALCOHOL USE WOULD INCREASE PCSK9 EXPRESSION IN CSF. METHODS: PCSK9 LEVELS IN CSF WERE MEASURED IN INDIVIDUALS WITH AUD (N = 42) ADMITTED TO AN INPATIENT REHABILITATION PROGRAM AND CONTROLS (N = 25). CSF SAMPLES IN AUD WERE ASSESSED AT 2 TIME POINTS, AT DAY 5 AND DAY 21 AFTER ADMISSION. FURTHERMORE, PLASMA SAMPLES WERE COLLECTED AND MEASURED FROM THE INDIVIDUALS WITH AUD. RESULTS: PCSK9 IN CSF WAS SIGNIFICANTLY INCREASED IN THE AUD GROUP AT DAY 5 AND DAY 21 COMPARED TO THE CONTROLS (P < 0.0001). PLASMA PCSK9 LEVELS WERE CORRELATED POSITIVELY WITH CSF PCSK9 LEVELS IN AUD (P = 0.0493). CONCLUSIONS: OUR DATA SUGGEST THAT PCSK9 IS ELEVATED IN THE CSF OF INDIVIDUALS WITH AUD, WHICH MAY INDICATE A POTENTIAL ROLE OF PCSK9 IN AUD. ADDITIONAL STUDIES ARE NECESSARY TO FURTHER ELUCIDATE THE FUNCTIONS OF PCSK9 IN THE BRAIN. 2019 4 522 40 ASSOCIATIONS BETWEEN NEIGHBORHOOD SOCIOECONOMIC DEPRIVATION, IFNGAMMA, AND HIGH-DENSITY LIPOPROTEIN PARTICLE SIZE: DATA FROM THE WASHINGTON, D.C. CARDIOVASCULAR HEALTH AND NEEDS ASSESSMENT. INTRODUCTION: NEIGHBORHOOD SOCIOECONOMIC DEPRIVATION IS ASSOCIATED WITH INCREASED CARDIOVASCULAR RISK FACTORS, INCLUDING INFLAMMATION. INFLAMMATION PLAYS AN IMPORTANT ROLE IN MODIFYING THE CARDIOPROTECTIVE FUNCTION OF HIGH-DENSITY LIPOPROTEIN (HDL). MOREOVER, RECENT STUDIES SUGGEST THAT VERY HIGH HDL IS ASSOCIATED WITH ADVERSE CARDIOVASCULAR DISEASE (CVD) OUTCOMES. THUS, WE SOUGHT TO EXPLORE THE RELATIONSHIPS BETWEEN NEIGHBORHOOD SOCIOECONOMIC DEPRIVATION AS A MARKER OF CHRONIC STRESS, INFLAMMATION, PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) (A CORE COMPONENT OF THE HDL PROTEOME), HDL CHARACTERISITCS, AND BIOLOGICAL AGING AS A PREDICTOR OF CVD AND ALL-CAUSE MORTALITY. METHODS: SIXTY AFRICAN AMERICAN SUBJECTS WERE RECRUITED TO THE NIH CLINICAL CENTER AS PART OF A COMMUNITY-BASED PARTICIPATORY RESEARCH-DESIGNED OBSERVATIONAL STUDY. NEIGHBORHOOD DEPRIVATION INDEX (NDI), A MARKER OF NEIGHBORHOOD SOCIOECONOMIC DEPRIVATION, WAS MEASURED USING US CENSUS DATA. HDL CHARACTERISTICS (CHOLESTEROL, PARTICLE NUMBER, SIZE, SUBSPECIES) WERE DETERMINED FROM NMR LIPOPROTEIN PROFILING, AND PLASMA CYTOKINES (IL-1BETA, IL-6, IL-8, TNFALPHA, IFNGAMMA) WERE MEASURED USING AN ELISA-BASED MULTIPLEX TECHNIQUE. EPIGENETIC CLOCK BIOMARKERS OF AGING WERE MEASURED USING DNA METHYLATION DATA OBTAINED FROM PARTICIPANTS' BUFFY COAT SAMPLES. WE USED LINEAR REGRESSION MODELING ADJUSTED FOR ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (ASCVD) RISK SCORE, BODY MASS INDEX (BMI), AND LIPID-LOWERING MEDICATION USE TO INVESTIGATE RELATIONSHIPS OF INTEREST. RESULTS: NDI DIRECTLY ASSOCIATED WITH LARGE HDL PARTICLE COUNT (H7P) AND IFNGAMMA AND TRENDED TOWARD SIGNIFICANCE WITH HDL-C AND PCSK9. IFNGAMMA AND PCSK9 THEN DIRECTLY ASSOCIATED WITH H7P. H7P ALSO DIRECTLY ASSOCIATED WITH HIGHER DNA METHYLATION PHENOTYPIC AGE (PHENOAGE). CONCLUSION: WE HIGHLIGHT ASSOCIATIONS BETWEEN NEIGHBORHOOD SOCIOECONOMIC DEPRIVATION, IFNGAMMA, PCSK9, HDL SUBSPECIES, AND EPIGENETIC BIOMARKERS OF AGING. TAKEN TOGETHER, OUR FINDINGS SUGGEST INDIRECT PATHWAYS LINKING NEIGHBORHOOD DEPRIVATION-RELATED STRESS AND INFLAMMATION TO HDL AND IMMUNE EPIGENETIC CHANGES. MOREOVER, THESE RESULTS ADD TO RECENT WORK SHOWING THE PATHOGENICITY OF HIGH HDL LEVELS AND UNDERSCORE THE NEED TO UNDERSTAND HOW CHRONIC STRESS-RELATED INFLAMMATION AND LIPOPROTEIN SUBSPECIES RELATE TO CVD RISK ACROSS DIVERSE POPULATIONS. 2023 5 2625 34 EPIGENOME-WIDE ASSOCIATION STUDY AND MULTI-TISSUE REPLICATION OF INDIVIDUALS WITH ALCOHOL USE DISORDER: EVIDENCE FOR ABNORMAL GLUCOCORTICOID SIGNALING PATHWAY GENE REGULATION. ALCOHOL USE DISORDER (AUD) IS A CHRONIC DEBILITATING DISORDER WITH LIMITED TREATMENT OPTIONS AND POORLY DEFINED PATHOPHYSIOLOGY. THERE ARE SUBSTANTIAL GENETIC AND EPIGENETIC COMPONENTS; HOWEVER, THE UNDERLYING MECHANISMS CONTRIBUTING TO AUD REMAIN LARGELY UNKNOWN. WE CONDUCTED THE LARGEST DNA METHYLATION EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) ANALYSES CURRENTLY AVAILABLE FOR AUD (TOTAL N = 625) AND EMPLOYED A TOP HIT REPLICATION (N = 4798) USING A CROSS-TISSUE/CROSS-PHENOTYPIC APPROACH WITH THE GOAL OF IDENTIFYING NOVEL EPIGENETIC TARGETS RELEVANT TO AUD. RESULTS SHOW THAT A NETWORK OF DIFFERENTIALLY METHYLATED REGIONS IN GLUCOCORTICOID SIGNALING AND INFLAMMATION-RELATED GENES WERE ASSOCIATED WITH ALCOHOL USE BEHAVIORS. A TOP PROBE CONSISTENTLY ASSOCIATED ACROSS ALL COHORTS WAS LOCATED IN THE LONG NON-CODING RNA GROWTH ARREST SPECIFIC FIVE GENE (GAS5) (P < 10(-24)). GAS5 HAS BEEN IMPLICATED IN REGULATING TRANSCRIPTIONAL ACTIVITY OF THE GLUCOCORTICOID RECEPTOR AND HAS MULTIPLE FUNCTIONS RELATED TO APOPTOSIS, IMMUNE FUNCTION AND VARIOUS CANCERS. ENDOPHENOTYPIC ANALYSES USING PERIPHERAL CORTISOL LEVELS AND NEUROIMAGING PARADIGMS SHOWED THAT METHYLOMIC VARIATION IN GAS5 NETWORK-RELATED PROBES WERE ASSOCIATED WITH STRESS PHENOTYPES. POSTMORTEM BRAIN ANALYSES DOCUMENTED INCREASED GAS5 EXPRESSION IN THE AMYGDALA OF INDIVIDUALS WITH AUD. OUR DATA SUGGEST THAT ALCOHOL USE IS ASSOCIATED WITH DIFFERENTIAL METHYLATION IN THE GLUCOCORTICOID SYSTEM THAT MIGHT INFLUENCE STRESS AND INFLAMMATORY REACTIVITY AND SUBSEQUENTLY RISK FOR AUD. 2021 6 6720 30 VITAMIN D METABOLISM GENES ARE DIFFERENTIALLY METHYLATED IN INDIVIDUALS WITH CHRONIC KNEE PAIN. CONTEXT: RECENT EVIDENCE SUGGESTS THAT VITAMIN D MAY INTERACT WITH THE EPIGENOME AND PLAY A ROLE IN THE PAIN EXPERIENCE. IN ORDER FOR PROPER FUNCTIONING TO OCCUR, THERE MUST BE AN ADEQUATE LEVEL OF VITAMIN D PRESENT, MADE POSSIBLE BY ENZYMATIC REACTIONS THAT ALLOW VITAMIN D TO BE BIOLOGICALLY ACTIVE. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE EPIGENETIC LANDSCAPE OF GENES INVOLVED IN VITAMIN D METABOLISM IN INDIVIDUALS WITH AND WITHOUT CHRONIC KNEE PAIN. PROCEDURES: COMMUNITY-DWELLING INDIVIDUALS RECRUITED AS PART OF A LARGER STUDY FOCUSED ON KNEE PAIN PROVIDED DEMOGRAPHIC, CLINICAL AND PAIN-RELATED INFORMATION, AS WELL AS AN INTRAVENOUS BLOOD SAMPLE TO DETERMINE DNA METHYLATION LEVELS AT CPG SITES. MAIN FINDINGS: THERE WERE DIFFERENCES IN DNA METHYLATION BETWEEN THOSE WITH AND WITHOUT PAIN IN GENES THAT CODE FOR ENZYMES RELATED TO VITAMIN D METABOLISM: CYP24A1 (24-HYDROXYLASE) AND CYP27B1 (1-?-HYDROXYLASE). THERE WAS ALSO HYPERMETHYLATION ON THE GENE THAT CODES FOR THE VITAMIN D RECEPTOR (VDR). PRINCIPAL CONCLUSIONS: THE PRESENCE OF CHRONIC PAIN IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS IN GENES RESPONSIBLE FOR THE EXPRESSION OF ENZYMES INVOLVED IN VITAMIN D METABOLISM AND CELLULAR FUNCTION. THESE RESULTS LAY GROUNDWORK IN UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION BETWEEN VITAMIN D AND CHRONIC PAIN. 2023 7 3608 35 IN SEARCH FOR GENES RELATED TO ATHEROSCLEROSIS AND DYSLIPIDEMIA USING ANIMAL MODELS. ATHEROSCLEROSIS IS A MULTIFACTORIAL CHRONIC DISEASE THAT AFFECTS LARGE ARTERIES AND MAY LEAD TO FATAL CONSEQUENCES. ACCORDING TO CURRENT UNDERSTANDING, INFLAMMATION AND LIPID ACCUMULATION ARE THE TWO KEY MECHANISMS OF ATHEROSCLEROSIS DEVELOPMENT. ANIMAL MODELS BASED ON GENETICALLY MODIFIED MICE HAVE BEEN DEVELOPED TO INVESTIGATE THESE ASPECTS. ONE SUCH MODEL IS LOW-DENSITY LIPOPROTEIN (LDL) RECEPTOR KNOCKOUT (KO) MICE (LDLR(-/-)), WHICH ARE CHARACTERIZED BY A MODERATE INCREASE OF PLASMA LDL CHOLESTEROL LEVELS. ANOTHER WIDELY USED GENETICALLY MODIFIED MOUSE STRAIN IS APOLIPOPROTEIN-E KO MICE (APOE(-/-)) THAT LACKS THE PRIMARY LIPOPROTEIN REQUIRED FOR THE UPTAKE OF LIPOPROTEINS THROUGH THE HEPATIC RECEPTORS, LEADING TO EVEN GREATER PLASMA CHOLESTEROL INCREASE THAN IN LDLR(-/-) MICE. THESE AND OTHER ANIMAL MODELS ALLOWED FOR CONDUCTING GENETIC STUDIES, SUCH AS GENOME-WIDE ASSOCIATION STUDIES, MICROARRAYS, AND GENOTYPING METHODS, WHICH HELPED IDENTIFYING MORE THAN 100 MUTATIONS THAT CONTRIBUTE TO ATHEROSCLEROSIS DEVELOPMENT. HOWEVER, TRANSLATION OF THE RESULTS OBTAINED IN ANIMAL MODELS FOR HUMAN SITUATIONS WAS SLOW AND CHALLENGING. AT THE SAME TIME, GENETIC STUDIES CONDUCTED IN HUMANS WERE LIMITED BY LOW SAMPLE SIZES AND HIGH HETEROGENEITY IN PREDICTIVE SUBCLINICAL PHENOTYPES. IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE ON THE USE OF KO MICE FOR IDENTIFICATION OF GENES IMPLICATED IN ATHEROSCLEROSIS AND PROVIDE A LIST OF GENES INVOLVED IN ATHEROSCLEROSIS-ASSOCIATED INFLAMMATORY PATHWAYS AND THEIR BRIEF CHARACTERISTICS. MOREOVER, WE DISCUSS THE APPROACHES FOR CANDIDATE GENE SEARCH IN ANIMALS AND HUMANS AND DISCUSS THE PROGRESS MADE IN THE FIELD OF EPIGENETIC STUDIES THAT APPEAR TO BE PROMISING FOR IDENTIFICATION OF NOVEL BIOMARKERS AND THERAPEUTIC TARGETS. 2020 8 5710 27 SIRT1 DEFICIENCY IN MICROGLIA CONTRIBUTES TO COGNITIVE DECLINE IN AGING AND NEURODEGENERATION VIA EPIGENETIC REGULATION OF IL-1BETA. AGING IS THE PREDOMINANT RISK FACTOR FOR NEURODEGENERATIVE DISEASES. ONE KEY PHENOTYPE AS THE BRAIN AGES IS AN ABERRANT INNATE IMMUNE RESPONSE CHARACTERIZED BY PROINFLAMMATION. HOWEVER, THE MOLECULAR MECHANISMS UNDERLYING AGING-ASSOCIATED PROINFLAMMATION ARE POORLY DEFINED. WHETHER CHRONIC INFLAMMATION PLAYS A CAUSAL ROLE IN COGNITIVE DECLINE IN AGING AND NEURODEGENERATION HAS NOT BEEN ESTABLISHED. HERE WE REPORT A MECHANISTIC LINK BETWEEN CHRONIC INFLAMMATION AND AGING MICROGLIA AND A CAUSAL ROLE OF AGING MICROGLIA IN NEURODEGENERATIVE COGNITIVE DEFICITS. WE SHOWED THAT SIRT1 IS REDUCED WITH THE AGING OF MICROGLIA AND THAT MICROGLIAL SIRT1 DEFICIENCY HAS A CAUSATIVE ROLE IN AGING- OR TAU-MEDIATED MEMORY DEFICITS VIA IL-1BETA UPREGULATION IN MICE. INTERESTINGLY, THE SELECTIVE ACTIVATION OF IL-1BETA TRANSCRIPTION BY SIRT1 DEFICIENCY IS LIKELY MEDIATED THROUGH HYPOMETHYLATING THE SPECIFIC CPG SITES ON IL-1BETA PROXIMAL PROMOTER. IN HUMANS, HYPOMETHYLATION OF IL-1BETA IS STRONGLY ASSOCIATED WITH CHRONOLOGICAL AGE AND WITH ELEVATED IL-1BETA TRANSCRIPTION. OUR FINDINGS REVEAL A NOVEL EPIGENETIC MECHANISM IN AGING MICROGLIA THAT CONTRIBUTES TO COGNITIVE DEFICITS IN AGING AND NEURODEGENERATIVE DISEASES. 2015 9 2119 24 EPIGENETIC HISTONE MODIFICATION REGULATES DEVELOPMENTAL LEAD EXPOSURE INDUCED HYPERACTIVITY IN RATS. LEAD (PB) EXPOSURE WAS COMMONLY CONSIDERED AS A HIGH ENVIRONMENTAL RISK FACTOR FOR THE DEVELOPMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD). HOWEVER, THE MOLECULAR BASIS OF THIS PATHOLOGICAL PROCESS STILL REMAINS ELUSIVE. IN LIGHT OF THE ROLE OF EPIGENETICS IN MODULATING THE NEUROLOGICAL DISEASE AND THE CAUSATIVE ENVIRONMENT, THE ALTERATIONS OF HISTONE MODIFICATIONS IN THE HIPPOCAMPUS OF RATS EXPOSED BY VARIOUS DOSES OF LEAD, ALONG WITH CONCOMITANT BEHAVIORAL DEFICITS, WERE INVESTIGATED IN THIS STUDY. ACCORDING TO THE FREE AND FORCED OPEN FIELD TEST, THERE SHOWED THAT IN A DOSAGE-DEPENDENT MANNER, LEAD EXPOSURE COULD RESULT IN THE INCREASED LOCOMOTOR ACTIVITY OF RATS, THAT IS, HYPERACTIVITY: A SUBTYPE OF ADHD. WESTERN BLOTTING ASSAYS REVEALED THAT THE LEVELS OF HISTONE ACETYLATION INCREASED SIGNIFICANTLY IN THE HIPPOCAMPUS BY CHRONIC LEAD EXPOSURE, WHILE NO DRAMATIC CHANGES WERE DETECTED IN TERMS OF EXPRESSION YIELDS OF ADHD-RELATED DOPAMINERGIC PROTEINS, INDICATING THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN THIS TOXICANT-INVOLVED PATHOGENESIS. IN ADDITION, THE INCREASED LEVEL OF HISTONE ACETYLATION MIGHT BE ATTRIBUTED TO THE ENZYMATIC ACTIVITY OF P300, A TYPICAL HISTONE ACETYLTRANSFERASE, AS THE TRANSCRIPTIONAL LEVEL OF P300 WAS SIGNIFICANTLY INCREASED UPON HIGHER-DOSE PB EXPOSURE. IN SUMMARY, THIS STUDY FIRST DISCOVERED THE EPIGENETIC MECHANISM BRIDGING THE ENVIRONMENTAL INFLUENCE (PB) AND THE DISEASE ITSELF (ADHD) IN THE HISTONE MODIFICATION LEVEL, PAVING THE WAY FOR THE COMPREHENSIVE UNDERSTANDING OF ADHD'S ETIOLOGY AND IN FURTHER STEPS, ESTABLISHING THE THERAPY STRATEGY OF THIS WIDESPREAD NEUROLOGICAL DISORDER. 2014 10 948 23 CHRONIC METABOLIC DERANGEMENT-INDUCED COGNITIVE DEFICITS AND NEUROTOXICITY ARE ASSOCIATED WITH REST INACTIVATION. CHRONIC METABOLIC ALTERATIONS MAY REPRESENT A RISK FACTOR FOR THE DEVELOPMENT OF COGNITIVE IMPAIRMENT, DEMENTIA, OR NEURODEGENERATIVE DISEASES. HYPERGLYCEMIA AND OBESITY ARE KNOWN TO IMPRINT EPIGENETIC MARKERS THAT COMPROMISE THE PROPER EXPRESSION OF CELL SURVIVAL GENES. HERE, WE SHOWED THAT CHRONIC HYPERGLYCEMIA (60 DAYS) INDUCED BY A SINGLE INTRAPERITONEAL INJECTION OF STREPTOZOTOCIN COMPROMISED COGNITION BY REDUCING HIPPOCAMPAL ERK SIGNALING AND BY INDUCING NEUROTOXICITY IN RATS. THE MECHANISMS APPEAR TO BE LINKED TO REDUCED ACTIVE DNA DEMETHYLATION AND DIMINISHED EXPRESSION OF THE NEUROPROTECTIVE TRANSCRIPTION FACTOR REST. THE IMPACT OF THE RELATIONSHIP BETWEEN ADIPOSITY AND DNA HYPERMETHYLATION ON REST EXPRESSION WAS ALSO DEMONSTRATED IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN OBESE CHILDREN WITH REDUCED LEVELS OF BLOOD ASCORBATE. THE REVERSIBLE NATURE OF EPIGENETIC MODIFICATIONS AND THE COGNITIVE IMPAIRMENT REPORTED IN OBESE CHILDREN, ADOLESCENTS, AND ADULTS SUGGEST THAT THE CORRECTION OF THE ANTHROPOMETRY AND THE PERIPHERAL METABOLIC ALTERATIONS WOULD PROTECT BRAIN HOMEOSTASIS AND REDUCE THE RISK OF DEVELOPING NEURODEGENERATIVE DISEASES. 2019 11 4707 27 NMR PLASMA METABOLOMICS STUDY OF PATIENTS OVERCOMING ACUTE MYOCARDIAL INFARCTION: IN THE FIRST 12 H AFTER ONSET OF CHEST PAIN WITH STATISTICAL DISCRIMINATION TOWARDS METABOLOMIC BIOMARKERS. ACUTE MYOCARDIAL INFARCTION (AMI) IS ONE OF THE LEADING CAUSES OF DEATH AMONG ADULTS IN OLDER AGE. UNDERSTANDING MECHANISMS HOW ORGANISM RESPONDS TO ISCHEMIA IS ESSENTIAL FOR THE ISCHEMIC PATIENT'S PREVENTION AND TREATMENT. DESPITE THE GREAT PREVALENCE AND INCIDENCE ONLY A SMALL NUMBER OF STUDIES UTILIZE A METABOLOMIC APPROACH TO DESCRIBE AMI CONDITION. RECENT STUDIES HAVE SHOWN THE IMPACT OF METABOLITES ON EPIGENETIC CHANGES, IN THESE STUDIES PLASMA METABOLITES WERE RELATED TO NEUROLOGICAL OUTCOME OF THE PATIENTS MAKING METABOLOMIC STUDIES INCREASINGLY INTERESTING. THE AIM OF THIS STUDY WAS TO DESCRIBE METABOLOMIC RESPONSE OF AN ORGANISM TO ISCHEMIC STRESS THROUGH THE CHANGES IN ENERGETIC METABOLITES AND AMINOACIDS IN BLOOD PLASMA IN PATIENTS OVERCOMING ACUTE MYOCARDIAL INFARCTION. BLOOD PLASMA FROM PATIENTS IN THE FIRST 12 H AFTER ONSET OF CHEST PAIN WAS COLLECTED AND COMPARED WITH VOLUNTEERS WITHOUT ANY HISTORY OF ISCHEMIC DISEASES VIA NMR SPECTROSCOPY. LOWERED PLASMA LEVELS OF PYRUVATE, ALANINE, GLUTAMINE AND NEUROTRANSMITTER PRECURSORS TYROSINE AND TRYPTOPHAN WERE FOUND. FURTHER, WE OBSERVED INCREASED PLASMA LEVELS OF 3-HYDROXYBUTYRATE AND ACETOACETATE IN BALANCE WITH DECREASED LEVEL OF LIPOPROTEINS FRACTION, SUGGESTING THE ONGOING KETONIC STATE OF AN ORGANISM. DISCRIMINATORY ANALYSIS SHOWED VERY PROMISING PERFORMANCE WHERE COMPOUNDS: LIPOPROTEINS, ALANINE, PYRUVATE, GLUTAMINE, TRYPTOPHAN AND 3-HYDROXYBUTYRATE WERE OF THE HIGHEST DISCRIMINATORY POWER WITH FEASIBILITY OF SUCCESSFUL STATISTICAL DISCRIMINATION. 2020 12 405 30 ANALYSIS OF EPIGENETIC MECHANISMS REGULATING OPIOID RECEPTOR GENE TRANSCRIPTION. OPIOID DRUGS ARE GENERALLY USED FOR MODERATE AND SEVERE PAIN REDUCTIONS WHICH ACT THROUGH OPIOID RECEPTORS. STUDIES ON TRANSCRIPTIONAL REGULATION OF OPIOID RECEPTORS ARE STILL INVALUABLE BECAUSE NOT ONLY TRANSCRIPTION IS THE FIRST STEP TO PRODUCE PROTEIN PRODUCTS IN CELLS, BUT THE RECEPTOR TRANSCRIPTION LEVELS ALSO AFFECT THE PAIN REDUCTION BY OPIOIDS, AS OBSERVED IN STUDIES OF HETEROZYGOUS OPIOID RECEPTOR KNOCKOUT MICE.THERE ARE GROWING EVIDENCES THAT EPIGENETIC REGULATION HAS PLAYED SIGNIFICANT ROLES IN TRANSCRIPTIONAL REGULATION OF GENES, INCLUDING OPIOID RECEPTORS. IN GENERAL, EPIGENETIC MECHANISMS INCLUDE THREE MAIN REGULATORY FACTORS: DNA METHYLATION, CHROMATIN MODIFICATION, AND NONCODING RNAS (SUCH AS MICRORNA). FROM PREVIOUS STUDIES OF OURS AND OTHERS ON OPIOID RECEPTORS, THOSE EPIGENETIC FACTORS WERE CLEARLY INVOLVED IN REGULATING OPIOID RECEPTOR EXPRESSION IN VIVO AND IN VITRO. IN THIS CHAPTER, AMONG THOSE THREE TECHNIQUES WE DESCRIBE MORE DETAILS OF DNA METHYLATION METHODS BECAUSE OF EMERGING CONCEPTS OF DNA METHYLATION WITH THE RECENT DISCOVERY OF 5-HYDROXYMETHYLCYTOSINE CONVERTING ENZYME, TET1. ANOTHER ANALYTICAL METHOD OF THE EPIGENETIC FACTORS, CHROMATIN MODIFICATION, WILL BE DESCRIBED BRIEFLY AND INFORMATION OF ANALYZING NONCODING RNAS IS BRIEFLY MENTIONED IN SUBHEADING 1. 2015 13 315 30 ALCOHOL, DNA METHYLATION, AND CANCER. CANCER IS ONE OF THE MOST SIGNIFICANT DISEASES ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION, AND CHRONIC DRINKING IS A STRONG RISK FACTOR FOR CANCER, PARTICULARLY OF THE UPPER AERODIGESTIVE TRACT, LIVER, COLORECTUM, AND BREAST. SEVERAL FACTORS CONTRIBUTE TO ALCOHOL-INDUCED CANCER DEVELOPMENT (I.E., CARCINOGENESIS), INCLUDING THE ACTIONS OF ACETALDEHYDE, THE FIRST AND PRIMARY METABOLITE OF ETHANOL, AND OXIDATIVE STRESS. HOWEVER, INCREASING EVIDENCE SUGGESTS THAT ABERRANT PATTERNS OF DNA METHYLATION, AN IMPORTANT EPIGENETIC MECHANISM OF TRANSCRIPTIONAL CONTROL, ALSO COULD BE PART OF THE PATHOGENETIC MECHANISMS THAT LEAD TO ALCOHOL-INDUCED CANCER DEVELOPMENT. THE EFFECTS OF ALCOHOL ON GLOBAL AND LOCAL DNA METHYLATION PATTERNS LIKELY ARE MEDIATED BY ITS ABILITY TO INTERFERE WITH THE AVAILABILITY OF THE PRINCIPAL BIOLOGICAL METHYL DONOR, S-ADENOSYLMETHIONINE (SAME), AS WELL AS PATHWAYS RELATED TO IT. SEVERAL MECHANISMS MAY MEDIATE THE EFFECTS OF ALCOHOL ON DNA METHYLATION, INCLUDING REDUCED FOLATE LEVELS AND INHIBITION OF KEY ENZYMES IN ONE-CARBON METABOLISM THAT ULTIMATELY LEAD TO LOWER SAME LEVELS, AS WELL AS INHIBITION OF ACTIVITY AND EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION (I.E., DNA METHYLTRANSFERASES). FINALLY, VARIATIONS (I.E., POLYMORPHISMS) OF SEVERAL GENES INVOLVED IN ONE-CARBON METABOLISM ALSO MODULATE THE RISK OF ALCOHOL-ASSOCIATED CARCINOGENESIS. 2013 14 6775 31 [ALCOHOL DEPENDENCE MEDIATED BY MONOAMINE NEUROTRANSMITTERS IN THE CENTRAL NERVOUS SYSTEM]. ALCOHOL DEPENDENCE, A CHRONIC RELAPSING BRAIN DISEASE WITH THE CHARACTERISTICS OF DRINKING ALCOHOL OUT OF CONTROL, HAS BECOME A SERIOUS SOCIAL PROBLEM. MONOAMINE NEUROTRANSMITTERS, MAINLY INCLUDING DOPAMINE AND 5-HYDROXYTRYP NOTTAMINE, PLAY IMPORTANT ROLES IN THE OCCURRENCE, DEVELOPMENT AND NEURAL DYSFUNCTION OF ALCOHOL DEPENDENCE SYNDROME. IN THIS REVIEW, THE ROLES OF KEY FACTORS OF THE MONOAMINE SYSTEM (DOPAMINE RECEPTOR GENES, 5-HYDROXYTRYPTAMINE RECEPTOR GENES, TRANSPORTER GENES, TYROSINE HYDROXYLASE GENE, TRYPTOPHANHYDROXYLASE GENE AND MONOAMINE OXIDASE GENE) IN ALCOHOL DEPENDENCE WERE DISCUSSED, AND STRATEGIES FOR FURTHER STUDIES OF MOLECULAR MECHANISMS WERE PROPOSED BASED ON GENE KNOCKOUT MICE MODELS GENERATED IN OUR LABORATORY. THEN, COMBINING WITH STUDIES ON TYROSINE HYDROXYLASE ACTIVATOR CAMKII IN OUR LAB, THERAPEUTIC TARGETS WERE DISCUSSED. BESIDES, EPIGENETIC STRATEGIES FOR PREVENTION AND TREATMENT OF ALCOHOL DEPENDENCE SYNDROME WERE PROPOSED. FURTHERMORE, MANIPULATING METHYLATION LEVELS IN GENE REGULATORY REGIONS AND ALTERNATIVE SPLICING OF PRE-MRNAS MIGHT ALSO HAVE CLINICAL IMPLICATIONS. FINALLY, BASED ON NEW FINDINGS ON GENETIC POLYMORPHISM, IT IS OF GREAT POTENTIAL TO CARRY OUT INDIVIDUAL PREVENTION AND TREATMENT FOR PATIENTS SUFFERING FROM ALCOHOL DEPENDENCE. 2014 15 6889 27 [S-ADENOSYL L-METHIONINE IN CNS DISEASES]. S-ADENOSYL L-METHIONINE (SAME) IS THE NATURAL, UNIVERSAL METHYL GROUP DONOR, PARTICIPATING IN TRANSMETHYLATION REACTIONS, KNOWN AND COMMONLY USED AS A DIETARY SUPPLEMENT SINCE 1952. IT PLAYS AN IMPORTANT ROLE IN THE SYNTHESIS OF NEUROMEDIATORS AND MELATONIN AND MECHANISMS OF EPIGENETIC REGULATION. THE AIM OF THIS ARTICLE IS TO REVIEW THE LITERATURE ABOUT POSSIBILITIES OF SAME APPLICATION IN THE THERAPY OF CNS DISEASES: DEPRESSION, DEMENTIA SYNDROMES, SCHIZOPHRENIA AND SOMATIC DISORDERS. SAME IS THE PROMISING DIETARY SUPPLEMENT, WHICH MAY BE SUCCESSFULLY USED AS A SUBSTANCE INCREASING EFFECTIVENESS OF THE TREATMENT OF DEPRESSION, WITH ANTIDEPRESSANTS IN MONOTHERAPY IN MILD DEPRESSIVE STATES OR DEPRESSIVE SYMPTOMS. SAME ADDITION TO ANTIPSYCHOTIC DRUG, MAY LEAD TO THE IMPROVEMENT OF THE QUALITY OF LIFE AND REDUCTION OF AGGRESSIVENESS OF PATIENTS. SAME MAY BE AN EFFECTIVE SUBSTANCE IN THE THERAPY AND PROPHYLAXIS OF MILD COGNITIVE IMPAIRMENTS AND MILD DEMENTIA SYNDROME. SAME POSSESSES SOME HEPATOPROTECTIVE ACTION, SO IT MAY DECREASE THE RISK OF THE DEVELOPMENT OF NEOPLASM, ALCOHOL-INDUCED LIVER DISEASE (ALD) AND CIRRHOSIS. SAME IMPROVES THE FUNCTIONS OF JOINTS AND DECREASES THE EXPERIENCE OF PAIN IN RHEUMATOID ARTHRITIS (RA). 2011 16 4648 45 NEUROPEPTIDE Y IN ALCOHOL ADDICTION AND AFFECTIVE DISORDERS. NEUROPEPTIDE Y (NPY), A NEUROPEPTIDE HIGHLY CONSERVED THROUGHOUT EVOLUTION, IS PRESENT AT HIGH LEVELS IN THE CENTRAL NERVOUS SYSTEM (CNS), AS WELL AS IN PERIPHERAL TISSUES SUCH AS THE GUT AND CARDIOVASCULAR SYSTEM. THE PEPTIDE EXERTS ITS EFFECTS VIA MULTIPLE RECEPTOR SUBTYPES, ALL BELONGING TO THE G-PROTEIN-COUPLED RECEPTOR SUPERFAMILY. OF THESE SUBTYPES, THE Y1 AND THE Y2 ARE THE MOST THOROUGHLY CHARACTERIZED, FOLLOWED BY THE Y5 SUBTYPE. NPY AND ITS RECEPTORS HAVE BEEN SHOWN TO BE OF IMPORTANCE IN CENTRAL REGULATION OF EVENTS UNDERLYING, FOR EXAMPLE, AFFECTIVE DISORDERS, DRUG/ALCOHOL USE DISORDERS, AND ENERGY HOMEOSTASIS. FURTHERMORE, WITHIN THE CNS, NPY ALSO AFFECTS SLEEP REGULATION AND CIRCADIAN RHYTHM, MEMORY FUNCTION, TISSUE GROWTH, AND PLASTICITY. THE POTENTIAL ROLES OF NPY IN THE ETIOLOGY AND PATHOPHYSIOLOGY OF MOOD AND ANXIETY DISORDERS, AS WELL AS ALCOHOL USE DISORDERS, HAVE BEEN EXTENSIVELY STUDIED. THIS FOCUS WAS PROMPTED BY EARLY INDICATIONS FOR AN INVOLVEMENT OF NPY IN ACUTE RESPONSES TO STRESS, AND, LATER, ALSO DATA POINTING TO A ROLE IN ALTERATIONS WITHIN THE CNS DURING CHRONIC, OR REPEATED, EXPOSURE TO ADVERSE EVENTS. THESE FUNCTIONS OF NPY, IN ADDITION TO THE PEPTIDE'S REGULATION OF DISEASE STATES, SUGGEST THAT MODULATION OF THE ACTIVITY OF THE NPY SYSTEM VIA RECEPTOR AGONISTS/ANTAGONISTS MAY BE A PUTATIVE TREATMENT MECHANISM IN AFFECTIVE DISORDERS AS WELL AS ALCOHOL USE DISORDERS. IN THIS REVIEW, WE PRESENT AN OVERVIEW OF FINDINGS WITH REGARD TO THE NPY SYSTEM IN RELATION TO ANXIETY AND STRESS, ACUTE AS WELL AS CHRONIC; FURTHERMORE WE DISCUSS POST-TRAUMATIC STRESS DISORDER AND, IN PART DEPRESSION. IN ADDITION, WE SUMMARIZE FINDINGS ON ALCOHOL USE DISORDERS AND RELATED BEHAVIORS. FINALLY, WE BRIEFLY TOUCH UPON GENETIC AS WELL AS EPIGENETIC MECHANISMS THAT MAY BE OF IMPORTANCE FOR NPY FUNCTION AND REGULATION. IN CONCLUSION, WE SUGGEST THAT MODULATION OF NPY-ERGIC ACTIVITY WITHIN THE CNS, VIA LIGANDS AIMED AT DIFFERENT RECEPTOR SUBTYPES, MAY BE ATTRACTIVE TARGETS FOR TREATMENT DEVELOPMENT FOR AFFECTIVE DISORDERS, AS WELL AS FOR ALCOHOL USE DISORDERS. 2017 17 6324 32 THE ROLE OF ALPHA-SYNUCLEIN IN THE PATHOPHYSIOLOGY OF ALCOHOLISM. ALCOHOLISM HAS COMPLEX ETIOLOGY AND THERE IS EVIDENCE FOR BOTH GENETIC AND ENVIRONMENTAL FACTORS IN ITS PATHOPHYSIOLOGY. CHRONIC, LONG-TERM ALCOHOL ABUSE AND ALCOHOL DEPENDENCE ARE ASSOCIATED WITH NEURONAL LOSS WITH THE PREFRONTAL CORTEX BEING PARTICULARLY SUSCEPTIBLE TO NEUROTOXIC DAMAGE. THIS BRAIN REGION IS INVOLVED IN THE DEVELOPMENT AND PERSISTENCE OF ALCOHOL ADDICTION AND NEUROTOXIC DAMAGE IS LIKELY TO EXACERBATE THE REINFORCING EFFECTS OF ALCOHOL AND MAY HINDER TREATMENT. UNDERSTANDING THE MECHANISM OF ALCOHOL'S NEUROTOXIC EFFECTS ON THE BRAIN AND THE GENETIC RISK FACTORS ASSOCIATED WITH ALCOHOL ABUSE ARE THE FOCUS OF CURRENT RESEARCH. BECAUSE OF ITS WELL-ESTABLISHED ROLE IN NEURODEGENERATIVE AND NEUROPSYCHOLOGICAL DISORDERS, AND ITS EMERGING ROLE IN THE PATHOPHYSIOLOGY OF ADDICTION, HERE WE REVIEW THE GENETIC AND EPIGENETIC FACTORS INVOLVED IN REGULATING ALPHA-SYNUCLEIN EXPRESSION AND ITS POTENTIAL ROLE IN THE PATHOPHYSIOLOGY OF CHRONIC ALCOHOL ABUSE. ELUCIDATION OF THE MECHANISMS OF ALPHA-SYNUCLEIN REGULATION MAY PROVE BENEFICIAL IN UNDERSTANDING THE ROLE OF THIS KEY SYNAPTIC PROTEIN IN DISEASE AND ITS POTENTIAL FOR THERAPEUTIC MODULATION IN THE TREATMENT OF SUBSTANCE USE DISORDERS AS WELL AS OTHER NEURODEGENERATIVE DISEASES. 2013 18 2507 31 EPIGENETICS AND OBESITY: THE DEVIL IS IN THE DETAILS. OBESITY IS A COMPLEX DISEASE WITH MULTIPLE WELL-DEFINED RISK FACTORS. NEVERTHELESS, SUSCEPTIBILITY TO OBESITY AND ITS SEQUELAE WITHIN OBESOGENIC ENVIRONMENTS VARIES GREATLY FROM ONE PERSON TO THE NEXT, SUGGESTING A ROLE FOR GENE X ENVIRONMENT INTERACTIONS IN THE ETIOLOGY OF THE DISORDER. EPIGENETIC REGULATION OF THE HUMAN GENOME PROVIDES A PUTATIVE MECHANISM BY WHICH SPECIFIC ENVIRONMENTAL EXPOSURES CONVEY RISK FOR OBESITY AND OTHER HUMAN DISEASES AND IS ONE POSSIBLE MECHANISM THAT UNDERLIES THE GENE X ENVIRONMENT/TREATMENT INTERACTIONS OBSERVED IN EPIDEMIOLOGICAL STUDIES AND CLINICAL TRIALS. A STUDY PUBLISHED IN BMC MEDICINE THIS MONTH BY WANG ET AL. REPORTS ON AN EXAMINATION OF DNA METHYLATION IN PERIPHERAL BLOOD LEUKOCYTES OF LEAN AND OBESE ADOLESCENTS, COMPARING METHYLATION PATTERNS BETWEEN THE TWO GROUPS. THE AUTHORS IDENTIFIED TWO GENES THAT WERE DIFFERENTIALLY METHYLATED, BOTH OF WHICH HAVE ROLES IN IMMUNE FUNCTION. HERE WE OVERVIEW THE FINDINGS FROM THIS STUDY IN THE CONTEXT OF THOSE EMERGING FROM OTHER RECENT GENETIC AND EPIGENETIC STUDIES, DISCUSS THE STRENGTHS AND WEAKNESSES OF THE STUDY AND SPECULATE ON THE FUTURE OF EPIGENETICS IN CHRONIC DISEASE RESEARCH. 2010 19 1870 31 EMERGING ROLE OF EPIGENETIC MECHANISMS IN ALCOHOL ADDICTION. ALCOHOL USE DISORDER (AUD) IS A COMPLEX BRAIN DISORDER WITH AN ARRAY OF PERSISTENT BEHAVIORAL AND NEUROCHEMICAL MANIFESTATIONS. BOTH GENETIC AND ENVIRONMENTAL FACTORS ARE KNOWN TO CONTRIBUTE TO THE DEVELOPMENT OF AUD, AND RECENT STUDIES ON ALCOHOL EXPOSURE AND SUBSEQUENT CHANGES IN GENE EXPRESSION SUGGEST THE IMPORTANCE OF EPIGENETIC MECHANISMS. IN PARTICULAR, HISTONE MODIFICATIONS AND DNA METHYLATION HAVE EMERGED AS IMPORTANT REGULATORS OF GENE EXPRESSION AND ASSOCIATED PHENOTYPES OF AUD. GIVEN THE THERAPEUTIC POTENTIAL OF EPIGENETIC TARGETS, THIS REVIEW AIMS TO SUMMARIZE THE ROLE OF EPIGENETIC REGULATION IN OUR CURRENT UNDERSTANDING OF AUD BY EVALUATING KNOWN EPIGENETIC SIGNATURES OF BRAIN REGIONS CRITICAL TO ADDICTIVE BEHAVIORS IN BOTH ANIMAL AND HUMAN STUDIES THROUGHOUT VARIOUS STAGES OF AUD. MORE SPECIFICALLY, THE EFFECTS OF ACUTE AND CHRONIC ALCOHOL EXPOSURE, TOLERANCE, AND POSTEXPOSURE WITHDRAWAL ON EPIGENETICALLY INDUCED CHANGES TO GENE EXPRESSION AND SYNAPTIC PLASTICITY WITHIN KEY BRAIN REGIONS AND THE ASSOCIATED BEHAVIORAL PHENOTYPES HAVE BEEN DISCUSSED. UNDERSTANDING THE CONTRIBUTION OF EPIGENETIC REGULATION TO CRUCIAL SIGNALING PATHWAYS MAY PROVE VITAL FOR FUTURE DEVELOPMENT OF NOVEL BIOMARKERS AND TREATMENT AGENTS IN AMELIORATING OR PREVENTING AUD. 2017 20 4370 30 MIRNAS AND THEIR ROLE IN THE CORRELATION BETWEEN SCHIZOPHRENIA AND CANCER (REVIEW). SCHIZOPHRENIA (SZ) AND CANCER (CA) HAVE A BROAD SPECTRUM OF CLINICAL PHENOTYPES AND A COMPLEX BIOLOGICAL BACKGROUND, IMPLICATING A LARGE NUMBER OF GENETIC AND EPIGENETIC FACTORS. SZ IS A CHRONIC NEURODEVELOPMENTAL DISORDER SIGNIFIED BY AN INCREASE IN THE EXPRESSION OF APOPTOTIC MOLECULAR SIGNALS, WHEREAS CA IS CONVERSELY CHARACTERIZED BY AN INCREASE IN APPROPRIATE MOLECULAR SIGNALING THAT STIMULATES UNCONTROLLED CELL PROLIFERATION. THE RATHER LOW RISK OF DEVELOPING CA IN PATIENTS SUFFERING FROM SZ IS A HYPOTHESIS THAT IS STILL UNDER DEBATE. RECENT EVIDENCE HAS INDICATED THAT MICRORNAS (MIRNAS OR MIRS), A LARGE GROUP OF SMALL NON?CODING OLIGONOUCLEOTIDES, MAY PLAY A SIGNIFICANT ROLE IN THE DEVELOPMENT OF CA AND MAJOR PSYCHIATRIC DISORDERS, SUCH AS SZ, BIPOLAR DISORDER, AUTISM SPECTRUM DISORDERS, SUICIDALITY AND DEPRESSION, THROUGH THEIR INTERFERENCE WITH THE EXPRESSION OF MULTIPLE GENES. FOR INSTANCE, THE POSSIBLE ROLE OF LET?7, MIR?98 AND MIR?183 AS BIOMARKERS FOR CA AND SZ WAS INVESTIGATED IN OUR PREVIOUS RESEARCH STUDIES. THEREFORE, FURTHER INVESTIGATIONS ON THE EXPRESSION PROFILES OF THESE REGULATORY, SMALL RNA MOLECULES AND THE MOLECULAR PATHWAYS THROUGH WHICH THEY EXERT THEIR CONTROL MAY PROVIDE A PLAUSIBLE EXPLANATION AS TO WHETHER THERE IS A CORRELATION BETWEEN PSYCHIATRIC DISORDERS AND LOW RISK OF DEVELOPING CA. 2016