1 6145 355 THE EXPANDING PHENOTYPES OF COHESINOPATHIES: ONE RING TO RULE THEM ALL! PRESERVATION AND DEVELOPMENT OF LIFE DEPEND ON THE ADEQUATE SEGREGATION OF SISTER CHROMATIDS DURING MITOSIS AND MEIOSIS. THIS PROCESS IS ENSURED BY THE COHESIN MULTI-SUBUNIT COMPLEX. MUTATIONS IN THIS COMPLEX HAVE BEEN ASSOCIATED WITH AN INCREASING NUMBER OF DISEASES, TERMED COHESINOPATHIES. THE BEST CHARACTERIZED COHESINOPATHY IS CORNELIA DE LANGE SYNDROME (CDLS), IN WHICH INTELLECTUAL AND GROWTH RETARDATIONS ARE THE MAIN PHENOTYPIC MANIFESTATIONS. DESPITE SOME OVERLAP, THE CLINICAL MANIFESTATIONS OF COHESINOPATHIES VARY CONSIDERABLY. NOVEL ROLES OF THE COHESIN COMPLEX HAVE EMERGED DURING THE PAST DECADES, SUGGESTING THAT IMPORTANT CELL CYCLE REGULATORS EXERT IMPORTANT BIOLOGICAL EFFECTS THROUGH NON-COHESION-RELATED FUNCTIONS AND BROADENING THE POTENTIAL PATHOMECHANISMS INVOLVED IN COHESINOPATHIES. THIS REVIEW FOCUSES ON NON-COHESION-RELATED FUNCTIONS OF THE COHESIN COMPLEX, GENE DOSAGE EFFECT, EPIGENETIC REGULATION AND TGF-BETA IN COHESINOPATHY CONTEXT, ESPECIALLY IN COMPARISON TO CHRONIC ATRIAL AND INTESTINAL DYSRHYTHMIA (CAID) SYNDROME, A VERY DISTINCT COHESINOPATHY CAUSED BY A HOMOZYGOUS SHUGOSHIN-1 (SGO1) MUTATION (K23E) AND CHARACTERIZED BY PACEMAKER FAILURE IN BOTH HEART (SICK SINUS SYNDROME FOLLOWED BY ATRIAL FLUTTER) AND GUT (CHRONIC INTESTINAL PSEUDO-OBSTRUCTION) WITH NO INTELLECTUAL OR GROWTH DELAY. WE DISCUSS THE POSSIBLE IMPACT OF SGO1 ALTERATIONS IN HUMAN PATHOLOGIES AND THE POTENTIAL IMPACT OF THE SGO1 K23E MUTATION IN THE SINUS NODE AND GUT DEVELOPMENT AND FUNCTIONS. WE SUGGEST THAT THE HUMAN PHENOTYPES OBSERVED IN CDLS, CAID SYNDROME AND OTHER COHESINOPATHIES CAN INFORM FUTURE STUDIES INTO THE LESS WELL-KNOWN NON-COHESION-RELATED FUNCTIONS OF COHESIN COMPLEX GENES. ABBREVIATIONS: AD: ALZHEIMER DISEASE; AFF4: AF4/FMR2 FAMILY MEMBER 4; ANKRD11: ANKYRIN REPEAT DOMAIN 11; APC: ANAPHASE PROMOTER COMPLEX; ASD: ATRIAL SEPTAL DEFECT; ATRX: ATRX CHROMATIN REMODELER; ATRX: ALPHA THALASSEMIA X-LINKED INTELLECTUAL DISABILITY SYNDROME; BIRC5: BACULOVIRAL IAP REPEAT CONTAINING 5; BMP: BONE MORPHOGENETIC PROTEIN; BRD4: BROMODOMAIN CONTAINING 4; BUB1: BUB1 MITOTIC CHECKPOINT SERINE/THREONINE KINASE; CAID: CHRONIC ATRIAL AND INTESTINAL DYSRHYTHMIA; CDK1: CYCLIN DEPENDENT KINASE 1; CDLS: CORNELIA DE LANGE SYNDROME; CHD: CONGENITAL HEART DISEASE; CHOPS: COGNITIVE IMPAIRMENT, COARSE FACIES, HEART DEFECTS, OBESITY, PULMONARY INVOLVEMENT, SHORT STATURE, AND SKELETAL DYSPLASIA; CIPO: CHRONIC INTESTINAL PSEUDO-OBSTRUCTION; C-KIT: KIT PROTO-ONCOGENE RECEPTOR TYROSINE KINASE; COATS: COHESIN ACETYLTRANSFERASES; CTCF: CCCTC-BINDING FACTOR; DDX11: DEAD/H-BOX HELICASE 11; ERG: TRANSCRIPTIONAL REGULATOR ERG; ESCO2: ESTABLISHMENT OF SISTER CHROMATID COHESION N-ACETYLTRANSFERASE 2; GJC1: GAP JUNCTION PROTEIN GAMMA 1; H2A: HISTONE H2A; H3K4: HISTONE H3 LYSINE 4; H3K9: HISTONE H3 LYSINE 9; HCN4: HYPERPOLARIZATION ACTIVATED CYCLIC NUCLEOTIDE GATED POTASSIUM AND SODIUM CHANNEL 4;P HDAC8: HISTONE DEACETYLASES 8; HP1: HETEROCHROMATIN PROTEIN 1; ICC: INTERSTITIAL CELLS OF CAJAL; ICC-MP: MYENTERIC PLEXUS INTERSTITIAL CELLS OF CAJAL; ICC-DMP: DEEP MUSCULAR PLEXUS INTERSTITIAL CELLS OF CAJAL; I(F): PACEMAKER FUNNY CURRENT; IP3: INOSITOL TRISPHOSPHATE; JNK: C-JUN N-TERMINAL KINASE; LDS: LOEYS-DIETZ SYNDROME; LOAD: LATE-ONSET ALZHEIMER DISEASE; MAPK: MITOGEN-ACTIVATED PROTEIN KINASE; MAU: MAU SISTER CHROMATID COHESION FACTOR; MFS: MARFAN SYNDROME; NIPBL: NIPBL, COHESIN LOADING FACTOR; OCT4: OCTAMER-BINDING PROTEIN 4; P38: P38 MAP KINASE; PDA: PATENT DUCTUS ARTERIOSUS; PDS5: PDS5 COHESIN ASSOCIATED FACTOR; P-H3: PHOSPHO HISTONE H3; PLK1: POLO LIKE KINASE 1; POPDC1: POPEYE DOMAIN CONTAINING 1; POPDC2: POPEYE DOMAIN CONTAINING 2; PP2A: PROTEIN PHOSPHATASE 2; RAD21: RAD21 COHESIN COMPLEX COMPONENT; RBS: ROBERTS SYNDROME; REC8: REC8 MEIOTIC RECOMBINATION PROTEIN; RNAP2: RNA POLYMERASE II; SAN: SINOATRIAL NODE; SCN5A: SODIUM VOLTAGE-GATED CHANNEL ALPHA SUBUNIT 5; SEC: SUPER ELONGATION COMPLEX; SGO1: SHOGOSHIN-1; SMAD: SMAD FAMILY MEMBER; SMC1A: STRUCTURAL MAINTENANCE OF CHROMOSOMES 1A; SMC3: STRUCTURAL MAINTENANCE OF CHROMOSOMES 3; SNV: SINGLE NUCLEOTIDE VARIANT; SOX2: SRY-BOX 2; SOX17: SRY-BOX 17; SSS: SICK SINUS SYNDROME; STAG2: COHESIN SUBUNIT SA-2; TADS: TOPOLOGY ASSOCIATED DOMAINS; TBX: T-BOX TRANSCRIPTION FACTORS; TGF-BETA: TRANSFORMING GROWTH FACTOR BETA; TGFBR: TRANSFORMING GROWTH FACTOR BETA RECEPTOR; TOF: TETRALOGY OF FALLOT; TREK1: TREK-1 K(+) CHANNEL SUBUNIT; VSD: VENTRICULAR SEPTAL DEFECT; WABS: WARSAW BREAKAGE SYNDROME; WAPL: WAPL COHESIN RELEASE FACTOR. 2019 2 4484 53 MOLECULAR SIGNATURE OF CAID SYNDROME: NONCANONICAL ROLES OF SGO1 IN REGULATION OF TGF-BETA SIGNALING AND EPIGENOMICS. BACKGROUND & AIMS: A GENERALIZED HUMAN PACEMAKING SYNDROME, CHRONIC ATRIAL AND INTESTINAL DYSRHYTHMIA (CAID) (OMIM 616201), IS CAUSED BY A HOMOZYGOUS SGO1 MUTATION (K23E), LEADING TO CHRONIC INTESTINAL PSEUDO-OBSTRUCTION AND ARRHYTHMIAS. BECAUSE CAID PATIENTS DO NOT SHOW PHENOTYPES CONSISTENT WITH PERTURBATION OF KNOWN ROLES OF SGO1, WE HYPOTHESIZED THAT NONCANONICAL ROLES OF SGO1 DRIVE THE CLINICAL MANIFESTATIONS OBSERVED. METHODS: TO IDENTIFY A MOLECULAR SIGNATURE FOR CAID SYNDROME, WE ACHIEVED UNBIASED SCREENS IN CELL LINES AND GUT TISSUES FROM CAID PATIENTS VS WILD-TYPE CONTROLS. WE PERFORMED RNA SEQUENCING ALONG WITH STABLE ISOTOPE LABELING WITH AMINO ACIDS IN CELL CULTURE. IN ADDITION, WE DETERMINED THE GENOME-WIDE DNA METHYLATION AND CHROMATIN ACCESSIBILITY SIGNATURES USING REDUCED REPRESENTATIVE BISULFITE SEQUENCING AND ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN WITH HIGH-THROUGHPUT SEQUENCING. FUNCTIONAL STUDIES INCLUDED PATCH-CLAMP, QUANTITATION OF TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) SIGNALING, AND IMMUNOHISTOCHEMISTRY IN CAID PATIENT GUT BIOPSY SPECIMENS. RESULTS: PROTEOME AND TRANSCRIPTOME STUDIES CONVERGE ON CELL-CYCLE REGULATION, CARDIAC CONDUCTION, AND SMOOTH MUSCLE REGULATION AS DRIVERS OF CAID SYNDROME. SPECIFICALLY, THE INWARD RECTIFIER CURRENT, AN IMPORTANT REGULATOR OF CELLULAR FUNCTION, WAS DISRUPTED. IMMUNOHISTOCHEMISTRY CONFIRMED OVEREXPRESSION OF BUDDING UNINHIBITED BY BENZIMIDAZOLES 1 (BUB1) IN PATIENTS, IMPLICATING THE TGF-BETA PATHWAY IN CAID PATHOGENESIS. CANONICAL TGF-BETA SIGNALING WAS UP-REGULATED AND UNCOUPLED FROM NONCANONICAL SIGNALING IN CAID PATIENTS. REDUCED REPRESENTATIVE BISULFITE SEQUENCING AND ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN WITH HIGH-THROUGHPUT SEQUENCING EXPERIMENTS SHOWED SIGNIFICANT CHANGES OF CHROMATIN STATES IN CAID, POINTING TO EPIGENETIC REGULATION AS A POSSIBLE PATHOLOGIC MECHANISM. CONCLUSIONS: OUR FINDINGS POINT TO IMPAIRED INWARD RECTIFIER POTASSIUM CURRENT, DYSREGULATION OF CANONICAL TGF-BETA SIGNALING, AND EPIGENETIC REGULATION AS POTENTIAL DRIVERS OF INTESTINAL AND CARDIAC MANIFESTATIONS OF CAID SYNDROME. TRANSCRIPT PROFILING AND GENOMICS DATA ARE AS FOLLOWS: REPOSITORY URL: HTTPS://WWW.NCBI.NLM.NIH.GOV/GEO; SUPERSERIES GSE110612 WAS COMPOSED OF THE FOLLOWING SUBSERIES: GSE110309, GSE110576, AND GSE110601. 2019 3 1092 45 COHESIN MUTATIONS IN MYELOID MALIGNANCIES. COHESIN IS A MULTISUBUNIT PROTEIN COMPLEX THAT FORMS A RING-LIKE STRUCTURE AROUND DNA. IT IS ESSENTIAL FOR SISTER CHROMATID COHESION, CHROMATIN ORGANIZATION, TRANSCRIPTIONAL REGULATION, AND DNA DAMAGE REPAIR AND PLAYS A MAJOR ROLE IN DYNAMICALLY SHAPING THE GENOME ARCHITECTURE AND MAINTAINING DNA INTEGRITY. THE CORE COMPLEX SUBUNITS STAG2, RAD21, SMC1, AND SMC3, AS WELL AS ITS MODULATORS PDS5A/B, WAPL, AND NIPBL, HAVE BEEN FOUND TO BE RECURRENTLY MUTATED IN HEMATOLOGIC AND SOLID MALIGNANCIES. THESE MUTATIONS ARE FOUND ACROSS THE FULL SPECTRUM OF MYELOID NEOPLASIA, INCLUDING PEDIATRIC DOWN SYNDROME-ASSOCIATED ACUTE MEGAKARYOBLASTIC LEUKEMIA, MYELODYSPLASTIC SYNDROMES, CHRONIC MYELOMONOCYTIC LEUKEMIA, AND DE NOVO AND SECONDARY ACUTE MYELOID LEUKEMIAS. THE MECHANISMS BY WHICH COHESIN MUTATIONS ACT AS DRIVERS OF CLONAL EXPANSION AND DISEASE PROGRESSION ARE STILL POORLY UNDERSTOOD. RECENT STUDIES HAVE DESCRIBED THE IMPACT OF COHESIN ALTERATIONS ON SELF-RENEWAL AND DIFFERENTIATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS, WHICH ARE ASSOCIATED WITH CHANGES IN CHROMATIN AND EPIGENETIC STATE DIRECTING LINEAGE COMMITMENT, AS WELL AS GENOMIC INTEGRITY. HEREIN, WE REVIEW THE ROLE OF THE COHESIN COMPLEX IN HEALTHY AND MALIGNANT HEMATOPOIESIS. WE DISCUSS CLINICAL IMPLICATIONS OF COHESIN MUTATIONS IN MYELOID MALIGNANCIES AND DISCUSS OPPORTUNITIES FOR THERAPEUTIC TARGETING. 2021 4 5822 24 STRESS IN THE ONSET AND AGGRAVATION OF LEARNING DISABILITIES. DESPITE SUBSTANTIAL GROUNDS FOR SUCH RESEARCH, THE ROLE OF CHRONIC EXPOSURE TO STRESSORS IN THE ONSET AND AGGRAVATION OF LEARNING DISABILITIES (LDS) IS LARGELY UNEXPLORED. IN THIS REVIEW, WE FIRST CONSIDER THE HORMONAL, (EPI)GENETIC, AND NEUROBIOLOGICAL MECHANISMS THAT MIGHT UNDERLIE THE IMPACT OF ADVERSE CHILDHOOD EXPERIENCES, A FORM OF CHRONIC STRESSORS, ON THE ONSET OF LDS. WE THEN FOUND THAT STRESS FACTORS COMBINED WITH FEELINGS OF INFERIORITY, LOW SELF-ESTEEM, AND PEER VICTIMIZATION COULD POTENTIALLY FURTHER AGGRAVATE ACADEMIC FAILURES IN CHILDREN WITH LDS. SINCE EFFECTIVE EVIDENCE-BASED INTERVENTIONS FOR REDUCING CHRONIC STRESS IN CHILDREN WITH LDS COULD IMPROVE THEIR ACADEMIC PERFORMANCE, CONSIDERATION OF THE ROLE OF EXPOSURE TO STRESSORS IN CHILDREN WITH LDS HAS BOTH THEORETICAL AND PRACTICAL IMPORTANCE, ESPECIALLY WHEN DELIVERED IN COMBINATION WITH ACADEMIC INTERVENTIONS. 2021 5 6569 40 TRANSPLANTATION OF EPIGENETICALLY MODIFIED ADULT CARDIAC C-KIT+ CELLS RETARDS REMODELING AND IMPROVES CARDIAC FUNCTION IN ISCHEMIC HEART FAILURE MODEL. CARDIAC C-KIT+ CELLS HAVE A MODEST CARDIOGENIC POTENTIAL THAT COULD LIMIT THEIR EFFICACY IN HEART DISEASE TREATMENT. THE PRESENT STUDY WAS DESIGNED TO AUGMENT THE CARDIOGENIC POTENTIAL OF CARDIAC C-KIT+ CELLS THROUGH CLASS I HISTONE DEACETYLASE (HDAC) INHIBITION AND EVALUATE THEIR THERAPEUTIC POTENCY IN THE CHRONIC HEART FAILURE (CHF) ANIMAL MODEL. MYOCARDIAL INFARCTION (MI) WAS CREATED BY CORONARY ARTERY OCCLUSION IN RATS. C-KIT+ CELLS WERE TREATED WITH MOCETINOSTAT (MOCE), A SPECIFIC CLASS I HDAC INHIBITOR. AT 3 WEEKS AFTER MI, CHF ANIMALS WERE RETROGRADELY INFUSED WITH UNTREATED (CONTROL) OR MOCE-TREATED C-KIT+ CELLS (MOCE/C-KIT+ CELLS) AND EVALUATED AT 3 WEEKS AFTER CELL INFUSION. WE FOUND THAT CLASS I HDAC INHIBITION IN C-KIT+ CELLS ELEVATED THE LEVEL OF ACETYLATED HISTONE H3 (ACH3) AND INCREASED ACH3 LEVELS IN THE PROMOTER REGIONS OF PLURIPOTENT AND CARDIAC-SPECIFIC GENES. EPIGENETIC CHANGES WERE ACCOMPANIED BY INCREASED EXPRESSION OF CARDIAC-SPECIFIC MARKERS. TRANSPLANTATION OF CHF RATS WITH EITHER CONTROL OR MOCE/C-KIT+ CELLS RESULTED IN AN IMPROVEMENT IN CARDIAC FUNCTION, RETARDATION OF CHF REMODELING MADE EVIDENT BY INCREASED VASCULARIZATION AND SCAR SIZE, AND CARDIOMYOCYTE HYPERTROPHY REDUCTION. COMPARED WITH CHF INFUSED WITH CONTROL CELLS, INFUSION OF MOCE/C-KIT+ CELLS RESULTED IN A FURTHER REDUCTION IN LEFT VENTRICLE END-DIASTOLIC PRESSURE AND TOTAL COLLAGEN AND AN INCREASE IN INTERLEUKIN-6 EXPRESSION. THE LOW ENGRAFTMENT OF INFUSED CELLS SUGGESTS THAT PARACRINE EFFECTS MIGHT ACCOUNT FOR THE BENEFICIAL EFFECTS OF C-KIT+ CELLS IN CHF. IN CONCLUSION, SELECTIVE INHIBITION OF CLASS I HDACS INDUCED EXPRESSION OF CARDIAC MARKERS IN C-KIT+ CELLS AND PARTIALLY AUGMENTED THE EFFICACY OF THESE CELLS FOR CHF REPAIR. SIGNIFICANCE: THE STUDY HAS SHOWN THAT SELECTIVE CLASS 1 HISTONE DEACETYLASE INHIBITION IS SUFFICIENT TO REDIRECT C-KIT+ CELLS TOWARD A CARDIAC FATE. EPIGENETICALLY MODIFIED C-KIT+ CELLS IMPROVED CONTRACTILE FUNCTION AND RETARDED REMODELING OF THE CONGESTIVE HEART FAILURE HEART. THIS STUDY PROVIDES NEW INSIGHTS INTO THE EFFICACY OF CARDIAC C-KIT+ CELLS IN THE ISCHEMIC HEART FAILURE MODEL. 2015 6 2713 33 EXERCISE TRAINING AND EPIGENETIC REGULATION: MULTILEVEL MODIFICATION AND REGULATION OF GENE EXPRESSION. EXERCISE TRAINING ELICITS ACUTE AND ADAPTIVE LONG TERM CHANGES IN HUMAN PHYSIOLOGY THAT MEDIATE THE IMPROVEMENT OF PERFORMANCE AND HEALTH STATE. THE RESPONSES ARE INTEGRATIVE AND ORCHESTRATED BY SEVERAL MECHANISMS, AS GENE EXPRESSION. GENE EXPRESSION IS ESSENTIAL TO CONSTRUCT THE ADAPTATION OF THE BIOLOGICAL SYSTEM TO EXERCISE TRAINING, SINCE THERE ARE MOLECULAR PROCESSES MEDIATING OXIDATIVE AND NON-OXIDATIVE METABOLISM, ANGIOGENESIS, CARDIAC AND SKELETAL MYOFIBER HYPERTROPHY, AND OTHER PROCESSES THAT LEADS TO A GREATER PHYSIOLOGICAL STATUS. EPIGENETIC IS THE FIELD THAT STUDIES ABOUT GENE EXPRESSION CHANGES HERITABLE BY MEIOSIS AND MITOSIS, BY CHANGES IN CHROMATIN AND DNA CONFORMATION, BUT NOT IN DNA SEQUENCE, THAT STUDIES THE REGULATION ON GENE EXPRESSION THAT IS INDEPENDENT OF GENOTYPE. THE FIELD APPROACHES MECHANISMS OF DNA AND CHROMATIN CONFORMATIONAL CHANGES THAT INHIBIT OR INCREASE GENE EXPRESSION AND DETERMINE TISSUE SPECIFIC PATTERN. THE THREE MAJOR STUDIED EPIGENETIC MECHANISMS ARE DNA METHYLATION, HISTONE MODIFICATION, AND REGULATION OF NONCODING RNA-ASSOCIATED GENES. THIS REVIEW ELUCIDATES THESE MECHANISMS, FOCUSING ON THE RELATIONSHIP BETWEEN THEM AND THEIR RELATIONSHIP WITH EXERCISE TRAINING, PHYSICAL PERFORMANCE AND THE ENHANCEMENT OF HEALTH STATUS. ON THIS CHAPTER, WE CLARIFIED THE RELATIONSHIP OF EPIGENETIC MODULATIONS AND THEIR INTIMAL RELATIONSHIP WITH ACUTE AND CHRONIC EFFECT OF EXERCISE TRAINING, CONCENTRATING OUR EFFORT ON SKELETAL MUSCLE, HEART AND VASCULAR RESPONSES, THAT ARE THE MOST RESPONSIVE SYSTEMS AGAINST TO EXERCISE TRAINING AND PLAY CRUCIAL ROLE ON PHYSICAL PERFORMANCE AND IMPROVEMENT OF HEALTH STATE. 2017 7 5550 44 ROLE OF EPIGENETICS IN INFLAMMATION-ASSOCIATED DISEASES. THERE IS CONSIDERABLE EVIDENCE SUGGESTING THAT EPIGENETIC MECHANISMS MAY MEDIATE DEVELOPMENT OF CHRONIC INFLAMMATION BY MODULATING THE EXPRESSION OF PRO-INFLAMMATORY CYTOKINE TNF-ALPHA, INTERLEUKINS, TUMOR SUPPRESSOR GENES, ONCOGENES AND AUTOCRINE AND PARACRINE ACTIVATION OF THE TRANSCRIPTION FACTOR NF-KAPPAB. THESE MOLECULES ARE CONSTITUTIVELY PRODUCED BY A VARIETY OF CELLS UNDER CHRONIC INFLAMMATORY CONDITIONS, WHICH IN TURN LEADS TO THE DEVELOPMENT OF MAJOR DISEASES SUCH AS AUTOIMMUNE DISORDERS, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEURODEGENERATIVE DISEASES AND CANCER. DISTINCT OR GLOBAL CHANGES IN THE EPIGENETIC LANDSCAPE ARE HALLMARKS OF CHRONIC INFLAMMATION DRIVEN DISEASES. EPIGENETICS INCLUDE CHANGES TO DISTINCT MARKERS ON THE GENOME AND ASSOCIATED CELLULAR TRANSCRIPTIONAL MACHINERY THAT ARE COPIED DURING CELL DIVISION (MITOSIS AND MEIOSIS). THESE CHANGES APPEAR FOR A SHORT SPAN OF TIME AND THEY NECESSARILY DO NOT MAKE PERMANENT CHANGES TO THE PRIMARY DNA SEQUENCE ITSELF. HOWEVER, THE MOST FREQUENTLY OBSERVED EPIGENETIC CHANGES INCLUDE ABERRANT DNA METHYLATION, AND HISTONE ACETYLATION AND DEACETYLATION. IN THIS CHAPTER, WE FOCUS ON PRO-INFLAMMATORY MOLECULES THAT ARE REGULATED BY ENZYMES INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS ARGININE AND LYSINE METHYL TRANSFERASES, DNA METHYLTRANSFERASE, HISTONE ACETYLTRANSFERASES AND HISTONE DEACETYLASES AND THEIR ROLE IN INFLAMMATION DRIVEN DISEASES. AGENTS THAT MODULATE OR INHIBIT THESE EPIGENETIC MODIFICATIONS, SUCH AS HAT OR HDAC INHIBITORS HAVE SHOWN GREAT POTENTIAL IN INHIBITING THE PROGRESSION OF THESE DISEASES. GIVEN THE PLASTICITY OF THESE EPIGENETIC CHANGES AND THEIR READINESS TO RESPOND TO INTERVENTION BY SMALL MOLECULE INHIBITORS, THERE IS A TREMENDOUS POTENTIAL FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS THAT WILL SERVE AS DIRECT OR ADJUVANT THERAPEUTIC COMPOUNDS IN THE TREATMENT OF THESE DISEASES. 2013 8 2184 33 EPIGENETIC MECHANISMS THAT UNDERPIN METABOLIC AND CARDIOVASCULAR DISEASES. CELLULAR COMMITMENT TO A SPECIFIC LINEAGE IS CONTROLLED BY DIFFERENTIAL SILENCING OF GENES, WHICH IN TURN DEPENDS ON EPIGENETIC PROCESSES SUCH AS DNA METHYLATION AND HISTONE MODIFICATION. DURING EARLY EMBRYOGENESIS, THE MAMMALIAN GENOME IS 'WIPED CLEAN' OF MOST EPIGENETIC MODIFICATIONS, WHICH ARE PROGRESSIVELY RE-ESTABLISHED DURING EMBRYONIC DEVELOPMENT. THUS, THE EPIGENOME OF EACH MATURE CELLULAR LINEAGE CARRIES THE RECORD OF ITS DEVELOPMENTAL HISTORY. THE SUBSEQUENT TRAJECTORY AND PATTERN OF DEVELOPMENT ARE ALSO RESPONSIVE TO ENVIRONMENTAL INFLUENCES, AND SUCH PLASTICITY IS LIKELY TO HAVE AN EPIGENETIC BASIS. EPIGENETIC MARKS MAY BE TRANSMITTED ACROSS GENERATIONS, EITHER DIRECTLY BY PERSISTING THROUGH MEIOSIS OR INDIRECTLY THROUGH REPLICATION IN THE NEXT GENERATION OF THE CONDITIONS IN WHICH THE EPIGENETIC CHANGE OCCURRED. DEVELOPMENTAL PLASTICITY EVOLVED TO MATCH AN ORGANISM TO ITS ENVIRONMENT, AND A MISMATCH BETWEEN THE PHENOTYPIC OUTCOME OF ADAPTIVE PLASTICITY AND THE CURRENT ENVIRONMENT INCREASES THE RISK OF METABOLIC AND CARDIOVASCULAR DISEASE. THESE CONSIDERATIONS POINT TO EPIGENETIC PROCESSES AS A KEY MECHANISM THAT UNDERPINS THE DEVELOPMENTAL ORIGINS OF CHRONIC NONCOMMUNICABLE DISEASE. HERE, WE REVIEW THE EVIDENCE THAT ENVIRONMENTAL INFLUENCES DURING MAMMALIAN DEVELOPMENT LEAD TO STABLE CHANGES IN THE EPIGENOME THAT ALTER THE INDIVIDUAL'S SUSCEPTIBILITY TO CHRONIC METABOLIC AND CARDIOVASCULAR DISEASE, AND DISCUSS THE CLINICAL IMPLICATIONS. 2009 9 3064 39 GENOME-WIDE DNA METHYLATION ENCODES CARDIAC TRANSCRIPTIONAL REPROGRAMMING IN HUMAN ISCHEMIC HEART FAILURE. ISCHEMIC CARDIOMYOPATHY (ICM) IS THE CLINICAL ENDPOINT OF CORONARY HEART DISEASE AND A LEADING CAUSE OF HEART FAILURE. DESPITE GROWING DEMANDS TO DEVELOP PERSONALIZED APPROACHES TO TREAT ICM, PROGRESS IS LIMITED BY INADEQUATE KNOWLEDGE OF ITS PATHOGENESIS. SINCE EPIGENETICS HAS BEEN IMPLICATED IN THE DEVELOPMENT OF OTHER CHRONIC DISEASES, THE CURRENT STUDY WAS DESIGNED TO DETERMINE WHETHER TRANSCRIPTIONAL AND/OR EPIGENETIC CHANGES ARE SUFFICIENT TO DISTINGUISH ICM FROM OTHER ETIOLOGIES OF HEART FAILURE. SPECIFICALLY, WE HYPOTHESIZE THAT GENOME-WIDE DNA METHYLATION ENCODES TRANSCRIPTIONAL REPROGRAMMING IN ICM. RNA-SEQUENCING ANALYSIS WAS PERFORMED ON HUMAN ISCHEMIC LEFT VENTRICULAR TISSUE OBTAINED FROM PATIENTS WITH END-STAGE HEART FAILURE, WHICH ENRICHED KNOWN TARGETS OF THE POLYCOMB METHYLTRANSFERASE EZH2 COMPARED TO NON-ISCHEMIC HEARTS. COMBINED RNA SEQUENCING AND GENOME-WIDE DNA METHYLATION ANALYSIS REVEALED A ROBUST GENE EXPRESSION PATTERN CONSISTENT WITH SUPPRESSION OF OXIDATIVE METABOLISM, INDUCED ANAEROBIC GLYCOLYSIS, AND ALTERED CELLULAR REMODELING. LASTLY, KLF15 WAS IDENTIFIED AS A PUTATIVE UPSTREAM REGULATOR OF METABOLIC GENE EXPRESSION THAT WAS ITSELF REGULATED BY EZH2 IN A SET DOMAIN-DEPENDENT MANNER. OUR OBSERVATIONS THEREFORE DEFINE A NOVEL ROLE OF DNA METHYLATION IN THE METABOLIC REPROGRAMMING OF ICM. FURTHERMORE, WE IDENTIFY EZH2 AS AN EPIGENETIC REGULATOR OF KLF15 ALONG WITH DNA HYPERMETHYLATION, AND WE PROPOSE A NOVEL MECHANISM THROUGH WHICH CORONARY HEART DISEASE REPROGRAMS THE EXPRESSION OF BOTH INTERMEDIATE ENZYMES AND UPSTREAM REGULATORS OF CARDIAC METABOLISM SUCH AS KLF15. 2019 10 1141 32 CONCERTED CELL AND IN VIVO SCREEN FOR PANCREATIC DUCTAL ADENOCARCINOMA (PDA) CHEMOTHERAPEUTICS. PDA IS A MAJOR CAUSE OF US CANCER-RELATED DEATHS. ONCOGENIC KRAS PRESENTS IN 90% OF HUMAN PDAS. KRAS MUTATIONS OCCUR EARLY IN PRE-NEOPLASTIC LESIONS BUT ARE INSUFFICIENT TO CAUSE PDA. OTHER CONTRIBUTING FACTORS EARLY IN DISEASE PROGRESSION INCLUDE CHRONIC PANCREATITIS, ALTERATIONS IN EPIGENETIC REGULATORS, AND TUMOR SUPPRESSOR GENE MUTATION. GPCRS ACTIVATE HETEROTRIMERIC G-PROTEINS THAT STIMULATE INTRACELLULAR CALCIUM AND ONCOGENIC KRAS SIGNALING, THEREBY PROMOTING PANCREATITIS AND PROGRESSION TO PDA. BY CONTRAST, RGS PROTEINS INHIBIT GI/Q-COUPLED GPCRS TO NEGATIVELY REGULATE PDA PROGRESSION. RGS16::GFP IS EXPRESSED IN RESPONSE TO CAERULEIN-INDUCED ACINAR CELL DEDIFFERENTIATION, EARLY NEOPLASIA, AND THROUGHOUT PDA PROGRESSION. IN GENETICALLY ENGINEERED MOUSE MODELS OF PDA, RGS16::GFP IS USEFUL FOR PRE-CLINICAL RAPID IN VIVO VALIDATION OF NOVEL CHEMOTHERAPEUTICS TARGETING EARLY LESIONS IN PATIENTS FOLLOWING SUCCESSFUL RESECTION OR AT HIGH RISK FOR PROGRESSING TO PDA. CULTURED PRIMARY PDA CELLS EXPRESS RGS16::GFP IN RESPONSE TO CYTOTOXIC DRUGS. A HISTONE DEACETYLASE INHIBITOR, TSA, STIMULATED RGS16::GFP EXPRESSION IN PDA PRIMARY CELLS, POTENTIATED GEMCITABINE AND JQ1 CYTOTOXICITY IN CELL CULTURE, AND GEM + TSA + JQ1 INHIBITED TUMOR INITIATION AND PROGRESSION IN VIVO. HERE WE ESTABLISH THE USE OF RGS16::GFP EXPRESSION FOR TESTING DRUG COMBINATIONS IN CELL CULTURE AND VALIDATION OF BEST CANDIDATES IN OUR RAPID IN VIVO SCREEN. 2020 11 4717 34 NON-GENOMIC TRANSGENERATIONAL INHERITANCE OF DISEASE RISK. THAT THERE IS A HERITABLE OR FAMILIAL COMPONENT OF SUSCEPTIBILITY TO CHRONIC NON-COMMUNICABLE DISEASES SUCH AS TYPE 2 DIABETES, OBESITY AND CARDIOVASCULAR DISEASE IS WELL ESTABLISHED, BUT THERE IS INCREASING EVIDENCE THAT SOME ELEMENTS OF SUCH HERITABILITY ARE TRANSMITTED NON-GENOMICALLY AND THAT THE PROCESSES WHEREBY ENVIRONMENTAL INFLUENCES ACT DURING EARLY DEVELOPMENT TO SHAPE DISEASE RISK IN LATER LIFE CAN HAVE EFFECTS BEYOND A SINGLE GENERATION. SUCH HERITABILITY MAY OPERATE THROUGH EPIGENETIC MECHANISMS INVOLVING REGULATION OF EITHER IMPRINTED OR NON-IMPRINTED GENES BUT ALSO THROUGH BROADER MECHANISMS RELATED TO PARENTAL PHYSIOLOGY OR BEHAVIOUR. WE REVIEW EVIDENCE AND POTENTIAL MECHANISMS FOR NON-GENOMIC TRANSGENERATIONAL INHERITANCE OF 'LIFESTYLE' DISEASE AND PROPOSE THAT THE 'DEVELOPMENTAL ORIGINS OF DISEASE' PHENOMENON IS A MALADAPTIVE CONSEQUENCE OF AN ANCESTRAL MECHANISM OF DEVELOPMENTAL PLASTICITY THAT MAY HAVE HAD ADAPTIVE VALUE IN THE EVOLUTION OF GENERALIST SPECIES SUCH AS HOMO SAPIENS. 2007 12 1709 29 DYSFUNCTIONAL ERG SIGNALING DRIVES PULMONARY VASCULAR AGING AND PERSISTENT FIBROSIS. VASCULAR DYSFUNCTION IS A HALLMARK OF CHRONIC DISEASES IN ELDERLY. THE CONTRIBUTION OF THE VASCULATURE TO LUNG REPAIR AND FIBROSIS IS NOT FULLY UNDERSTOOD. HERE, WE PERFORMED AN EPIGENETIC AND TRANSCRIPTIONAL ANALYSIS OF LUNG ENDOTHELIAL CELLS (ECS) FROM YOUNG AND AGED MICE DURING THE RESOLUTION OR PROGRESSION OF BLEOMYCIN-INDUCED LUNG FIBROSIS. WE IDENTIFIED THE TRANSCRIPTION FACTOR ETS-RELATED GENE (ERG) AS PUTATIVE ORCHESTRATOR OF LUNG CAPILLARY HOMEOSTASIS AND REPAIR, AND WHOSE FUNCTION IS DYSREGULATED IN AGING. ERG DYSREGULATION IS ASSOCIATED WITH REDUCED CHROMATIN ACCESSIBILITY AND MALADAPTIVE TRANSCRIPTIONAL RESPONSES TO INJURY. LOSS OF ENDOTHELIAL ERG ENHANCES PARACRINE FIBROBLAST ACTIVATION IN VITRO, AND IMPAIRS LUNG FIBROSIS RESOLUTION IN YOUNG MICE IN VIVO. SCRNA-SEQ OF ERG DEFICIENT MOUSE LUNGS REVEALES TRANSCRIPTIONAL AND FIBROGENIC ABNORMALITIES RESEMBLING THOSE ASSOCIATED WITH AGING AND HUMAN LUNG FIBROSIS, INCLUDING REDUCED NUMBER OF GENERAL CAPILLARY (GCAP) ECS. OUR FINDINGS DEMONSTRATE THAT LUNG ENDOTHELIAL CHROMATIN REMODELING DETERIORATES WITH AGING LEADING TO ABNORMAL TRANSCRIPTION, VASCULAR DYSREPAIR, AND PERSISTENT FIBROSIS FOLLOWING INJURY. 2022 13 4774 37 NUCLEIC ACID APTAMERS TARGETING EPIGENETIC REGULATORS: AN INNOVATIVE THERAPEUTIC OPTION. EPIGENETIC MECHANISMS INCLUDE DNA METHYLATION, POSTTRANSLATIONAL MODIFICATIONS OF HISTONES, CHROMATIN REMODELING FACTORS, AND POST TRANSCRIPTIONAL GENE REGULATION BY NONCODING RNAS. ALL TOGETHER, THESE PROCESSES REGULATE GENE EXPRESSION BY CHANGING CHROMATIN ORGANIZATION AND DNA ACCESSIBILITY. TARGETING ENZYMATIC REGULATORS RESPONSIBLE FOR DNA AND CHROMATIN MODIFICATIONS HOLD PROMISE FOR MODULATING THE TRANSCRIPTIONAL REGULATION OF GENES THAT ARE INVOLVED IN CANCER, AS WELL AS IN CHRONIC NONCOMMUNICABLE METABOLIC DISEASES LIKE OBESITY, DIABETES, AND CARDIOVASCULAR DISEASES. INCREASINGLY STUDIES ARE EMERGING, LEADING TO THE IDENTIFICATION OF SPECIFIC AND EFFECTIVE MOLECULES TARGETING EPIGENETIC PATHWAYS INVOLVED IN DISEASE ONSET. IN THIS REGARD, RNA INTERFERENCE, WHICH USES SMALL RNAS TO REDUCE GENE EXPRESSION AND NUCLEIC ACID APTAMERS ARE ARISING AS VERY PROMISING CANDIDATES IN THERAPEUTIC APPROACH. COMMON TO ALL THESE STRATEGIES IS THE IMPERATIVE CHALLENGE OF SPECIFICITY. IN THIS REGARD, NUCLEIC ACID APTAMERS HAVE EMERGED AS AN ATTRACTIVE CLASS OF CARRIER MOLECULES DUE TO THEIR ABILITY TO BIND WITH HIGH AFFINITY TO SPECIFIC LIGANDS, THEIR HIGH CHEMICAL FLEXIBILITY AS WELL AS TISSUE PENETRATION CAPABILITY. IN THIS REVIEW, WE WILL FOCUS ON THE RECENT PROGRESS IN THE FIELD OF APTAMERS USED AS TARGETING MOIETIES ABLE TO RECOGNIZE AND REVERT EPIGENETICS MARKS INVOLVED IN DISEASES ONSET. 2018 14 1748 35 EARLY LIFE EVENTS AND THEIR CONSEQUENCES FOR LATER DISEASE: A LIFE HISTORY AND EVOLUTIONARY PERSPECTIVE. BIOMEDICAL SCIENCE HAS LITTLE CONSIDERED THE RELEVANCE OF LIFE HISTORY THEORY AND EVOLUTIONARY AND ECOLOGICAL DEVELOPMENTAL BIOLOGY TO CLINICAL MEDICINE. HOWEVER, THE OBSERVATIONS THAT EARLY LIFE INFLUENCES CAN ALTER LATER DISEASE RISK--THE "DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" (DOHAD) PARADIGM--HAVE LED TO A RECOGNITION THAT THESE PERSPECTIVES CAN INFORM OUR UNDERSTANDING OF HUMAN BIOLOGY. WE PROPOSE THAT THE DOHAD PHENOMENON CAN BE CONSIDERED AS A SUBSET OF THE BROADER PROCESSES OF DEVELOPMENTAL PLASTICITY BY WHICH ORGANISMS ADAPT TO THEIR ENVIRONMENT DURING THEIR LIFE COURSE. SUCH ADAPTIVE PROCESSES ALLOW GENOTYPIC VARIATION TO BE PRESERVED THROUGH TRANSIENT ENVIRONMENTAL CHANGES. CUES FOR PLASTICITY OPERATE PARTICULARLY DURING EARLY DEVELOPMENT; THEY MAY AFFECT A SINGLE ORGAN OR SYSTEM, BUT GENERALLY THEY INDUCE INTEGRATED ADJUSTMENTS IN THE MATURE PHENOTYPE, A PROCESS UNDERPINNED BY EPIGENETIC MECHANISMS AND INFLUENCED BY PREDICTION OF THE MATURE ENVIRONMENT. IN MAMMALS, AN ADVERSE INTRAUTERINE ENVIRONMENT RESULTS IN AN INTEGRATED SUITE OF RESPONSES, SUGGESTING THE INVOLVEMENT OF A FEW KEY REGULATORY GENES, THAT RESETS THE DEVELOPMENTAL TRAJECTORY IN EXPECTATION OF POOR POSTNATAL CONDITIONS. MISMATCH BETWEEN THE ANTICIPATED AND THE ACTUAL MATURE ENVIRONMENT EXPOSES THE ORGANISM TO RISK OF ADVERSE CONSEQUENCES-THE GREATER THE MISMATCH, THE GREATER THE RISK. FOR HUMANS, PREDICTION IS INACCURATE FOR MANY INDIVIDUALS BECAUSE OF CHANGES IN THE POSTNATAL ENVIRONMENT TOWARD ENERGY-DENSE NUTRITION AND LOW ENERGY EXPENDITURE, CONTRIBUTING TO THE EPIDEMIC OF CHRONIC NONCOMMUNICABLE DISEASE. THIS VIEW OF HUMAN DISEASE FROM THE PERSPECTIVES OF LIFE HISTORY BIOLOGY AND EVOLUTIONARY THEORY OFFERS NEW APPROACHES TO PREVENTION, DIAGNOSIS AND INTERVENTION. 2007 15 1093 21 COHESIN RAD21 GENE PROMOTER METHYLATION IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS THE MOST COMMON TYPE OF LEUKEMIA IN ADULTS AND IS CHARACTERIZED BY THE PRESENCE OF SPECIFIC CYTOGENETIC ABNORMALITIES. CLL RESEARCH HAS BEEN FOCUSED ON EPIGENETIC PROCESSES LIKE GENE PROMOTER METHYLATION OF CPG ISLANDS. IN THE PRESENT STUDY, THE METHYLATION STATUS OF THE RAD21 GENE IS STUDIED AND ASSOCIATED WITH CYTOGENETIC FINDINGS IN CLL PATIENTS IN ORDER TO INVESTIGATE ITS POSSIBLE IMPLICATION IN CLL PATHOGENESIS AND THE FORMATION OF CLL CHROMOSOMAL ABNORMALITIES. 2018 16 1396 40 DIET INDUCED EPIGENETIC CHANGES AND THEIR IMPLICATIONS FOR HEALTH. DIETARY EXPOSURES CAN HAVE CONSEQUENCES FOR HEALTH YEARS OR DECADES LATER AND THIS RAISES QUESTIONS ABOUT THE MECHANISMS THROUGH WHICH SUCH EXPOSURES ARE 'REMEMBERED' AND HOW THEY RESULT IN ALTERED DISEASE RISK. THERE IS GROWING EVIDENCE THAT EPIGENETIC MECHANISMS MAY MEDIATE THE EFFECTS OF NUTRITION AND MAY BE CAUSAL FOR THE DEVELOPMENT OF COMMON COMPLEX (OR CHRONIC) DISEASES. EPIGENETICS ENCOMPASSES CHANGES TO MARKS ON THE GENOME (AND ASSOCIATED CELLULAR MACHINERY) THAT ARE COPIED FROM ONE CELL GENERATION TO THE NEXT, WHICH MAY ALTER GENE EXPRESSION, BUT WHICH DO NOT INVOLVE CHANGES IN THE PRIMARY DNA SEQUENCE. THESE INCLUDE THREE DISTINCT, BUT CLOSELY INTER-ACTING, MECHANISMS INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING MICRORNAS (MIRNA) WHICH, TOGETHER, ARE RESPONSIBLE FOR REGULATING GENE EXPRESSION NOT ONLY DURING CELLULAR DIFFERENTIATION IN EMBRYONIC AND FOETAL DEVELOPMENT BUT ALSO THROUGHOUT THE LIFE-COURSE. THIS REVIEW SUMMARIZES THE GROWING EVIDENCE THAT NUMEROUS DIETARY FACTORS, INCLUDING MICRONUTRIENTS AND NON-NUTRIENT DIETARY COMPONENTS SUCH AS GENISTEIN AND POLYPHENOLS, CAN MODIFY EPIGENETIC MARKS. IN SOME CASES, FOR EXAMPLE, EFFECTS OF ALTERED DIETARY SUPPLY OF METHYL DONORS ON DNA METHYLATION, THERE ARE PLAUSIBLE EXPLANATIONS FOR THE OBSERVED EPIGENETIC CHANGES, BUT TO A LARGE EXTENT, THE MECHANISMS RESPONSIBLE FOR DIET-EPIGENOME-HEALTH RELATIONSHIPS REMAIN TO BE DISCOVERED. IN ADDITION, RELATIVELY LITTLE IS KNOWN ABOUT WHICH EPIGENOMIC MARKS ARE MOST LABILE IN RESPONSE TO DIETARY EXPOSURES. GIVEN THE PLASTICITY OF EPIGENETIC MARKS AND THEIR RESPONSIVENESS TO DIETARY FACTORS, THERE IS POTENTIAL FOR THE DEVELOPMENT OF EPIGENETIC MARKS AS BIOMARKERS OF HEALTH FOR USE IN INTERVENTION STUDIES. 2011 17 375 23 AN ENERGETIC VIEW OF STRESS: FOCUS ON MITOCHONDRIA. ENERGY IS REQUIRED TO SUSTAIN LIFE AND ENABLE STRESS ADAPTATION. AT THE CELLULAR LEVEL, ENERGY IS LARGELY DERIVED FROM MITOCHONDRIA - UNIQUE MULTIFUNCTIONAL ORGANELLES WITH THEIR OWN GENOME. FOUR MAIN ELEMENTS CONNECT MITOCHONDRIA TO STRESS: (1) ENERGY IS REQUIRED AT THE MOLECULAR, (EPI)GENETIC, CELLULAR, ORGANELLAR, AND SYSTEMIC LEVELS TO SUSTAIN COMPONENTS OF STRESS RESPONSES; (2) GLUCOCORTICOIDS AND OTHER STEROID HORMONES ARE PRODUCED AND METABOLIZED BY MITOCHONDRIA; (3) RECIPROCALLY, MITOCHONDRIA RESPOND TO NEUROENDOCRINE AND METABOLIC STRESS MEDIATORS; AND (4) EXPERIMENTALLY MANIPULATING MITOCHONDRIAL FUNCTIONS ALTERS PHYSIOLOGICAL AND BEHAVIORAL RESPONSES TO PSYCHOLOGICAL STRESS. THUS, MITOCHONDRIA ARE ENDOCRINE ORGANELLES THAT PROVIDE BOTH THE ENERGY AND SIGNALS THAT ENABLE AND DIRECT STRESS ADAPTATION. NEURAL CIRCUITS REGULATING SOCIAL BEHAVIOR - AS WELL AS PSYCHOPATHOLOGICAL PROCESSES - ARE ALSO INFLUENCED BY MITOCHONDRIAL ENERGETICS. AN INTEGRATIVE VIEW OF STRESS AS AN ENERGY-DRIVEN PROCESS OPENS NEW OPPORTUNITIES TO STUDY MECHANISMS OF ADAPTATION AND REGULATION ACROSS THE LIFESPAN. 2018 18 2378 31 EPIGENETIC REGULATION OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE SWITCHING IN ATHEROSCLEROTIC ARTERY REMODELING: A MINI-REVIEW. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY EXTENSIVE REMODELING OF MEDIUM AND LARGE-SIZED ARTERIES. INWARD REMODELING (=LUMEN SHRINKAGE) OF THE VASCULAR WALLS IS THE UNDERLYING CAUSE FOR ISCHEMIA IN TARGET ORGANS. THEREFORE, INWARD REMODELING CAN BE CONSIDERED THE PREDOMINANT FEATURE OF ATHEROSCLEROTIC PATHOLOGY. OUTWARD REMODELING (=LUMEN ENLARGEMENT) IS A PHYSIOLOGICAL RESPONSE COMPENSATING FOR LUMEN SHRINKAGE CAUSED BY NEOINTIMAL HYPERPLASIA, BUT AS A PATHOLOGICAL RESPONSE TO CHANGES IN BLOOD FLOW, OUTWARD REMODELING LEADS TO SUBSTANTIAL ARTERIAL WALL THINNING. THINNED VASCULAR WALLS ARE PRONE TO RUPTURE, AND SUBSEQUENT THROMBUS FORMATION ACCOUNTS FOR THE MAJORITY OF ACUTE CARDIOVASCULAR EVENTS. PATHOLOGICAL REMODELING IS DRIVEN BY INFLAMMATORY CELLS WHICH INDUCE VASCULAR SMOOTH MUSCLE CELLS TO SWITCH FROM QUIESCENT TO A PROLIFERATIVE AND MIGRATORY PHENOTYPE. AFTER DECADES OF INTENSIVE RESEARCH, THE MOLECULAR MECHANISMS OF ARTERIAL REMODELING ARE STARTING TO UNFOLD. IN THIS MINI-REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE EPIGENETIC AND TRANSCRIPTIONAL REGULATION OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE SWITCHING FROM THE CONTRACTILE TO THE SYNTHETIC PHENOTYPE INVOLVED IN ARTERIAL REMODELING AND DISCUSS POTENTIAL THERAPEUTIC OPTIONS. 2021 19 2468 34 EPIGENETIC TOXICOLOGY AS TOXICANT-INDUCED CHANGES IN INTRACELLULAR SIGNALLING LEADING TO ALTERED GAP JUNCTIONAL INTERCELLULAR COMMUNICATION. COMMUNICATION MECHANISMS [EXTRA-, INTRA-, AND GAP JUNCTIONAL INTER-CELLULAR COMMUNICATION (GJIC)] CONTROL, FROM THE FERTILIZED EGG, THROUGH EMBRYOGENESIS TO MATURITY AND AGING, WHETHER A CELL PROLIFERATES, DIFFERENTIATES, DIES BY APOPTOSIS, OR IF DIFFERENTIATED, ADAPTIVELY RESPONDS TO ENDOGENOUS AND EXOGENOUS SIGNALS. FROM THE EGG TO THE 100 TRILLION CELLS IN THE HUMAN BODY, HEALTH IS MAINTAINED WHEN THESE COMMUNICATION PROCESSES BETWEEN STEM, PROGENITOR AND TERMINALLY DIFFERENTIATED CELLS ARE INTEGRATED. EACH CELL CHOICE INVOLVES 'EPIGENETIC' MECHANISMS TO ALTER THE EXPRESSION OF GENES AT THE TRANSCRIPTIONAL, TRANSLATIONAL OR POST-TRANSLATIONAL LEVELS. DISRUPTION OF THE COMMUNICATION MECHANISMS CAN BE EITHER ADAPTIVE OR MALADAPTIVE. MODULATION OF EXTRA-CELLULAR COMMUNICATION, EITHER BY GENETIC IMBALANCES OF GROWTH FACTORS, HORMONES OR NEUROTRANSMITTERS OR BY ENVIRONMENTAL, EXOGENOUS CHEMICALS CAN TRIGGER SIGNAL TRANSDUCING INTRA-CELLULAR MECHANISMS. THESE INTRA-CELLULAR SIGNALS CAN MODULATE GENE EXPRESSION AT THE TRANSCRIPTIONAL, TRANSLATIONAL OR POST-TRANSLATIONAL LEVELS WHILE ALSO MODULATING GJIC. UNTIMELY OR CHRONIC DISRUPTION OF GJIC DURING EMBRYONIC OR FETAL DEVELOPMENT COULD LEAD TO EMBRYONIC LETHALITY OR TERATOGENESIS. BY MODULATION OF GJIC, HOMEOSTATIC CONTROL OF CELL GROWTH, DIFFERENTIATION OR APOPTOSIS COULD LEAD TO SPECIFIC DISEASES, SUCH AS NEUROLOGICAL, CARDIOVASCULAR, REPRODUCTIVE OR ENDOCRINOLOGICAL DYSFUNCTION. CHEMICAL MODULATION OR ONCOGENE DOWN-REGULATION OF GJIC IN INITIATED TISSUES HAS BEEN SHOWN TO LEAD TO TUMOR PROMOTION. GENETIC SYNDROMES CARRYING A MUTATED GAP JUNCTION GENE, TOGETHER WITH SOME TRANSGENIC AND KNOCK-OUT GAP JUNCTION GENE MICE, PROVIDE EVIDENCE FOR THE IMPORTANCE OF THIS ORGANELLE FOUND ONLY IN METAZOANS. IMPLICATIONS FOR 'THRESHOLDS' TO TOXICANTS AND FOR RISK ASSESSMENT ARE EVIDENT. 1998 20 2361 33 EPIGENETIC REGULATION OF SKELETAL TISSUE INTEGRITY AND OSTEOPOROSIS DEVELOPMENT. BONE TURNOVER IS SOPHISTICATEDLY BALANCED BY A DYNAMIC COUPLING OF BONE FORMATION AND RESORPTION AT VARIOUS RATES. THE ORCHESTRATION OF THIS CONTINUOUS REMODELING OF THE SKELETON FURTHER AFFECTS OTHER SKELETAL TISSUES THROUGH ORGAN CROSSTALK. CHRONIC EXCESSIVE BONE RESORPTION COMPROMISES BONE MASS AND ITS POROUS MICROSTRUCTURE AS WELL AS PROPER BIOMECHANICS. THIS ACCELERATES THE DEVELOPMENT OF OSTEOPOROTIC DISORDERS, A LEADING CAUSE OF SKELETAL DEGENERATION-ASSOCIATED DISABILITY AND PREMATURE DEATH. BONE-FORMING CELLS PLAY IMPORTANT ROLES IN MAINTAINING BONE DEPOSIT AND OSTEOCLASTIC RESORPTION. A POOR ORGANELLE MACHINERY, SUCH AS MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS, AND DEFECTIVE AUTOPHAGY, ETC., DYSREGULATES GROWTH FACTOR SECRETION, MINERALIZATION MATRIX PRODUCTION, OR OSTEOCLAST-REGULATORY CAPACITY IN OSTEOBLASTIC CELLS. A PLETHORA OF EPIGENETIC PATHWAYS REGULATE BONE FORMATION, SKELETAL INTEGRITY, AND THE DEVELOPMENT OF OSTEOPOROSIS. MICRORNAS INHIBIT PROTEIN TRANSLATION BY BINDING THE 3'-UNTRANSLATED REGION OF MRNAS OR PROMOTE TRANSLATION THROUGH POST-TRANSCRIPTIONAL PATHWAYS. DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATION OF HISTONES ALTER THE CHROMATIN STRUCTURE, HINDERING HISTONE ENRICHMENT IN PROMOTER REGIONS. MICRORNA-PROCESSING ENZYMES AND DNA AS WELL AS HISTONE MODIFICATION ENZYMES CATALYZE THESE MODIFYING REACTIONS. GAIN AND LOSS OF THESE EPIGENETIC MODIFIERS IN BONE-FORMING CELLS AFFECT THEIR EPIGENETIC LANDSCAPES, INFLUENCING BONE HOMEOSTASIS, MICROARCHITECTURAL INTEGRITY, AND OSTEOPOROTIC CHANGES. THIS ARTICLE CONVEYS PRODUCTIVE INSIGHTS INTO BIOLOGICAL ROLES OF DNA METHYLATION, MICRORNA, AND HISTONE MODIFICATION AND HIGHLIGHTS THEIR INTERACTIONS DURING SKELETAL DEVELOPMENT AND BONE LOSS UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS. 2020