1 5430 110 REGULATORS INVOLVED IN TROPHOBLAST SYNCYTIALIZATION IN THE PLACENTA OF INTRAUTERINE GROWTH RESTRICTION. PLACENTAL DYSFUNCTION REFERS TO THE INSUFFICIENCY OF PLACENTAL PERFUSION AND CHRONIC HYPOXIA DURING EARLY PREGNANCY, WHICH IMPAIRS PLACENTAL FUNCTION AND CAUSES INADEQUATE SUPPLY OF OXYGEN AND NUTRIENTS TO THE FETUS, AFFECTING FETAL DEVELOPMENT AND HEALTH. FETAL INTRAUTERINE GROWTH RESTRICTION, ONE OF THE MOST COMMON OUTCOMES OF PREGNANCY-INDUCED HYPERTENSIONS, CAN BE CAUSED BY PLACENTAL DYSFUNCTION, RESULTING FROM DEFICIENT TROPHOBLAST SYNCYTIALIZATION, INADEQUATE TROPHOBLAST INVASION AND IMPAIRED VASCULAR REMODELING. DURING PLACENTAL DEVELOPMENT, CYTOTROPHOBLASTS FUSE TO FORM A MULTINUCLEATED SYNCYTIA BARRIER, WHICH SUPPLIES OXYGEN AND NUTRIENTS TO MEET THE METABOLIC DEMANDS FOR FETAL GROWTH. A REDUCTION IN THE CELL FUSION INDEX AND THE NUMBER OF NUCLEI IN THE SYNCYTIOTROPHOBLAST ARE FOUND IN THE PLACENTAS OF PREGNANCIES COMPLICATED BY IUGR, SUGGESTING THAT THE OCCURRENCE OF IUGR MAY BE RELATED TO INADEQUATE TROPHOBLAST SYNCYTIALIZATION. DURING THE MULTIPLE PROCESSES OF TROPHOBLASTS SYNCYTIALIZATION, SPECIFIC PROTEINS AND SEVERAL SIGNALING PATHWAYS ARE INVOLVED IN COORDINATING THESE EVENTS AND REGULATING PLACENTAL FUNCTION. IN ADDITION, EPIGENETIC MODIFICATIONS, CELL METABOLISM, SENESCENCE, AND AUTOPHAGY ARE ALSO INVOLVED. STUDY FINDINGS HAVE INDICATED SEVERAL ABNORMALLY EXPRESSED SYNCYTIALIZATION-RELATED PROTEINS AND SIGNALING PATHWAYS IN THE PLACENTAS OF PREGNANCIES COMPLICATED BY IUGR, SUGGESTING THAT THESE ELEMENTS MAY PLAY A CRUCIAL ROLE IN THE OCCURRENCE OF IUGR. IN THIS REVIEW, WE DISCUSS THE REGULATORS OF TROPHOBLAST SYNCYTIALIZATION AND THEIR ABNORMAL EXPRESSION IN THE PLACENTAS OF PREGNANCIES COMPLICATED BY IUGR. 2023 2 850 19 CHILDREN WITH CHRONIC IMMUNE THROMBOCYTOPENIA EXHIBIT HIGH EXPRESSION OF HUMAN ENDOGENOUS RETROVIRUSES TRIM28 AND SETDB1. CHRONIC IMMUNE THROMBOCYTOPENIA (CITP) IS AN AUTOIMMUNE DISEASE WHOSE UNDERLYING BIOLOGIC MECHANISMS REMAIN ELUSIVE. HUMAN ENDOGENOUS RETROVIRUSES (HERVS) DERIVE FROM ANCESTRAL INFECTIONS AND CONSTITUTE ABOUT 8% OF OUR GENOME. A WEALTH OF CLINICAL AND EXPERIMENTAL STUDIES HIGHLIGHTS THEIR PIVOTAL PATHOGENETIC ROLE IN AUTOIMMUNE DISEASES. EPIGENETIC MECHANISMS, SUCH AS THOSE MODULATED BY TRIM28 AND SETDB1, ARE INVOLVED IN HERV ACTIVATION AND REGULATION OF IMMUNE RESPONSE. WE ASSESSED, THROUGH A POLYMERASE CHAIN REACTION REAL-TIME TAQMAN AMPLIFICATION ASSAY, THE TRANSCRIPTION LEVELS OF POL GENES OF HERV-H, HERV-K, AND HERV-W; ENV GENES OF SYNCYTIN (SYN)1, SYN2, AND HERV-W; AS WELL AS TRIM28 AND SETDB1 IN WHOLE BLOOD FROM 34 CHILDREN WITH CITP AND AGE-MATCHED HEALTHY CONTROLS (HC). THE TRANSCRIPTIONAL LEVELS OF ALL HERV SEQUENCES, WITH THE EXCEPTION OF HERV-W-ENV, WERE SIGNIFICANTLY ENHANCED IN CHILDREN WITH CITP AS COMPARED TO HC. PATIENTS ON ELTROMBOPAG TREATMENT EXHIBITED LOWER EXPRESSION OF SYN1, SYN2, AND HERV-W-ENV AS COMPARED TO UNTREATED PATIENTS. THE MRNA CONCENTRATIONS OF TRIM28 AND SETDB1 WERE SIGNIFICANTLY HIGHER AND WERE POSITIVELY CORRELATED WITH THOSE OF HERVS IN CITP PATIENTS. THE OVER-EXPRESSIONS OF HERVS AND TRIM28/SETDB1 AND THEIR POSITIVE CORRELATIONS IN PATIENTS WITH CITP ARE SUGGESTIVE CLUES OF THEIR CONTRIBUTION TO THE PATHOGENESIS OF THE DISEASE AND SUPPORT INNOVATIVE INTERVENTIONS TO INHIBIT HERV AND TRIM28/SETDB1 EXPRESSIONS IN PATIENTS UNRESPONSIVE TO STANDARD THERAPIES. 2023 3 4457 26 MOLECULAR MECHANISMS MEDIATED BY HUMAN ENDOGENOUS RETROVIRUSES (HERVS) IN AUTOIMMUNITY. EIGHT PER CENT OF THE HUMAN GENOME IS DERIVED FROM THE INTEGRATION OF RETROVIRAL SEQUENCES THAT WERE INCORPORATED IN OUR DNA MORE THAN 25 MILLION YEARS AGO. ALTHOUGH SOME OF THESE ELEMENTS SHOW MUTATIONS AND DELETIONS, SOME HERVS ARE TRANSCRIPTIONALLY ACTIVE AND PRODUCE FUNCTIONAL PROTEINS. DIFFERENT MECHANISMS HAVE BEEN DESCRIBED WHICH LINK HERVS TO SOME CHRONIC DISEASES SUCH AS SEVERAL CANCERS, NERVOUS SYSTEM DISEASES AND AUTOIMMUNE RHEUMATIC AND CONNECTIVE TISSUE DISEASES. THEY COULD CAUSE DISEASE BECAUSE OF THEIR CAPACITY FOR BEING MOVED AND INSERTED NEXT TO CERTAIN GENES WHOSE EXPRESSION WOULD BE CONSEQUENTIALLY ALTERED. ANOTHER WAY IN WHICH DISEASE COULD POTENTIALLY ARISE IS WHEN HERV-ENCODED PROTEINS ARE EXPRESSED. THESE PROTEINS WOULD BE CONSIDERED AS [FOREIGN] AND THEY COULD TRIGGER B-CELLS TO PRODUCE ANTIBODIES AGAINST THEM, WHICH, IN TURN, MIGHT CROSS-REACT WITH OTHER PROTEINS OF OUR BODIES. THIS MECHANISM COULD GIVE RISE TO AUTOIMMUNE DISEASES SUCH AS RHEUMATOID ARTHRITIS (RA), LUPUS ERYTHEMATOSUS, SJOGREN'S SYNDROME (SJS), MIXED CONNECTIVE TISSUE DISEASES AND INFLAMMATORY NEUROLOGICAL DISEASE. FURTHERMORE, IT SHOULD BE POINTED OUT THAT HERV-PROTEINS MAY ACT AS SUPERANTIGENS. INTERESTINGLY, SOME ENVIRONMENTAL AGENTS SEEM TO INDUCE THE EXPRESSION OF HERVS. THUS, ULTRAVIOLET LIGHT AND SEVERAL CHEMICAL AGENTS COULD REACTIVATE SUCH SEQUENCES BY ALTERING THEIR STRUCTURE WITHOUT MODIFYING THEIR NUCLEOTIDE COMPOSITION WHEN THE METHYLATION PATTERN IS CHANGED. THEREFORE, THE EPIGENETIC CHANGES OBSERVED IN PATHOLOGICAL CONDITIONS SUCH AS SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) OR CANCER COULD BE TRANSLATED INTO AN EFFECT ON THE ACTIVATION OF SOME OF THE RETROELEMENTS PRESENT IN OUR GENOME WHICH ULTIMATELY COULD HAVE A DIRECT OR INDIRECT ROLE ON THE INITIATION AND CLINICAL EVOLUTION OF CERTAIN CHRONIC DISEASES. 2009 4 5321 31 PULMONARY ARTERY SMOOTH MUSCLE CELL PROLIFERATION AND MIGRATION IN FETAL LAMBS ACCLIMATIZED TO HIGH-ALTITUDE LONG-TERM HYPOXIA: ROLE OF HISTONE ACETYLATION. HIGH-ALTITUDE LONG-TERM HYPOXIA (LTH) IS KNOWN TO INDUCE PULMONARY ARTERIAL SMOOTH MUSCLE CELL (PASMC) PROLIFERATION IN THE FETUS, LEADING TO PULMONARY ARTERIAL REMODELING AND PULMONARY HYPERTENSION OF THE NEWBORN. THE MECHANISMS UNDERLYING THESE CONDITIONS REMAIN ENIGMATIC HOWEVER. WE HYPOTHESIZED THAT EPIGENETIC ALTERATIONS IN FETAL PASMC INDUCED BY HIGH-ALTITUDE LTH MAY PLAY AN IMPORTANT ROLE IN MODULATING THEIR PROLIFERATION DURING PULMONARY ARTERIAL REMODELING. TO TEST THIS HYPOTHESIS, WE HAVE ANALYZED EPIGENETIC ALTERATIONS IN THE PULMONARY VASCULATURE OF FETAL LAMBS EXPOSED TO HIGH-ALTITUDE LTH [PREGNANT EWES WERE KEPT AT 3,801 M ALTITUDE FROM ~40 TO 145 DAYS GESTATION] OR TO SEA LEVEL ATMOSPHERE. INTRAPULMONARY ARTERIES WERE ISOLATED, AND FETAL PASMC WERE CULTURED FROM BOTH CONTROL AND LTH FETUSES. COMPARED WITH CONTROLS, IN LTH FETUS PULMONARY ARTERIES MEASUREMENTS OF HISTONE ACETYLATION AND GLOBAL DNA METHYLATION DEMONSTRATED REDUCED LEVELS OF GLOBAL HISTONE 4 ACETYLATION AND DNA METHYLATION, ACCOMPANIED BY THE LOSS OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P21. TREATMENT OF LTH FETAL PASMCS WITH HISTONE DEACETYLASE (HDAC) INHIBITOR TRICHOSTATIN A DECREASED THEIR PROLIFERATION RATE, IN PART BECAUSE OF ALTERED EXPRESSION OF P21 AT BOTH RNA AND PROTEIN LEVEL. IN PASMC OF LTH FETUSES, HDAC INHIBITION ALSO DECREASED PDGF-INDUCED CELL MIGRATION AND ERK1/2 ACTIVATION AND MODULATED GLOBAL DNA METHYLATION. ON THE BASIS OF THESE OBSERVATIONS, WE PROPOSE THAT EPIGENETIC ALTERATIONS (REDUCED HISTONE ACETYLATION AND DNA METHYLATION) CAUSED BY CHRONIC HYPOXIA LEADS TO FETAL PASMC PROLIFERATION AND VESSEL REMODELING ASSOCIATED WITH VASCULAR PROLIFERATIVE DISEASE AND THAT THIS PROCESS IS REGULATED BY P21. 2012 5 3813 26 INTRAUTERINE GROWTH RESTRICTION INHIBITS EXPRESSION OF EUKARYOTIC ELONGATION FACTOR 2 KINASE, A REGULATOR OF PROTEIN TRANSLATION. NUTRIENT DEPRIVATION SUPPRESSES PROTEIN SYNTHESIS BY BLOCKING PEPTIDE ELONGATION. TRANSCRIPTIONAL UPREGULATION AND ACTIVATION OF EUKARYOTIC ELONGATION FACTOR 2 KINASE (EEF2K) BLOCKS PEPTIDE ELONGATION BY PHOSPHORYLATING EUKARYOTIC ELONGATION FACTOR 2. PREVIOUS STUDIES EXAMINING PLACENTAS FROM INTRAUTERINE GROWTH RESTRICTED (IUGR) NEWBORN INFANTS SHOW DECREASED EEF2K EXPRESSION AND ACTIVITY DESPITE CHRONIC NUTRIENT DEPRIVATION. HOWEVER, THE EFFECT OF IUGR ON HEPATIC EEF2K EXPRESSION IN THE FETUS IS UNKNOWN. WE, THEREFORE, EXAMINED THE TRANSCRIPTIONAL REGULATION OF HEPATIC EEF2K GENE EXPRESSION IN A SPRAGUE-DAWLEY RAT MODEL OF IUGR. WE FOUND DECREASED HEPATIC EEF2K MRNA AND PROTEIN LEVELS IN IUGR OFFSPRING AT BIRTH COMPARED WITH CONTROL, CONSISTENT WITH PREVIOUS PLACENTAL OBSERVATIONS. FURTHERMORE, THE CPG ISLAND WITHIN THE EEF2K PROMOTER DEMONSTRATED INCREASED METHYLATION AT A CRITICAL USF 1/2 TRANSCRIPTION FACTOR BINDING SITE. IN VITRO METHYLATION OF THIS BINDING SITE CAUSED NEAR COMPLETE LOSS OF EEF2K PROMOTER ACTIVITY, DESIGNATING THIS PROMOTER AS METHYLATION SENSITIVE. THE EEF2K PROMOTOR IN IUGR OFFSPRING ALSO LOST THE PROTECTIVE HISTONE COVALENT MODIFICATIONS ASSOCIATED WITH UNMETHYLATED CGIS. IN ADDITION, THE +1 NUCLEOSOME WAS DISPLACED 3' AND RNA POLYMERASE LOADING WAS REDUCED AT THE IUGR EEF2K PROMOTER. OUR FINDINGS PROVIDE EVIDENCE TO EXPLAIN WHY IUGR-INDUCED CHRONIC NUTRIENT DEPRIVATION DOES NOT RESULT IN THE UPREGULATION OF EEF2K GENE TRANSCRIPTION. 2016 6 6453 26 THIOREDOXIN INTERACTING PROTEIN (TXNIP) INDUCES INFLAMMATION THROUGH CHROMATIN MODIFICATION IN RETINAL CAPILLARY ENDOTHELIAL CELLS UNDER DIABETIC CONDITIONS. CHRONIC HYPERGLYCEMIA AND ACTIVATION OF RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE) ARE KNOWN RISK FACTORS FOR MICROVASCULAR DISEASE DEVELOPMENT IN DIABETIC RETINOPATHY. THIOREDOXIN-INTERACTING PROTEIN (TXNIP), AN ENDOGENOUS INHIBITOR OF ANTIOXIDANT THIOREDOXIN (TRX), PLAYS A CAUSATIVE ROLE IN DIABETES AND ITS VASCULAR COMPLICATIONS. HEREIN WE INVESTIGATE WHETHER HG AND RAGE INDUCE INFLAMMATION IN RAT RETINAL ENDOTHELIAL CELLS (EC) UNDER DIABETIC CONDITIONS IN CULTURE THROUGH TXNIP ACTIVATION AND WHETHER EPIGENETIC MECHANISMS PLAY A ROLE IN INFLAMMATORY GENE EXPRESSION. WE SHOW THAT RAGE ACTIVATION BY ITS LIGAND S100B OR HG TREATMENT OF RETINAL EC INDUCES THE EXPRESSION OF TXNIP AND INFLAMMATORY GENES SUCH AS COX2, VEGF-A, AND ICAM1. TXNIP SILENCING BY SIRNA IMPEDES RAGE AND HG EFFECTS WHILE STABLE OVER-EXPRESSION OF A CDNA FOR HUMAN TXNIP IN EC ELEVATES INFLAMMATION. P38 MAPK-NF-KAPPAB SIGNALING PATHWAY AND HISTONE H3 LYSINE (K) NINE MODIFICATIONS ARE INVOLVED IN TXNIP-INDUCED INFLAMMATION. CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAYS REVEAL THAT TXNIP OVER-EXPRESSION IN EC ABOLISHES H3K9 TRI-METHYLATION, A MARKER FOR GENE INACTIVATION, AND INCREASES H3K9 ACETYLATION, AN INDICATOR OF GENE INDUCTION, AT PROXIMAL COX2 PROMOTER BEARING THE NF-KAPPAB-BINDING SITE. THESE FINDINGS HAVE IMPORTANT IMPLICATIONS TOWARD UNDERSTANDING THE MOLECULAR MECHANISMS OF OCULAR INFLAMMATION AND ENDOTHELIAL DYSFUNCTION IN DIABETIC RETINOPATHY. 2009 7 3869 23 JNK1 REGULATES HISTONE ACETYLATION IN TRIGEMINAL NEURONS FOLLOWING CHEMICAL STIMULATION. TRIGEMINAL NERVE FIBERS IN NASAL AND ORAL CAVITIES ARE SENSITIVE TO VARIOUS ENVIRONMENTAL HAZARDOUS STIMULI, WHICH TRIGGER MANY NEUROTOXIC PROBLEMS SUCH AS CHRONIC MIGRAINE HEADACHE AND TRIGEMINAL IRRITATED DISORDERS. HOWEVER, THE ROLE OF JNK KINASE CASCADE AND ITS EPIGENETIC MODULATION OF HISTONE REMODELING IN TRIGEMINAL GANGLION (TG) NEURONS ACTIVATED BY ENVIRONMENTAL NEUROTOXINS REMAINS UNKNOWN. HERE WE INVESTIGATED THE ROLE OF JNK/C-JUN CASCADE IN THE REGULATION OF ACETYLATION OF H3 HISTONE IN TG NEURONS FOLLOWING IN VITRO STIMULATION BY A NEURO-INFLAMMATORY AGENT, MUSTARD OIL (MO). WE FOUND THAT MO STIMULATION ELICITED JNK/C-JUN PATHWAY SIGNIFICANTLY BY ENHANCING PHOSPHO-JNK1, PHOSPHO-C-JUN EXPRESSION, AND C-JUN ACTIVITY, WHICH WERE CORRELATED WITH AN ELEVATED ACETYLATED H3 HISTONE IN TG NEURONS. HOWEVER, INCREASES IN PHOSPHO-C-JUN AND C-JUN ACTIVITY WERE SIGNIFICANTLY BLOCKED BY A JNK INHIBITOR, SP600125. WE ALSO FOUND THAT ALTERED H3 HISTONE REMODELING, ASSESSED BY H3 ACETYLATION IN TRIGGERED TG NEURONS, WAS REDUCED BY SP600125. THE STUDY SUGGESTS THAT THE ACTIVATED JNK SIGNALING IN REGULATION OF HISTONE REMODELING MAY CONTRIBUTE TO NEURO-EPIGENTIC CHANGES IN PERIPHERAL SENSORY NEURONS FOLLOWING ENVIRONMENTAL NEUROTOXIC EXPOSURE. 2008 8 218 33 ACUTE HYPOXIA AND CHRONIC ISCHEMIA INDUCE DIFFERENTIAL TOTAL CHANGES IN PLACENTAL EPIGENETIC MODIFICATIONS. PREECLAMPSIA IS A COMMON OBSTETRICAL COMPLICATION, HALLMARKED BY NEW-ONSET HYPERTENSION. BELIEVED TO RESULT FROM PLACENTAL INSUFFICIENCY AND CHRONIC PLACENTAL ISCHEMIA, THE SYMPTOMS OF PREECLAMPSIA ARE CAUSED BY RELEASE OF PATHOGENIC FACTORS FROM THE PLACENTA ITSELF, ALTHOUGH THE MECHANISMS OF THEIR REGULATION ARE IN MANY CASES UNKNOWN. ONE POTENTIAL MECHANISM IS THROUGH CHANGES IN PLACENTAL EPIGENETIC CHROMATIN MODIFICATIONS, PARTICULARLY HISTONE ACETYLATION AND DNA METHYLATION. HERE, WE DETERMINED THE EFFECTS OF CHRONIC ISCHEMIA ON GLOBAL EPIGENETIC MODIFICATIONS IN THE RODENT PLACENTA IN VIVO AND ACUTE HYPOXIA IN BEWO PLACENTAL TROPHOBLAST CELLS IN VITRO. PLACENTAL INSUFFICIENCY VIA UTERINE ARTERY RESTRICTION INCREASED MATERNAL BLOOD PRESSURE AND FETAL DEMISE WHILE DECREASING PLACENTAL AND FETAL MASS. GLOBAL PLACENTAL HISTONE H3 ACETYLATION LEVELS WERE SIGNIFICANTLY DECREASED AT H3 K9, K14, K18, K27, AND K56. INTERESTINGLY, WHEN BEWO-IMMORTALIZED PLACENTAL TROPHOBLAST CELLS WERE CULTURED IN OXYGEN CONCENTRATIONS MIMICKING HEALTHY AND ISCHEMIC PLACENTAS, THERE WAS A SIGNIFICANT INCREASE IN ACETYLATED AT K9, K18, K27, AND K56. THIS WAS ASSOCIATED WITH A SMALL BUT SIGNIFICANT DECREASE IN PLACENTAL ACETYL-COA, SUGGESTING DEPLETION IN THE SOURCE OF ACETYL GROUP DONORS. FINALLY, WHILE GLOBAL METHYLATION OF CYTOSINE FROM PLACENTAL DNA WAS LOW IN BOTH GROUPS OF ANIMALS (<1%), THERE WAS APPROXIMATELY 50% INCREASE IN 5-MC IN RESPONSE TO CHRONIC ISCHEMIA. THIS SUGGESTS ACUTE HYPOXIA AND CHRONIC ISCHEMIA INDUCE DIFFERENTIAL GLOBAL CHANGES IN HISTONE ACETYLATION IN THE PLACENTA AND THAT CHRONICALLY ALTERED METABOLIC PROFILES COULD AFFECT HISTONE ACETYLATION IN THE PLACENTA, THEREBY REGULATING PRODUCTION OF PATHOGENIC FACTORS FROM THE PLACENTA DURING PREECLAMPSIA. 2019 9 673 20 BRAHMA-RELATED GENE 1 (BRG1) EPIGENETICALLY REGULATES CAM ACTIVATION DURING HYPOXIC PULMONARY HYPERTENSION. AIMS: ESTABLISHMENT OF AN INFLAMMATORY MILIEU FOLLOWING ELEVATED LEUKOCYTE ADHESION TO THE VASCULAR ENDOTHELIUM, WHICH IS MEDIATED BY TRANSCRIPTIONAL ACTIVATION OF CELL ADHESION MOLECULES (CAMS), CONTRIBUTES TO THE PATHOGENESIS OF CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION (HPH). THE EPIGENETIC SWITCH THAT DICTATES CAM TRANSACTIVATION IN RESPONSE TO HYPOXIA IN ENDOTHELIAL CELLS LEADING UP TO HPH IS NOT FULLY APPRECIATED. METHODS AND RESULTS: WE REPORT HERE THAT BRAHMA-RELATED GENE 1 (BRG1) AND BRAHMA (BRM), TWO CATALYTIC COMPONENTS OF THE MAMMALIAN CHROMATIN REMODELLING COMPLEX, WERE INDUCED IN CULTURED ENDOTHELIAL CELLS CHALLENGED WITH HYPOXIA IN VITRO AS WELL AS IN PULMONARY ARTERIES IN AN ANIMAL MODEL OF HPH. OVER-EXPRESSION OF BRG1/BRM ENHANCED, WHILE THE DEPLETION OF BRG1/BRM ATTENUATED, CAM TRANSACTIVATION AND ADHESION OF LEUKOCYTES. ENDOTHELIAL-SPECIFIC DELETION OF BRG1/BRM AMELIORATED VASCULAR INFLAMMATION AND HPH IN MICE. CHROMATIN IMMUNOPRECIPITATION (CHIP) AND RE-CHIP ASSAYS REVEALED THAT HYPOXIA UP-REGULATED THE OCCUPANCIES OF BRG1 AND BRM ON CAM PROMOTERS IN A NUCLEAR FACTOR KAPPAB (NF-KAPPAB) -DEPENDENT MANNER. FINALLY, BRG1 AND BRM ACTIVATED CAM TRANSCRIPTION BY ALTERING THE CHROMATIN STRUCTURE SURROUNDING THE CAM PROMOTERS. CONCLUSION: OUR DATA SUGGEST THAT BRG1 PROVIDES THE CRUCIAL EPIGENETIC LINK TO HYPOXIA-INDUCED CAM INDUCTION AND LEUKOCYTE ADHESION THAT ENGENDERS ENDOTHELIAL MALFUNCTION AND PATHOGENESIS OF HPH. AS SUCH, TARGETING BRG1 IN ENDOTHELIAL CELLS MAY YIELD PROMISING STRATEGIES IN THE INTERVENTION AND/OR PREVENTION OF HPH. 2013 10 2216 23 EPIGENETIC MODIFICATIONS IN CHRONIC MYELOID LEUKEMIA CELLS THROUGH RUXOLITINIB TREATMENT. CHRONIC MYELOID LEUKEMIA IS A CLONAL MALIGNANCY OF HEMATOPOIETIC STEM CELL THAT IS CHARACTERIZED BY THE OCCURRENCE OF T(9;22)(Q34;Q11.2) TRANSLOCATION, NAMED PHILADELPHIA CHROMOSOME. RUXOLITINIB IS A POWERFUL JANUS TYROSINE KINASE 1 AND 2 INHIBITOR THAT IS USED FOR MYELOFIBROSIS TREATMENT. DNA-HISTONE CONNECTION MEDIATES A WIDE RANGE OF GENES THAT CODE METHYLATION, DEMETHYLATION, ACETYLATION, DEACETYLATION, UBIQUITINATION, AND PHOSPHORYLATION ENZYMES. EPIGENETIC MODIFICATIONS REGULATE CHROMATIN COMPACTNESS, WHICH PLAYS PIVOTAL ROLES IN CRITICAL BIOLOGICAL PROCESSES INCLUDING THE TRANSCRIPTIONAL ACTIVITY AND CELL PROLIFERATION AS WELL AS VARIOUS PATHOLOGICAL MECHANISMS, INCLUDING CML. THIS STUDY IS AIMED TO DETERMINE THE ALTERATIONS OF THE EXPRESSION LEVELS OF EPIGENETIC MODIFICATION-RELATED GENES AFTER RUXOLITINIB TREATMENT. TOTAL RNA WAS ISOLATED FROM K-562 CELLS TREATED WITH THE IC(50) VALUE OF RUXOLITINIB AND UNTREATED K-562 CONTROL CELLS. A REVERSE TRANSCRIPTION PROCEDURE WAS PERFORMED FOR COMPLEMENTARY DNA SYNTHESIS, AND GENE EXPRESSIONS WERE DETECTED BY REAL-TIME POLYMERASE CHAIN REACTION COMPARED WITH THE UNTREATED CELLS. RUXOLITINIB TREATMENT CAUSED A SIGNIFICANT ALTERATION IN THE EXPRESSION LEVELS OF EPIGENETIC REGULATION-RELATED GENES IN K-562 CELLS. OUR NOVEL RESULTS SUGGESTED THAT RUXOLITINIB HAS INHIBITOR EFFECTS ON EPIGENETIC MODIFICATION-REGULATOR GENES. 2019 11 3656 32 INDUCIBLE PRMT1 ABLATION IN ADULT VASCULAR SMOOTH MUSCLE LEADS TO CONTRACTILE DYSFUNCTION AND AORTIC DISSECTION. VASCULAR SMOOTH MUSCLE CELLS (VSMCS) HAVE REMARKABLE PLASTICITY IN RESPONSE TO DIVERSE ENVIRONMENTAL CUES. ALTHOUGH THESE CELLS ARE VERSATILE, CHRONIC STRESS CAN TRIGGER VSMC DYSFUNCTION, WHICH ULTIMATELY LEADS TO VASCULAR DISEASES SUCH AS AORTIC ANEURYSM AND ATHEROSCLEROSIS. PROTEIN ARGININE METHYLTRANSFERASE 1 (PRMT1) IS A MAJOR ENZYME CATALYZING ASYMMETRIC ARGININE DIMETHYLATION OF PROTEINS THAT ARE SOURCES OF ASYMMETRIC DIMETHYLARGININE (ADMA), AN ENDOGENOUS INHIBITOR OF NITRIC OXIDE SYNTHASE. ALTHOUGH A POTENTIAL ROLE OF PRMT1 IN VASCULAR PATHOGENESIS HAS BEEN PROPOSED, ITS ROLE IN VASCULAR FUNCTION HAS YET TO BE CLARIFIED. HERE, WE INVESTIGATED THE ROLE AND UNDERLYING MECHANISM OF PRMT1 IN VASCULAR SMOOTH MUSCLE CONTRACTILITY AND FUNCTION. THE EXPRESSION OF PRMT1 AND CONTRACTILE-RELATED GENES WAS SIGNIFICANTLY DECREASED IN THE AORTAS OF ELDERLY HUMANS AND PATIENTS WITH AORTIC ANEURYSMS. MICE WITH VSMC-SPECIFIC PRMT1 ABLATION (SMKO) EXHIBITED PARTIAL LETHALITY, LOW BLOOD PRESSURE AND AORTIC DILATION. THE PRMT1-ABLATED AORTAS SHOWED AORTIC DISSECTION WITH ELASTIC FIBER DEGENERATION AND CELL DEATH. EX VIVO AND IN VITRO ANALYSES INDICATED THAT PRMT1 ABLATION SIGNIFICANTLY DECREASED THE CONTRACTILITY OF THE AORTA AND TRACTION FORCES OF VSMCS. PRMT1 ABLATION DOWNREGULATED THE EXPRESSION OF CONTRACTILE GENES SUCH AS MYOCARDIN WHILE UPREGULATING THE EXPRESSION OF SYNTHETIC GENES, THUS CAUSING THE CONTRACTILE TO SYNTHETIC PHENOTYPIC SWITCH OF VSMCS. IN ADDITION, MECHANISTIC STUDIES DEMONSTRATED THAT PRMT1 DIRECTLY REGULATES MYOCARDIN GENE ACTIVATION BY MODULATING EPIGENETIC HISTONE MODIFICATIONS IN THE MYOCARDIN PROMOTER REGION. THUS, OUR STUDY DEMONSTRATES THAT VSMC PRMT1 IS ESSENTIAL FOR VASCULAR HOMEOSTASIS AND THAT ITS ABLATION CAUSES AORTIC DILATION/DISSECTION THROUGH IMPAIRED MYOCARDIN EXPRESSION. 2021 12 571 22 BCR-ABL INDUCES AUTOCRINE IGF-1 SIGNALING. BCR-ABL ONCOGENE IS RESPONSIBLE FOR THE INITIAL PHASE OF CHRONIC MYELOGENOUS LEUKEMIA (CML), WHICH IS EFFECTIVELY TREATED BY THE BCR-ABL INHIBITOR IMATINIB. OVER TIME PATIENTS BECOME RESISTANT TO TREATMENT AND PROGRESS TO BLAST CRISIS, AN EVENT THAT IS DRIVEN BY ADDITIONAL GENETIC AND EPIGENETIC ABERRATIONS. RECENTLY, WE SHOWED THAT RIZ1 EXPRESSION DECREASES IN BLAST CRISIS AND THAT RE-EXPRESSION OF RIZ1 INHIBITS IGF-1 EXPRESSION. IGF-1 SIGNALING IS REQUIRED IN MANY STAGES OF HEMATOPOIESIS AND INAPPROPRIATE ACTIVATION OF AUTOCRINE IGF-1 SIGNALING MAY FACILITATE TRANSFORMATION TO BLAST CRISIS. WE OBSERVED THAT IN 8 OUT OF 11 MATCHED CML PATIENT BIOPSIES THE IGF-1 EXPRESSION IS ELEVATED IN BLAST CRISIS. WE EXAMINED MECHANISMS USED BY CML BLAST CRISIS CELL LINES TO ACTIVATE IGF-1 EXPRESSION. WE FOUND THAT BCR-ABL ACTIVATES AUTOCRINE IGF-1 SIGNALING USING HCK AND STAT5B. INHIBITION OF THESE SIGNALING COMPONENTS USING SMALL MOLECULE DRUGS OR SHRNA DECREASES PROLIFERATION AND ENHANCES APOPTOSIS. TOGETHER, OUR STUDY SUGGESTS THAT ABERRANT IGF-1 SIGNALING IS AN IMPORTANT EVENT IN BLAST CRISIS TRANSFORMATION AND IT PROVIDES A MECHANISM TO EXPLAIN THE ACTIVITY OF IGF-1R AND HCK INHIBITORS IN BLOCKING CML BLAST CRISIS PHENOTYPES. 2008 13 589 22 BET BROMODOMAIN INHIBITORS SUPPRESS INFLAMMATORY ACTIVATION OF GINGIVAL FIBROBLASTS AND EPITHELIAL CELLS FROM PERIODONTITIS PATIENTS. BET BROMODOMAIN PROTEINS ARE IMPORTANT EPIGENETIC REGULATORS OF GENE EXPRESSION THAT BIND ACETYLATED HISTONE TAILS AND REGULATE THE FORMATION OF ACETYLATION-DEPENDENT CHROMATIN COMPLEXES. BET INHIBITORS SUPPRESS INFLAMMATORY RESPONSES IN MULTIPLE CELL TYPES AND ANIMAL MODELS, AND PROTECT AGAINST BONE LOSS IN EXPERIMENTAL PERIODONTITIS IN MICE. HERE, WE ANALYZED THE ROLE OF BET PROTEINS IN INFLAMMATORY ACTIVATION OF GINGIVAL FIBROBLASTS (GFS) AND GINGIVAL EPITHELIAL CELLS (GECS). WE SHOW THAT THE BET INHIBITORS I-BET151 AND JQ1 SIGNIFICANTLY REDUCED EXPRESSION AND/OR PRODUCTION OF DISTINCT, BUT OVERLAPPING, PROFILES OF CYTOKINE-INDUCIBLE MEDIATORS OF INFLAMMATION AND BONE RESORPTION IN GFS FROM HEALTHY DONORS (IL6, IL8, IL1B, CCL2, CCL5, COX2, AND MMP3) AND THE GEC LINE TIGK (IL6, IL8, IL1B, CXCL10, MMP9) WITHOUT AFFECTING CELL VIABILITY. ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASE AND NUCLEAR FACTOR-KAPPAB PATHWAYS WAS UNAFFECTED BY I-BET151, AS WAS THE HISTONE ACETYLATION STATUS, AND NEW PROTEIN SYNTHESIS WAS NOT REQUIRED FOR THE ANTI-INFLAMMATORY EFFECTS OF BET INHIBITION. I-BET151 AND JQ1 ALSO SUPPRESSED EXPRESSION OF INFLAMMATORY CYTOKINES, CHEMOKINES, AND OSTEOCLASTOGENIC MEDIATORS IN GFS AND TIGKS INFECTED WITH THE KEY PERIODONTAL PATHOGEN PORPHYROMONAS GINGIVALIS. NOTABLY, P. GINGIVALIS INTERNALIZATION AND INTRACELLULAR SURVIVAL IN GFS AND TIGKS REMAINED UNAFFECTED BY BET INHIBITORS. FINALLY, INHIBITION OF BET PROTEINS SIGNIFICANTLY REDUCED P. GINGIVALIS-INDUCED INFLAMMATORY MEDIATOR EXPRESSION IN GECS AND GFS FROM PATIENTS WITH PERIODONTITIS. OUR RESULTS DEMONSTRATE THAT BET INHIBITORS MAY BLOCK THE EXCESSIVE INFLAMMATORY MEDIATOR PRODUCTION BY RESIDENT CELLS OF THE GINGIVAL TISSUE AND IDENTIFY THE BET FAMILY OF EPIGENETIC READER PROTEINS AS A POTENTIAL THERAPEUTIC TARGET IN THE TREATMENT OF PERIODONTAL DISEASE. 2019 14 3633 32 INCREASE IN HDAC9 SUPPRESSES MYOBLAST DIFFERENTIATION VIA EPIGENETIC REGULATION OF AUTOPHAGY IN HYPOXIA. EXTREMELY REDUCED OXYGEN (O(2)) LEVELS ARE DETRIMENTAL TO MYOGENIC DIFFERENTIATION AND MULTINUCLEATED MYOTUBE FORMATION, AND CHRONIC EXPOSURE TO HIGH-ALTITUDE HYPOXIA HAS BEEN REPORTED TO BE AN IMPORTANT FACTOR IN SKELETAL MUSCLE ATROPHY. HOWEVER, HOW CHRONIC HYPOXIA CAUSES MUSCLE DYSFUNCTION REMAINS UNKNOWN. IN THE PRESENT STUDY, WE FOUND THAT SEVERE HYPOXIA (1% O(2)) SIGNIFICANTLY INHIBITED THE FUNCTION OF C2C12 CELLS (FROM A MYOBLAST CELL LINE). IMPORTANTLY, THE IMPAIRMENT WAS CONTINUOUSLY MANIFESTED EVEN DURING CULTURE UNDER NORMOXIC CONDITIONS FOR SEVERAL PASSAGES. MECHANISTICALLY, WE REVEALED THAT HISTONE DEACETYLASES 9 (HDAC9), A MEMBER OF THE HISTONE DEACETYLASE FAMILY, WAS SIGNIFICANTLY INCREASED IN C2C12 CELLS UNDER HYPOXIC CONDITIONS, THEREBY INHIBITING INTRACELLULAR AUTOPHAGY LEVELS BY DIRECTLY BINDING TO THE PROMOTER REGIONS OF ATG7, BECLIN1, AND LC3. THIS PHENOMENON RESULTED IN THE SEQUENTIAL DEPHOSPHORYLATION OF GSK3BETA AND INACTIVATION OF THE CANONICAL WNT PATHWAY, IMPAIRING THE FUNCTION OF THE C2C12 CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT HYPOXIA-INDUCED MYOBLAST DYSFUNCTION IS DUE TO ABERRANT EPIGENETIC REGULATION OF AUTOPHAGY, AND OUR EXPERIMENTAL EVIDENCE REVEALS THE POSSIBLE MOLECULAR PATHOGENESIS RESPONSIBLE FOR SOME MUSCLE DISEASES CAUSED BY CHRONIC HYPOXIA AND SUGGESTS A POTENTIAL THERAPEUTIC OPTION. 2019 15 717 24 CALCITONIN GENE-RELATED PEPTIDE REGULATES SPINAL MICROGLIAL ACTIVATION THROUGH THE HISTONE H3 LYSINE 27 TRIMETHYLATION VIA ENHANCER OF ZESTE HOMOLOG-2 IN RATS WITH NEUROPATHIC PAIN. BACKGROUND: CALCITONIN GENE-RELATED PEPTIDE (CGRP) AS A MEDIATOR OF MICROGLIAL ACTIVATION AT THE TRANSCRIPTIONAL LEVEL MAY FACILITATE NOCICEPTIVE SIGNALING. TRIMETHYLATION OF H3 LYSINE 27 (H3K27ME3) BY ENHANCER OF ZESTE HOMOLOG 2 (EZH2) IS AN EPIGENETIC MARK THAT REGULATES INFLAMMATORY-RELATED GENE EXPRESSION AFTER PERIPHERAL NERVE INJURY. IN THIS STUDY, WE EXPLORED THE RELATIONSHIP BETWEEN CGRP AND H3K27ME3 IN MICROGLIAL ACTIVATION AFTER NERVE INJURY, AND ELUCIDATED THE UNDERLYING MECHANISMS IN THE PATHOGENESIS OF CHRONIC NEUROPATHIC PAIN. METHODS: MICROGLIAL CELLS (BV2) WERE TREATED WITH CGRP AND DIFFERENTIALLY ENRICHMENTS OF H3K27ME3 ON GENE PROMOTERS WERE EXAMINED USING CHIP-SEQ. A CHRONIC CONSTRICTION INJURY (CCI) RAT MODEL WAS USED TO EVALUATE THE ROLE OF CGRP ON MICROGLIAL ACTIVATION AND EZH2/H3K27ME3 SIGNALING IN CCI-INDUCED NEUROPATHIC PAIN. RESULTS: OVEREXPRESSIONS OF EZH2 AND H3K27ME3 WERE CONFIRMED IN SPINAL MICROGLIA OF CCI RATS BY IMMUNOFLUORESCENCE. CGRP TREATMENT INDUCED THE INCREASED OF H3K27ME3 EXPRESSION IN THE SPINAL DORSAL HORN AND CULTURED MICROGLIAL CELLS (BV2) THROUGH EZH2. CHIP-SEQ DATA INDICATED THAT CGRP SIGNIFICANTLY ALTERED H3K27ME3 ENRICHMENTS ON GENE PROMOTERS IN MICROGLIA FOLLOWING CGRP TREATMENT, INCLUDING 173 GAINING H3K27ME3 AND 75 LOSING THIS MARK, WHICH MOSTLY ENRICHED IN REGULATION OF CELL GROWTH, PHAGOSOME, AND INFLAMMATION. QRT-PCR VERIFIED EXPRESSIONS OF REPRESENTATIVE CANDIDATE GENES (TRAF3IP2, BCL2L11, ITGAM, DAB2, NLRP12, WNT3, ADAM10) AND REAL-TIME CELL ANALYSIS (RTCA) VERIFIED MICROGLIAL PROLIFERATION. ADDITIONALLY, CGRP TREATMENT AND CCI INCREASED EXPRESSIONS OF ITGAM, ADAM10, MCP-1, AND CX3CR1, KEY MEDIATORS OF MICROGLIAL ACTIVATION IN SPINAL DORSAL HORN AND CULTURED MICROGLIAL CELLS. SUCH INCREASED EFFECTS INDUCED BY CCI WERE SUPPRESSED BY CGRP ANTAGONIST AND EZH2 INHIBITOR, WHICH WERE CONCURRENTLY ASSOCIATED WITH THE ATTENUATED MECHANICAL AND THERMAL HYPERALGESIA IN CCI RATS. CONCLUSION: OUR FINDINGS HIGHLY INDICATE THAT CGRP IS IMPLICATED IN THE GENESIS OF NEUROPATHIC PAIN THROUGH REGULATING MICROGLIAL ACTIVATION VIA EZH2-MEDIATED H3K27ME3 IN THE SPINAL DORSAL HORN. 2021 16 2784 22 EZH2 PROMOTES EXTRACELLULAR MATRIX DEGRADATION VIA NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN PULPITIS. PULPITIS IS A COMPLICATED CHRONIC INFLAMMATORY PROCESS WHICH CAN BE IN A DYNAMIC BALANCE BETWEEN DAMAGE AND REPAIR. THE EXTRACELLULAR MATRIX PLAYS AN IMPORTANT REGULATORY ROLE IN WOUND HEALING AND TISSUE REPAIR. THE AIM OF THIS STUDY WAS TO EXPLORE THE ROLE OF THE EPIGENETIC MARK, ENHANCER OF ZESTE HOMOLOG 2 (EZH2) ON THE DEGRADATION OF EXTRACELLULAR MATRIX DURING PULPITIS. QUANTITATIVE POLYMERASE CHAIN REACTION WAS USED TO ASSESS THE EXPRESSION OF MATRIX METALLOPROTEINASES (MMPS) AND TYPE I COLLAGEN IN HUMAN DENTAL PULP CELLS (HDPCS) UPON EZH2 AND EI1 (EZH2 INHIBITOR) STIMULATION. THE MECHANISM OF EZH2 AFFECTING EXTRACELLULAR MATRIX WAS EXPLORED THROUGH QUANTITATIVE POLYMERASE CHAIN REACTION AND WESTERN BLOT. A RAT MODEL OF DENTAL PULP INFLAMMATION WAS ESTABLISHED, AND THE EXPRESSION OF TYPE I COLLAGEN IN DENTAL PULP UNDER EZH2 STIMULATION WAS DETECTED BY IMMUNOHISTOCHEMICAL STAINING. EZH2 UPREGULATED THE EXPRESSION OF MMP-1, MMP-3, MMP-8, AND MMP-10 AND DECREASED THE PRODUCTION OF TYPE I COLLAGEN IN HDPCS, WHILE EI1 HAD THE OPPOSITE EFFECT. EZH2 ACTIVATED THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN HDPCS, THE INHIBITION OF WHICH REVERSED THE INDUCTION OF MMPS AND THE SUPPRESSION OF TYPE I COLLAGEN. EZH2 CAN DOWNREGULATE THE TYPE I COLLAGEN LEVELS IN AN EXPERIMENTAL MODEL OF DENTAL PULPITIS IN RATS. EZH2 PROMOTES EXTRACELLULAR MATRIX DEGRADATION VIA NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN PULPITIS. EZH2 CAN DECREASE THE TYPE I COLLAGEN LEVELS IN VIVO AND IN VITRO. 2021 17 1210 29 COX2 ENHANCES NEOVASCULARIZATION OF INFLAMMATORY TENOCYTES THROUGH THE HIF-1ALPHA/VEGFA/PDGFB PATHWAY. TENDON INJURIES ARE AMONG THE MOST CHALLENGING IN ORTHOPEDICS. DURING THE EARLY TENDON REPAIR, NEW BLOOD VESSEL FORMATION IS NECESSARY. HOWEVER, EXCESSIVE ANGIOGENESIS ALSO EXACERBATES SCAR FORMATION, LEADING TO PAIN AND DYSFUNCTION. A SIGNIFICANTLY WORSE OUTCOME WAS ASSOCIATED WITH HIGHER EXPRESSION LEVELS OF HYPOXIA-INDUCIBLE FACTOR-1 ALPHA (HIF-1ALPHA), AND ITS TRANSCRIPTIONAL TARGETS VASCULAR ENDOTHELIAL GROWTH FACTOR A (VEGFA) AND PLATELET-DERIVED GROWTH FACTOR B (PDGFB), BUT THE UNDERLYING MOLECULAR MECHANISMS REMAIN UNCLEAR. IN THIS STUDY, LIPOPOLYSACCHARIDE (LPS) WAS USED TO INDUCE AN INFLAMMATORY RESPONSE IN TENOCYTES. LPS INCREASED THE TENOCYTES' INFLAMMATORY FACTOR COX2 EXPRESSION AND ACTIVATED THE HIF-1ALPHA/VEGFA/PDGFB PATHWAY. MOREOVER, THE CONDITIONED MEDIUM FROM THE TENOCYTES BOOSTED RAT AORTIC VASCULAR ENDOTHELIAL CELL (RAOEC) ANGIOGENESIS. FURTHERMORE, TRICHOSTATIN A (TSA), AN INHIBITOR OF HISTONE DEACETYLASE, WAS USED TO TREAT INFLAMMATORY TENOCYTES. THE EXPRESSION LEVELS OF HIF-1ALPHA AND ITS TRANSCRIPTIONAL TARGETS VEGFA AND PDGFB DECREASED, RESULTING IN RAOEC ANGIOGENESIS INHIBITION. FINALLY, THE DUAL-LUCIFERASE REPORTER GENE ASSAY AND CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAY PROVED THAT THE HIF-1ALPHA/PDGFB PATHWAY PLAYED A MORE CRITICAL ROLE IN TENOCYTE ANGIOGENESIS THAN THE HIF-1ALPHA/VEGFA PATHWAY. TSA COULD ALLEVIATE ANGIOGENESIS MAINLY THROUGH EPIGENETIC REGULATION OF THE HIF-1ALPHA/PDGFB PATHWAY. TAKEN TOGETHER, TSA MIGHT BE A PROMISING ANTI-ANGIOGENESIS DRUG FOR ABNORMAL ANGIOGENESIS, WHICH IS INDUCED BY TENDON INJURIES. 2021 18 664 25 BLOOD REFLUX-INDUCED EPIGENETIC FACTORS HDACS AND DNMTS ARE ASSOCIATED WITH THE DEVELOPMENT OF HUMAN CHRONIC VENOUS DISEASE. BLOOD REFLUX AND METABOLIC REGULATION PLAY IMPORTANT ROLES IN CHRONIC VENOUS DISEASE (CVD) DEVELOPMENT. HISTONE DEACETYLASES (HDACS) AND DNA METHYLTRANSFERASES (DNMTS) SERVE AS REPRESSORS THAT INHIBIT METABOLIC SIGNALING, WHICH IS INDUCED BY PROATHEROGENIC FLOW TO PROMOTE AORTIC ENDOTHELIAL CELL (EC) DYSFUNCTION AND ATHEROSCLEROSIS. THE AIM OF THIS STUDY WAS TO ELUCIDATE THE RELATIONSHIP BETWEEN BLOOD REFLUX AND EPIGENETIC FACTORS HDACS AND DNMTS IN CVD. HUMAN VARICOSE VEINS WITH DIFFERENT LEVELS OF BLOOD REFLUX VERSUS NORMAL VEINS WITH NORMAL VENOUS FLOW WERE EXAMINED. THE RESULTS SHOW THAT HDAC-1, -2, -3, -5, AND -7 ARE OVEREXPRESSED IN THE ENDOTHELIUM OF VARICOSE VEINS WITH BLOOD REFLUX. BLOOD REFLUX-INDUCED HDACS ARE ENHANCED IN THE VARICOSE VEINS WITH A LONGER DURATION TIME OF BLOOD REFLUX. IN CONTRAST, THESE HDACS ARE RARELY EXPRESSED IN THE ENDOTHELIUM OF THE NORMAL VEIN WITH NORMAL VENOUS FLOW. SIMILAR RESULTS ARE OBTAINED FOR DNMT1 AND DNMT3A. OUR FINDINGS SUGGEST THAT THE EPIGENETIC FACTORS, HDACS AND DNMTS, ARE INDUCED IN VENOUS ECS IN RESPONSE TO BLOOD REFLUX BUT ARE INHIBITED IN RESPONSE TO NORMAL VENOUS FLOW. BLOOD REFLUX-INDUCED HDACS AND DNMTS COULD INHIBIT METABOLIC REGULATION AND PROMOTE VENOUS EC DYSFUNCTION, WHICH IS HIGHLY CORRELATED WITH CVD PATHOGENESIS. 2022 19 5122 31 POSSIBLE ROLE OF FRUCTOSAMINE 3-KINASE GENOTYPING FOR THE MANAGEMENT OF DIABETIC PATIENTS. DIABETES MELLITUS IS A GLOBAL PANDEMIC AND CONTINUES TO INCREASE IN NUMBERS AND SIGNIFICANCE. SEVERAL PATHOGENIC PROCESSES ARE INVOLVED IN THE DEVELOPMENT OF SUCH DISEASE AND THESE MECHANISMS COULD BE INFLUENCED BY GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. NON-ENZYMATIC GLYCATION REACTIONS OF PROTEINS HAVE BEEN STRONGLY RELATED TO PATHOGENESIS OF CHRONIC DIABETIC COMPLICATIONS. THE IDENTIFICATION OF FRUCTOSAMINE 3-KINASE (FN3K), AN ENZYME INVOLVED IN PROTEIN DEGLYCATION, A NEW FORM OF PROTEIN REPAIR, IS OF GREAT INTEREST. FN3K PHOSPHORYLATES FRUCTOSAMINES ON THE THIRD CARBON OF THEIR SUGAR MOIETY, MAKING THEM UNSTABLE AND CAUSING THEM TO DETACH FROM PROTEINS, SUGGESTING A PROTECTIVE ROLE OF THIS ENZYME. MOREOVER, THE VARIABILITY IN FN3K ACTIVITY HAS BEEN ASSOCIATED WITH SOME POLYMORPHISMS IN THE FN3K GENE. HERE WE ARGUE ABOUT GENETIC STUDIES AND EVIDENCE OF FN3K INVOLVEMENT IN DIABETES, TOGETHER WITH RESULTS OF OUR ANALYSIS OF THE FN3K GENE ON A CAUCASIAN COHORT OF DIABETIC PATIENTS. PRESENT KNOWLEDGE SUGGESTS THAT FN3K COULD ACT IN CONCERT WITH OTHER MOLECULAR MECHANISMS AND MAY IMPACT ON GENE EXPRESSION AND ACTIVITY OF OTHER ENZYMES INVOLVED IN DEGLYCATION PROCESS. 2015 20 6516 30 TRANSCRIPTIONAL AND EPIGENETIC FACTORS ASSOCIATED WITH EARLY THROMBOSIS OF FEMORAL ARTERY INVOLVED IN ARTERIOVENOUS FISTULA. ARTERIOVENOUS FISTULAS (AVFS), CREATED FOR HEMODIALYSIS IN END-STAGE RENAL DISEASE PATIENTS, MATURE THROUGH THE OUTWARD REMODELING OF THE OUTFLOW VEIN. HOWEVER, EARLY THROMBOSIS AND CHRONIC INFLAMMATION ARE DETRIMENTAL TO THE PROCESS OF AVF MATURATION AND PRECIPITATE AVF MATURATION FAILURE. FOR THE SUCCESSFUL REMODELING OF THE OUTFLOW VEIN, BLOOD FLOW THROUGH THE FISTULA IS ESSENTIAL, BUT EARLY ARTERIAL THROMBOSIS ATTENUATES THIS BLOOD FLOW, AND THE VESSELS BECOME THROMBOSED AND STENOSED, LEADING TO AVF FAILURE. THE ALTERED EXPRESSION OF VARIOUS PROTEINS INVOLVED IN MAINTAINING VESSEL PATENCY OR THROMBOSIS IS REGULATED BY GENES OF WHICH THE EXPRESSION IS REGULATED BY TRANSCRIPTION FACTORS AND MICRORNAS. IN THIS STUDY, USING THROMBOSED AND STENOSED ARTERIES FOLLOWING AVF CREATION, WE DELINEATED TRANSCRIPTION FACTORS AND MICRORNAS ASSOCIATED WITH DIFFERENTIALLY EXPRESSED GENES IN BULK RNA SEQUENCING DATA USING UPSTREAM AND CAUSAL NETWORK ANALYSIS. WE OBSERVED CHANGES IN MANY TRANSCRIPTION FACTORS AND MICRORNAS THAT ARE INVOLVED IN ANGIOGENESIS; VASCULAR SMOOTH MUSCLE CELL PROLIFERATION, MIGRATION, AND PHENOTYPIC CHANGES; ENDOTHELIAL CELL FUNCTION; HYPOXIA; OXIDATIVE STRESS; VESSEL REMODELING; IMMUNE RESPONSES; AND INFLAMMATION. THESE FACTORS AND MICRORNAS PLAY A CRITICAL ROLE IN THE UNDERLYING MOLECULAR MECHANISMS IN AVF MATURATION. WE ALSO OBSERVED EPIGENETIC FACTORS INVOLVED IN GENE REGULATION ASSOCIATED WITH THESE MOLECULAR MECHANISMS. THE RESULTS OF THIS STUDY INDICATE THE IMPORTANCE OF INVESTIGATING THE TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF AVF MATURATION AND MATURATION FAILURE AND TARGETING FACTORS PRECIPITATING EARLY THROMBOSIS AND STENOSIS. 2022