1  4501 88 MORPHOGENS AND HEPATIC STELLATE CELL FATE REGULATION IN CHRONIC LIVER DISEASE. HEPATIC STELLATE CELLS (HSC) ARE THE LIVER MESENCHYMAL CELL TYPE WHICH RESPONDS TO HEPATOCELLULAR DAMAGE AND PARTICIPATES IN WOUND HEALING. ALTHOUGH HSC MYOFIBROBLASTIC TRANS-DIFFERENTIATION (ACTIVATION) IS IMPLICATED IN EXCESSIVE EXTRACELLULAR MATRIX DEPOSITION, MOLECULAR UNDERSTANDING OF THIS PHENOTYPIC SWITCH FROM THE VIEWPOINT OF CELL FATE REGULATION IS LIMITED. RECENT STUDIES DEMONSTRATE THE ROLES OF ANTI-ADIPOGENIC MORPHOGENS (WNT, NECDIN, SHH) IN EPIGENETIC REPRESSION OF THE HSC DIFFERENTIATION GENE PPARGAMMA AS A CAUSAL EVENT IN HSC ACTIVATION. THESE MORPHOGENS HAVE POSITIVE CROSS-INTERACTIONS WHICH CONVERGE TO EPIGENETIC REPRESSION OF PPARGAMMA INVOLVING THE METHYL-CPG BINDING PROTEIN MECP2. HOWEVER, THESE MORPHOGENS EXPRESSED BY ACTIVATED HSC MAY ALSO PARTICIPATE IN CROSS-TALK BETWEEN HSC AND HEPATOBLASTS/HEPATOCYTES TO SUPPORT LIVER REGENERATION, AND THEIR ABERRANT REGULATION MAY CONTRIBUTE TO LIVER TUMORIGENESIS. IMPLICATIONS OF HSC-DERIVED MORPHOGENS IN THESE POSSIBILITIES ARE DISCUSSED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2  6757 46 WNT SIGNALING IN LIVER FIBROSIS: PROGRESS, CHALLENGES AND POTENTIAL DIRECTIONS. LIVER FIBROSIS IS A COMMON WOUND-HEALING RESPONSE TO CHRONIC LIVER INJURIES, INCLUDING ALCOHOLIC OR DRUG TOXICITY, PERSISTENT VIRAL INFECTION, AND GENETIC FACTORS. MYOFIBROBLASTIC TRANSDIFFERENTIATION (MTD) IS THE PIVOTAL EVENT DURING LIVER FIBROGENESIS, AND RESEARCH IN THE PAST FEW YEARS HAS IDENTIFIED KEY MEDIATORS AND MOLECULAR MECHANISMS RESPONSIBLE FOR MTD OF HEPATIC STELLATE CELLS (HSCS). HSCS ARE UNDIFFERENTIATED CELLS WHICH PLAY AN IMPORTANT ROLE IN LIVER REGENERATION. RECENT EVIDENCE DEMONSTRATES THAT HSCS DERIVE FROM MESODERM AND AT LEAST IN PART VIA SEPTUM TRANSVERSUM AND MESOTHELIUM, AND HSCS EXPRESS MARKERS FOR DIFFERENT CELL TYPES WHICH DERIVE FROM MULTIPOTENT MESENCHYMAL PROGENITORS. THERE IS A REGULATORY COMMONALITY BETWEEN DIFFERENTIATION OF ADIPOCYTES AND THAT OF HSC, AND THE SHIFT FROM ADIPOGENIC TO MYOGENIC OR NEURONAL PHENOTYPE CHARACTERIZES HSC MTD. CENTRAL OF THIS SHIFT IS A LOSS OF EXPRESSION OF THE MASTER ADIPOGENIC REGULATOR PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA (PPARGAMMA). RESTORED EXPRESSION OF PPARGAMMA AND/OR OTHER ADIPOGENIC TRANSCRIPTION GENES CAN REVERSE MYOFIBROBLASTIC HSCS TO DIFFERENTIATED CELLS. VERTEBRATE WNT AND DROSOPHILA WINGLESS ARE HOMOLOGOUS GENES, AND THEIR TRANSLATED PROTEINS HAVE BEEN SHOWN TO PARTICIPATE IN THE REGULATION OF CELL PROLIFERATION, CELL POLARITY, CELL DIFFERENTIATION, AND OTHER BIOLOGICAL ROLES. MORE RECENTLY, WNT SIGNALING IS IMPLICATED IN HUMAN FIBROSING DISEASES, SUCH AS PULMONARY FIBROSIS, RENAL FIBROSIS, AND LIVER FIBROSIS. BLOCKING THE CANONICAL WNT SIGNAL PATHWAY WITH THE CO-RECEPTOR ANTAGONIST DICKKOPF-1 (DKK1) ABROGATES THESE EPIGENETIC REPRESSIONS AND RESTORES THE GENE PPARGAMMA EXPRESSION AND HSC DIFFERENTIATION. THE IDENTIFIED MORPHOGEN MEDIATED EPIGENETIC REGULATION OF PPARGAMMA AND HSC DIFFERENTIATION ALSO SERVES AS NOVEL THERAPEUTIC TARGETS FOR LIVER FIBROSIS AND LIVER REGENERATION. IN CONCLUSION, THE WNT SIGNALING PROMOTES LIVER FIBROSIS BY ENHANCING HSC ACTIVATION AND SURVIVAL, AND WE HEREIN DISCUSS WHAT WE CURRENTLY KNOW AND WHAT WE EXPECT WILL COME IN THIS FIELD IN THE NEXT FUTURE.	2013	
                                                                                                      
3  5555 22 ROLE OF FLUORIDE INDUCED EPIGENETIC ALTERATIONS IN THE DEVELOPMENT OF SKELETAL FLUOROSIS. FLUORIDE IS AN ESSENTIAL TRACE ELEMENT REQUIRED FOR PROPER BONE AND TOOTH DEVELOPMENT. SYSTEMIC HIGH EXPOSURE TO FLUORIDE THROUGH ENVIRONMENTAL EXPOSURE (DRINKING WATER AND FOOD) MAY RESULT IN TOXICITY CAUSING A DISORDER CALLED FLUOROSIS. IN THE PRESENT STUDY, WE INVESTIGATED THE ALTERATION IN DNA METHYLATION PROFILE WITH CHRONIC EXPOSURE (30 DAYS) TO FLUORIDE (8 MG/L) AND ITS RELEVANCE IN THE DEVELOPMENT OF FLUOROSIS. WHOLE GENOME BISULFITE SEQUENCING (WGBS) WAS CARRIED OUT IN HUMAN OSTEOSARCOMA CELLS (HOS) EXPOSED TO FLUORIDE. WHOLE GENOME BISULFITE SEQUENCING (WGBS) AND FUNCTIONAL ANNOTATION OF DIFFERENTIALLY METHYLATED GENES INDICATE ALTERATIONS IN METHYLATION STATUS OF GENES INVOLVED IN BIOLOGICAL PROCESSES ASSOCIATED WITH BONE DEVELOPMENT PATHWAYS. COMBINED ANALYSIS OF PROMOTER DNA HYPER METHYLATION, STRING: FUNCTIONAL PROTEIN ASSOCIATION NETWORKS AND GENE EXPRESSION ANALYSIS REVEALED EPIGENETIC ALTERATIONS IN BMP1, METAP2, MMP11 AND BACH1 GENES, WHICH PLAYS A ROLE IN THE EXTRACELLULAR MATRIX DISASSEMBLY, COLLAGEN CATABOLIC/ORGANIZATION PROCESS, SKELETAL MORPHOGENESIS/DEVELOPMENT, OSSIFICATION AND OSTEOBLAST DEVELOPMENT. THE PRESENT STUDY SHOWS THAT FLUORIDE CAUSES PROMOTER DNA HYPERMETHYLATION IN BMP1, METAP2, MMP11 AND BACH1 GENES WITH SUBSEQUENT DOWN-REGULATION IN THEIR EXPRESSION LEVEL (RNA LEVEL). THE RESULTS IMPLIES THAT FLUORIDE INDUCED DNA HYPERMETHYLATION OF THESE GENES MAY HAMPER EXTRACELLULAR MATRIX DEPOSITION, CARTILAGE FORMATION, ANGIOGENESIS, VASCULAR SYSTEM DEVELOPMENT AND POROSITY OF BONE, THUS PROMOTE SKELETAL FLUOROSIS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4  4199 35 METABOLIC REPROGRAMMING AND CELL FATE REGULATION IN ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) SHOULD BE DEFINED AS A LIFE-STYLE METABOLIC DISEASE. ITS PATHOGENESIS IS DRIVEN BY ALTERED CELL FATE OF BOTH PARENCHYMAL AND NON-PARENCHYMAL LIVER CELL TYPES, CONTRIBUTING TO DIFFERENT PATHOLOGIC SPECTRA. A CRITICAL TURNING POINT IN PROGRESSION OF ALD IS CHRONIC ALCOHOLIC STEATOHEPATITIS (ASH) OR ALCOHOLIC NEUTROPHILIC HEPATITIS (AH), WHICH MARKEDLY PREDISPOSES PATIENTS TO MOST DEVASTATING ALD SEQUELA, CIRRHOSIS AND LIVER CANCER. RESULTS: OUR RESEARCH IDENTIFIES THE PIVOTAL ROLES OF UNIQUE METABOLIC REPROGRAMMING IN M1 ACTIVATION OF HEPATIC MACROPHAGES (HM) AND MYOFIBROBLASTIC ACTIVATION (MF) OF HEPATIC STELLATE CELLS (HSC) IN THE GENESIS OF INFLAMMATION AND FIBROSIS, THE TWO KEY HISTOLOGICAL FEATURES OF CHRONIC ASH AND NEUTROPHILIC AH. FOR M1 HM ACTIVATION, HEIGHTENED PROINFLAMMATORY IRON REDOX SIGNALING IN ENDOSOMES OR CAVEOSOMES RESULTS FROM ALTERED IRON METABOLISM AND STORAGE, PROMOTING IKK/NF-KB ACTIVATION VIA INTERACTIVE ACTIVATION OF P21RAS, TAK1, AND PI3K. FOR MF CELL FATE REGULATION OF HSC, ACTIVATION OF THE MORPHOGEN WNT PATHWAY CAUSED BY THE NUCLEAR PROTEIN NECDIN OR THE SINGLE-PASS TRANS-MEMBRANE PROTEIN DLK1, REPROGRAMS LIPID METABOLISM VIA MECP2-MEDIATED EPIGENETIC REPRESSION OF THE KEY HSC QUIESCENCE GENE PPAR-GAMMA. CONCLUSIONS: THE FINDINGS FROM THESE STUDIES RE-ENFORCE THE IMPORTANCE OF METABOLIC REPROGRAMMING IN CELL FATE REGULATION REQUIRED FOR THE PATHOGENESIS OF ALD.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
5  3835 24 IONISING RADIATION INDUCES PROMOTER DNA HYPOMETHYLATION AND PERTURBS TRANSCRIPTIONAL ACTIVITY OF GENES INVOLVED IN MORPHOGENESIS DURING GASTRULATION IN ZEBRAFISH. EMBRYONIC DEVELOPMENT IS PARTICULARLY VULNERABLE TO STRESS AND DNA DAMAGE, AS MUTATIONS CAN ACCUMULATE THROUGH CELL PROLIFERATION IN A WIDE NUMBER OF CELLS AND ORGANS. HOWEVER, THE BIOLOGICAL EFFECTS OF CHRONIC EXPOSURE TO IONISING RADIATION (IR) AT LOW AND MODERATE DOSE RATES (< 6 MGY/H) REMAIN LARGELY CONTROVERSIAL, RAISING CONCERNS FOR ENVIRONMENTAL PROTECTION. THE PRESENT STUDY FOCUSES ON THE MOLECULAR EFFECTS OF IR (0.005 TO 50 MGY/H) ON ZEBRAFISH EMBRYOS AT THE GASTRULA STAGE (6 HPF), AT BOTH THE TRANSCRIPTOMICS AND EPIGENETICS LEVELS. OUR RESULTS SHOW THAT EXPOSURE TO IR MODIFIES THE EXPRESSION OF GENES INVOLVED IN MITOCHONDRIAL ACTIVITY FROM 0.5 TO 50 MGY/H. IN ADDITION, IMPORTANT DEVELOPMENTAL PATHWAYS, NAMELY, THE NOTCH, RETINOIC ACID, BMP AND WNT SIGNALLING PATHWAYS, WERE ALTERED AT 5 AND 50 MGY/H. TRANSCRIPTIONAL CHANGES OF GENES INVOLVED IN THE MORPHOGENESIS OF THE ECTODERM AND MESODERM WERE DETECTED AT ALL DOSE RATES, BUT WERE PROMINENT FROM 0.5 TO 50 MGY/H. AT THE EPIGENETIC LEVEL, EXPOSURE TO IR INDUCED A HYPOMETHYLATION OF DNA IN THE PROMOTER OF GENES THAT COLOCALISED WITH BOTH H3K27ME3 AND H3KME4 HISTONE MARKS AND CORRELATED WITH CHANGES IN TRANSCRIPTIONAL ACTIVITY. FINALLY, PATHWAY ENRICHMENT ANALYSIS DEMONSTRATED THAT THE DNA METHYLATION CHANGES OCCURRED IN THE PROMOTER OF IMPORTANT DEVELOPMENTAL GENES, INCLUDING MORPHOGENESIS OF THE ECTODERM AND MESODERM. TOGETHER, THESE RESULTS SHOW THAT THE TRANSCRIPTIONAL PROGRAM REGULATING MORPHOGENESIS IN GASTRULATING EMBRYOS WAS MODIFIED AT DOSE RATES GREATER THAN OR EQUAL TO 0.5 MGY/H, WHICH MIGHT PREDICT POTENTIAL NEUROGENESIS AND SOMITOGENESIS DEFECTS OBSERVED AT SIMILAR DOSE RATES LATER IN DEVELOPMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                 
6  1092 25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7  4483 23 MOLECULAR REGULATION OF MAMMALIAN HEPATIC ARCHITECTURE. THE ESSENTIAL LIVER EXOCRINE AND ENDOCRINE FUNCTIONS REQUIRE A PRECISE SPATIAL ARRANGEMENT OF THE HEPATIC LOBULE CONSISTING OF THE CENTRAL VEIN, PORTAL VEIN, HEPATIC ARTERY, INTRAHEPATIC BILE DUCT SYSTEM, AND HEPATOCYTE ZONATION. THIS ALLOWS BLOOD TO BE CARRIED THROUGH THE LIVER PARENCHYMA SAMPLED BY ALL HEPATOCYTES AND BILE PRODUCED BY THE HEPATOCYTES TO BE CARRIED OUT OF THE LIVER THROUGH THE INTRAHEPATIC BILE DUCT SYSTEM COMPOSED OF CHOLANGIOCYTES. THE MOLECULAR ORCHESTRATION OF MULTIPLE SIGNALING PATHWAYS AND EPIGENETIC FACTORS IS REQUIRED TO SET UP LINEAGE RESTRICTION OF THE BIPOTENTIAL HEPATOBLAST PROGENITOR INTO THE HEPATOCYTE AND CHOLANGIOCYTE CELL LINEAGES, AND TO FURTHER REFINE CELL FATE HETEROGENEITY WITHIN EACH CELL LINEAGE REFLECTED IN THE FUNCTIONAL HETEROGENEITY OF HEPATOCYTES AND CHOLANGIOCYTES. IN ADDITION TO THE COMPLEX MOLECULAR REGULATION, THERE IS A COMPLICATED MORPHOGENETIC CHOREOGRAPHY OBSERVED IN BUILDING THE REFINED HEPATIC EPITHELIAL ARCHITECTURE. GIVEN THE MULTIFACETED MOLECULAR AND CELLULAR REGULATION, IT IS NOT SURPRISING THAT IMPAIRMENT OF ANY OF THESE PROCESSES CAN RESULT IN ACUTE AND CHRONIC HEPATOBILIARY DISEASES. TO ENLIGHTEN THE DEVELOPMENT OF POTENTIAL MOLECULAR AND CELLULAR TARGETS FOR THERAPEUTIC OPTIONS, AN UNDERSTANDING OF HOW THE INTRICATE HEPATIC MOLECULAR AND CELLULAR INTERACTIONS ARE REGULATED IS IMPERATIVE. HERE, WE REVIEW THE SIGNALING PATHWAYS AND EPIGENETIC FACTORS REGULATING HEPATIC CELL LINEAGES, FATES, AND EPITHELIAL ARCHITECTURE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  3064 21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9  5939 39 TARGETING MECHANOTRANSDUCTION AT THE TRANSCRIPTIONAL LEVEL: YAP AND BRD4 ARE NOVEL THERAPEUTIC TARGETS FOR THE REVERSAL OF LIVER FIBROSIS. LIVER FIBROSIS IS THE RESULT OF A DEREGULATED WOUND HEALING PROCESS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX. HEPATIC STELLATE CELLS (HSCS), WHICH ARE ACTIVATED IN RESPONSE TO LIVER INJURY, ARE THE MAJOR SOURCE OF EXTRACELLULAR MATRIX AND DRIVE THE WOUND HEALING PROCESS. HOWEVER, CHRONIC LIVER DAMAGE LEADS TO PERPETUAL HSC ACTIVATION, PROGRESSIVE FORMATION OF PATHOLOGICAL SCAR TISSUE AND ULTIMATELY, CIRRHOSIS AND ORGAN FAILURE. HSC ACTIVATION IS TRIGGERED LARGELY IN RESPONSE TO MECHANOSIGNALING FROM THE MICROENVIRONMENT, WHICH INDUCES A PROFIBROTIC NUCLEAR TRANSCRIPTION PROGRAM THAT PROMOTES HSC PROLIFERATION AND EXTRACELLULAR MATRIX SECRETION THEREBY SETTING UP A POSITIVE FEEDBACK LOOP LEADING TO MATRIX STIFFENING AND SELF-SUSTAINED, PATHOLOGICAL, HSC ACTIVATION. DESPITE THE SIGNIFICANT PROGRESS IN OUR UNDERSTANDING OF LIVER FIBROSIS, THE MOLECULAR MECHANISMS THROUGH WHICH THE EXTRACELLULAR MATRIX PROMOTES HSC ACTIVATION ARE NOT WELL UNDERSTOOD AND NO EFFECTIVE THERAPIES HAVE BEEN APPROVED TO DATE THAT CAN TARGET THIS EARLY, REVERSIBLE, STAGE IN LIVER FIBROSIS. SEVERAL NEW LINES OF INVESTIGATION NOW PROVIDE IMPORTANT INSIGHT INTO THIS AREA OF STUDY AND IDENTIFY TWO NUCLEAR TARGETS WHOSE INHIBITION HAS THE POTENTIAL OF REVERSING LIVER FIBROSIS BY INTERFERING WITH HSC ACTIVATION: YES-ASSOCIATED PROTEIN (YAP), A TRANSCRIPTIONAL CO-ACTIVATOR AND EFFECTOR OF THE MECHANOSENSITIVE HIPPO PATHWAY, AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), AN EPIGENETIC REGULATOR OF GENE EXPRESSION. YAP AND BRD4 ACTIVITY IS INDUCED IN RESPONSE TO MECHANICAL STIMULATION OF HSCS AND EACH PROTEIN INDEPENDENTLY CONTROLS WAVES OF EARLY GENE EXPRESSION NECESSARY FOR HSC ACTIVATION. SIGNIFICANTLY, INHIBITION OF EITHER PROTEIN CAN REVERT THE CHRONIC ACTIVATION OF HSCS AND IMPEDE PATHOLOGICAL PROGRESSION OF LIVER FIBROSIS IN CLINICALLY RELEVANT MODEL SYSTEMS. IN THIS REVIEW WE WILL DISCUSS THE ROLES OF THESE NUCLEAR CO-ACTIVATORS IN HSC ACTIVATION, THEIR MECHANISM OF ACTION IN THE FIBROTIC PROCESS IN THE LIVER AND OTHER ORGANS, AND THE POTENTIAL OF TARGETING THEIR ACTIVITY WITH SMALL MOLECULE DRUGS FOR FIBROSIS REVERSAL.	2016	

10  2380 23 EPIGENETIC REGULATION OF WNT SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA. CERTAIN WNT AND WNT NETWORK TARGET GENES ARE EXPRESSED AT HIGHER OR LOWER LEVELS IN CHRONIC LYMPHOCYTIC LEUKEMIA COMPARED WITH NORMAL B-CELLS. THIS INCLUDES UPREGULATION OF NUCLEAR COMPLEX GENES, AS WELL AS GENES FOR CYTOPLASMIC PROTEINS AND WNT LIGANDS AND THEIR COGNATE RECEPTORS. IN ADDITION, EPIGENETIC SILENCING OF SEVERAL NEGATIVE REGULATORS OF THE WNT PATHWAY HAVE BEEN IDENTIFIED. THE BALANCE BETWEEN EPIGENETIC DOWNREGULATION OF NEGATIVE EFFECTOR GENES AND INCREASED EXPRESSION OF POSITIVE EFFECTOR GENES DEMONSTRATE THAT THE EPIGENETIC DOWNREGULATION OF WNT ANTAGONISTS IS ONE MECHANISM, PERHAPS THE MAIN MECHANISM, THAT IS PERMISSIVE TO ACTIVE WNT SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA. MOREOVER, CONSTITUTIVE ACTIVATION OF THE WNT NETWORK AND TARGET GENES IS LIKELY TO IMPACT ON ADDITIONAL INTERACTING SIGNALING PATHWAYS. BASED ON PUBLISHED STUDIES, WE PROPOSE A MODEL OF WNT SIGNALING THAT INVOLVES MAINLY PERMISSIVE EXPRESSION, AND SOMETIMES OVEREXPRESSION, OF POSITIVE EFFECTORS AND DOWNREGULATION OF NEGATIVE REGULATORS IN THE NETWORK. IN THIS MODEL, DNA METHYLATION, HISTONE MODIFICATIONS AND ALTERED EXPRESSION OF MICRORNA MOLECULES INTERACT TO ALLOW CONTINUOUS WNT SIGNALING.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
11  4605 25 NEGATIVE REGULATORS OF TGF-BETA1 SIGNALING IN RENAL FIBROSIS; PATHOLOGICAL MECHANISMS AND NOVEL THERAPEUTIC OPPORTUNITIES. ELEVATED EXPRESSION OF THE MULTIFUNCTIONAL CYTOKINE TRANSFORMING GROWTH FACTOR BETA1 (TGF-BETA1) IS CAUSATIVELY LINKED TO KIDNEY FIBROSIS PROGRESSION INITIATED BY DIABETIC, HYPERTENSIVE, OBSTRUCTIVE, ISCHEMIC AND TOXIN-INDUCED INJURY. THERAPEUTICALLY RELEVANT APPROACHES TO DIRECTLY TARGET THE TGF-BETA1 PATHWAY (E.G., NEUTRALIZING ANTIBODIES AGAINST TGF-BETA1), HOWEVER, REMAIN ELUSIVE IN HUMANS. TGF-BETA1 SIGNALING IS SUBJECTED TO EXTENSIVE NEGATIVE CONTROL AT THE LEVEL OF TGF-BETA1 RECEPTOR, SMAD2/3 ACTIVATION, COMPLEX ASSEMBLY AND PROMOTER ENGAGEMENT DUE TO ITS CRITICAL ROLE IN TISSUE HOMEOSTASIS AND NUMEROUS PATHOLOGIES. PROGRESSIVE KIDNEY INJURY IS ACCOMPANIED BY THE DEREGULATION (LOSS OR GAIN OF EXPRESSION) OF SEVERAL NEGATIVE REGULATORS OF THE TGF-BETA1 SIGNALING CASCADE BY MECHANISMS INVOLVING PROTEIN AND MRNA STABILITY OR EPIGENETIC SILENCING, FURTHER AMPLIFYING TGF-BETA1/SMAD3 SIGNALING AND FIBROSIS. EXPRESSION OF BONE MORPHOGENETIC PROTEINS 6 AND 7 (BMP6/7), SMAD7, SLOAN-KETTERING INSTITUTE PROTO-ONCOGENE (SKI) AND SKI-RELATED NOVEL GENE (SNON), PHOSPHATE TENSIN HOMOLOG ON CHROMOSOME 10 (PTEN), PROTEIN PHOSPHATASE MAGNESIUM/MANGANESE DEPENDENT 1A (PPM1A) AND KLOTHO ARE DRAMATICALLY DECREASED IN VARIOUS NEPHROPATHIES IN ANIMALS AND HUMANS ALBEIT WITH DIFFERENT KINETICS WHILE THE EXPRESSION OF SMURF1/2 E3 LIGASES ARE INCREASED. SUCH DEREGULATIONS FREQUENTLY INITIATE MALADAPTIVE RENAL REPAIR INCLUDING RENAL EPITHELIAL CELL DEDIFFERENTIATION AND GROWTH ARREST, FIBROTIC FACTOR (CONNECTIVE TISSUE GROWTH FACTOR (CTGF/CCN2), PLASMINOGEN ACTIVATOR INHIBITOR TYPE-1 (PAI-1), TGF-BETA1) SYNTHESIS/SECRETION, FIBROPROLIFERATIVE RESPONSES AND INFLAMMATION. THIS REVIEW ADDRESSES HOW LOSS OF THESE NEGATIVE REGULATORS OF TGF-BETA1 PATHWAY EXACERBATES RENAL LESION FORMATION AND DISCUSSES THE THERAPEUTIC VALUE IN RESTORING THE EXPRESSION OF THESE MOLECULES IN AMELIORATING FIBROSIS, THUS, PRESENTING NOVEL APPROACHES TO SUPPRESS TGF-BETA1 HYPERACTIVATION DURING CHRONIC KIDNEY DISEASE (CKD) PROGRESSION.	2021	
                                                                                                                                              
12  1764 30 EARLY-IMMEDIATE GENE EGR1 IS ASSOCIATED WITH TGFBETA1 REGULATION OF EPIGENETIC READER BROMODOMAIN-CONTAINING PROTEIN 4 VIA THE CANONICAL SMAD3 SIGNALING IN HEPATIC STELLATE CELLS IN VITRO AND IN VIVO. UPON CHRONIC DAMAGE TO THE LIVER, MULTIPLE CYTOKINES STIMULATE HEPATIC STELLATE CELLS (HSCS), CAUSING THE ALTERATIONS OF GENE EXPRESSION PROFILES AND THUS LEADING TO HSC ACTIVATION, A KEY STEP IN LIVER FIBROGENESIS. ACTIVATED HSCS ARE THE DOMINANT CONTRIBUTORS TO LIVER FIBROSIS. BROMODOMAIN CONTAINING PROTEIN 4 (BRD4), AN IMPORTANT EPIGENETIC READER, WAS DEMONSTRATED TO CONCENTRATE ON HUNDREDS OF ENHANCERS ASSOCIATED WITH GENES INVOLVED IN MULTIPLE PROFIBROTIC PATHWAYS, THEREBY DIRECTING HSC ACTIVATION AND THE FIBROTIC RESPONSES. THE PRESENT STUDIES WERE DESIGNED TO EXAMINE THE EFFECT OF TRANSFORMING GROWTH FACTOR BETA-1 (TGFBETA1), THE MOST POTENT PRO-FIBROTIC CYTOKINE, ON BRD4 EXPRESSION IN HSCS AND, IF SO, ELUCIDATED THE UNDERLYING MECHANISMS IN VITRO AND IN VIVO. THE EXPERIMENTS EMPLOYED THE HETEROGENEOUS TGFBETA1 KNOCKOUT (TGFBETA1(+/-) ) MICE, GENE KNOCKDOWN IN VIVO, AND A MODEL OF THIOACETAMIDE (TAA)-INDUCED LIVER INJURY. THE RESULTS REVEALED THAT TGFBETA1 ENHANCED BRD4 EXPRESSION IN HSCS, WHICH WAS MEDIATED, AT LEAST, BY SMAD3 SIGNALING AND EARLY-IMMEDIATE GENE EGR1 (EARLY GROWTH RESPONSE-1). TGFBETA1-INDUCED SMAD3 SIGNALING INCREASED EGR1 EXPRESSION AND PROMOTED EGR1 BINDING TO BRD4 PROMOTER AT A SITE AROUND -111 BP, PROMOTING BRD4 EXPRESSION. EGR1 KNOCKDOWN REDUCED BRD4 EXPRESSION IN HSCS IN A MOUSE MODEL OF TAA-INDUCED LIVER INJURY AND LESSENED LIVER FIBROSIS. DOUBLE FLUORESCENCE STAINING DEMONSTRATED A STRONG INCREASE IN BRD4 EXPRESSION IN ACTIVATED HSCS IN FIBROTIC AREAS OF THE HUMAN LIVERS, PARALLELING THE UPREGULATION OF P-SMAD3 AND EGR1. THIS RESEARCH SUGGESTED NOVEL MOLECULAR EVENTS UNDERLYING THE ROLES OF THE MASTER PRO-FIBROTIC CYTOKINE TGFBETA1 IN HSC ACTIVATION AND LIVER FIBROGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                  
13  6687 18 VALIDATION OF THE EPIGENETIC READER BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A THERAPEUTIC TARGET FOR TREATMENT OF AIRWAY REMODELING. STRUCTURAL REMODELING IS CENTRAL TO THE INITIATION AND PROGRESSION OF MANY CHRONIC LUNG DISEASES, REPRESENTING AN IMPORTANT UNMET NEED. WE EXAMINE THE EVIDENCE SUPPORTING BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A VALIDATED BIOLOGICAL TARGET FOR TREATMENT OF AIRWAY REMODELING. IN EPITHELIAL CELLS AND FIBROBLASTS, BRD4 SERVES AS A SCAFFOLD FOR CHROMATIN REMODELING COMPLEXES IN ACTIVE SUPER-ENHANCERS. IN RESPONSE TO INFLAMMATORY STIMULI, BRD4 IS REPOSITIONED TO INNATE AND MESENCHYMAL GENES ACTIVATING THEIR PRODUCTION. PROOF-OF-CONCEPT STUDIES SHOW PROMISING BENEFIT OF SELECTIVE BRD4 INHIBITORS IN DISRUPTING EPITHELIAL MESENCHYMAL TRANSITION AND MYOFIBROBLAST TRANSITION IN DIVERSE MODELS OF LUNG INJURY. RECENT IDENTIFICATION OF BIOMARKERS OF BRD4 PROVIDES A BASIS FOR FURTHER DRUG DEVELOPMENT FOR APPLICATION IN VIRAL-INDUCED AIRWAY INFLAMMATION, COPD AND INTERSTITIAL LUNG DISEASES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
14  5575 27 ROLE OF MICRORNAS IN SIGNALING PATHWAYS ASSOCIATED WITH THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS: A FOCUS ON EPITHELIAL-MESENCHYMAL TRANSITION. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC AND PROGRESSIVE DISEASE WITH HIGH MORTALITY AND UNCLEAR ETIOLOGY. PREVIOUS EVIDENCE SUPPORTS THAT THE ORIGIN OF THIS DISEASE IS ASSOCIATED WITH EPIGENETIC ALTERATIONS, AGE, AND ENVIRONMENTAL FACTORS. IPF INITIATES WITH CHRONIC EPITHELIAL LUNG INJURIES, FOLLOWED BY BASAL MEMBRANE DESTRUCTION, WHICH PROMOTES THE ACTIVATION OF MYOFIBROBLASTS AND EXCESSIVE SYNTHESIS OF EXTRACELLULAR MATRIX (ECM) PROTEINS, AS WELL AS EPITHELIAL-MESENCHYMAL TRANSITION (EMT). DUE TO MIRNAS' ROLE AS REGULATORS OF APOPTOSIS, PROLIFERATION, DIFFERENTIATION, AND CELL-CELL INTERACTION PROCESSES, SOME STUDIES HAVE INVOLVED MIRNAS IN THE BIOGENESIS AND PROGRESSION OF IPF. IN THIS CONTEXT, THE ANALYSIS AND DISCUSSION OF THE PROBABLE ASSOCIATION OF MIRNAS WITH THE SIGNALING PATHWAYS INVOLVED IN THE DEVELOPMENT OF IPF WOULD IMPROVE OUR KNOWLEDGE OF THE ASSOCIATED MOLECULAR MECHANISMS, THEREBY FACILITATING ITS EVALUATION AS A THERAPEUTIC TARGET FOR THIS SEVERE LUNG DISEASE. IN THIS WORK, THE MOST RECENT PUBLICATIONS EVALUATING THE ROLE OF MIRNAS AS REGULATORS OR ACTIVATORS OF SIGNAL PATHWAYS ASSOCIATED WITH THE PATHOGENESIS OF IPF WERE ANALYZED. THE SEARCH IN PUBMED WAS MADE USING THE FOLLOWING TERMS: "MIRNAS AND IDIOPATHIC PULMONARY FIBROSIS (IPF)"; "MIRNAS AND IPF AND SIGNALING PATHWAYS (SP)"; AND "MIRNAS AND IPF AND SP AND IPF PATHOGENESIS". ADDITIONALLY, WE FOCUS MAINLY ON THOSE WORKS WHERE THE SIGNALING PATHWAYS INVOLVED WITH EMT, FIBROBLAST DIFFERENTIATION, AND SYNTHESIS OF ECM COMPONENTS WERE ASSESSED. FINALLY, THE IMPORTANCE AND SIGNIFICANCE OF MIRNAS AS POTENTIAL THERAPEUTIC OR DIAGNOSTIC TOOLS FOR THE TREATMENT OF IPF ARE DISCUSSED.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15  4304 23 MICRORNA-223 PROTECTS NEURONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. MULTIPLE SCLEROSIS IS A CHRONIC INFLAMMATORY, DEMYELINATING, AND NEURODEGENERATIVE DISEASE AFFECTING THE BRAIN, SPINAL CORD AND OPTIC NERVES. NEURONAL DAMAGE IS TRIGGERED BY VARIOUS HARMFUL FACTORS THAT ENGAGE DIVERSE SIGNALLING CASCADES IN NEURONS; THUS, THERAPEUTIC APPROACHES TO PROTECT NEURONS WILL NEED TO FOCUS ON AGENTS THAT CAN TARGET MULTIPLE BIOLOGICAL PROCESSES. WE HAVE THEREFORE FOCUSED OUR ATTENTION ON MICRORNAS: SMALL NON-CODING RNAS THAT PRIMARILY FUNCTION AS POST-TRANSCRIPTIONAL REGULATORS THAT TARGET MESSENGER RNAS AND REPRESS THEIR TRANSLATION INTO PROTEINS. A SINGLE MICRORNA CAN TARGET MANY FUNCTIONALLY RELATED MESSENGER RNAS MAKING MICRORNAS POWERFUL EPIGENETIC REGULATORS. DYSREGULATION OF MICRORNAS HAS BEEN DESCRIBED IN MANY NEURODEGENERATIVE DISEASES INCLUDING MULTIPLE SCLEROSIS. HERE, WE REPORT THAT TWO MICRORNAS, MIR-223-3P AND MIR-27A-3P, ARE UPREGULATED IN NEURONS IN THE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS MOUSE MODEL OF CNS INFLAMMATION AND IN GREY MATTER-CONTAINING MULTIPLE SCLEROSIS LESIONS. PRIOR WORK HAS SHOWN PERIPHERAL BLOOD MONONUCLEAR CELL CONDITIONED MEDIA CAUSES SUBLETHAL DEGENERATION OF NEURONS IN CULTURE. WE FIND OVEREXPRESSION OF MIR-27A-3P OR MIR-223-3P PROTECTS DISSOCIATED CORTICAL NEURONS FROM CONDITION MEDIA MEDIATED DEGENERATION. INTRODUCTION OF MIR-223-3P IN VIVO IN MOUSE RETINAL GANGLION CELLS PROTECTS THEIR AXONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. IN SILICO ANALYSIS REVEALED THAT MESSENGER RNAS INVOLVED IN GLUTAMATE RECEPTOR SIGNALLING ARE ENRICHED AS MIR-27A-3P AND MIR-223-3P TARGETS. WE OBSERVE THAT ANTAGONISM OF NMDA AND AMPA TYPE GLUTAMATE RECEPTORS PROTECTS NEURONS FROM CONDITION MEDIA DEPENDENT DEGENERATION. OUR RESULTS SUGGEST THAT MIR-223-3P AND MIR-27A-3P ARE UPREGULATED IN RESPONSE TO INFLAMMATION TO MEDIATE A COMPENSATORY NEUROPROTECTIVE GENE EXPRESSION PROGRAM THAT DESENSITIZES NEURONS TO GLUTAMATE BY TARGETING MESSENGER RNAS INVOLVED IN GLUTAMATE RECEPTOR SIGNALLING.	2019	
                                                                                                                                                                                                          
16  4348 32 MIR-146A DYSREGULATES ENERGY METABOLISM DURING NEUROINFLAMMATION. ALZHEIMER'S DISEASE (AD) AND OTHER NEURODEGENERATIVE DISEASES ARE CHARACTERIZED BY CHRONIC NEUROINFLAMMATION AND A REDUCTION IN BRAIN ENERGY METABOLISM. AN IMPORTANT ROLE HAS EMERGED FOR SMALL, NON-CODING RNA MOLECULES KNOWN AS MICRORNAS (MIRNAS) IN THE PATHOPHYSIOLOGY OF MANY NEURODEGENERATIVE DISORDERS. AS EPIGENETIC REGULATORS, MIRNAS POSSESS THE CAPACITY TO REGULATE AND FINE TUNE PROTEIN PRODUCTION BY INHIBITING TRANSLATION. SEVERAL MIRNAS, WHICH INCLUDE MIR-146A, ARE ELEVATED IN THE BRAIN, CSF, AND PLASMA OF AD PATIENTS. MIR-146A PARTICIPATES IN PATHWAYS THAT REGULATE IMMUNE ACTIVATION AND HAS SEVERAL MRNA TARGETS WHICH ENCODE FOR PROTEINS INVOLVED IN CELLULAR ENERGY METABOLISM. AN ADDITIONAL ROLE FOR EXTRACELLULAR VESICLES (EVS) HAS ALSO EMERGED IN THE PROGRESSION AD, AS EVS CAN TRANSFER FUNCTIONALLY ACTIVE PROTEINS AND RNAS FROM DISEASED TO HEALTHY CELLS. IN THE CURRENT STUDY, WE EXPOSED VARIOUS CELL TYPES PRESENT WITHIN THE CNS TO IMMUNOMODULATORY MOLECULES AND OBSERVED SIGNIFICANT UPREGULATION OF MIR-146A EXPRESSION, BOTH WITHIN CELLS AND WITHIN THEIR SECRETED EVS. FURTHER, WE ASSESSED THE EFFECTS OF MIR-146A OVEREXPRESSION ON BIOENERGETIC FUNCTION IN PRIMARY RAT GLIAL CELLS AND FOUND SIGNIFICANT REDUCTIONS IN OXIDATIVE PHOSPHORYLATION AND GLYCOLYSIS. LASTLY, WE CORRELATED MIR-146A EXPRESSION LEVELS WITHIN VARIOUS REGIONS OF THE AD BRAIN TO DISEASE STAGING AND FOUND SIGNIFICANT, POSITIVE CORRELATIONS. THESE NOVEL RESULTS DEMONSTRATE THAT THE MODULATION OF MIR-146A IN RESPONSE TO NEUROINFLAMMATORY STIMULI MAY MEDIATE THE LOSS OF MITOCHONDRIAL INTEGRITY AND FUNCTION IN CELLS, THEREBY CONTRIBUTING TO THE PROGRESSION OF BETA-AMYLOID AND TAU PATHOLOGY IN THE AD BRAIN. MULTIPLE INFLAMMATORY STIMULI CAN UPREGULATE MIRNA-146A EXPRESSION WITHIN NEURONS, MIXED GLIAL CELLS, AND BRAIN ENDOTHELIAL CELLS, WHICH IS EITHER RETAINED WITHIN THESE CELLS OR RELEASED FROM THEM AS EXTRACELLULAR VESICLE CARGO. THE UPREGULATION OF MIR-146A DISRUPTS CELLULAR BIOENERGETICS IN MIXED GLIAL CELLS. THIS MECHANISM MAY PLAY A CRITICAL ROLE IN THE NEUROINFLAMMATORY RESPONSE OBSERVED DURING ALZHEIMER'S DISEASE.	2022	
                                                                                                    
17  6161 22 THE GENETICS OF ASTHMA: ADAM33 AS AN EXAMPLE OF A SUSCEPTIBILITY GENE. THE ABILITY TO IDENTIFY NOVEL DISEASE GENES BY POSITIONAL CLONING LED TO THE IDENTIFICATION OF A DISINTEGRIN AND METALLOPROTEASE (ADAM)33 GENE ON CHROMOSOME 20P13 AS A SUSCEPTIBILITY GENE FOR ASTHMA. CASE-CONTROL AND FAMILY-BASED ASSOCIATION STUDIES HAVE MOSTLY CONFIRMED A LINK BETWEEN ADAM33 AND ASTHMA. ITS RESTRICTED EXPRESSION TO MESENCHYMAL CELLS AS WELL AS ITS ASSOCIATION WITH BRONCHIAL HYPERRESPONSIVENESS AND ACCELERATED DECLINE IN LUNG FUNCTION OVER TIME POINT STRONGLY TO ITS INVOLVEMENT IN THE STRUCTURAL AIRWAY COMPONENTS OF ASTHMA, SUCH AS REMODELING. EXTENSIVE ALTERNATIVE SPLICING, EXPRESSION DURING BRANCHING MORPHOGENSIS IN THE DEVELOPING FETUS, IMPAIRED LUNG FUNCTION IN CHILDHOOD, THE PRODUCTION OF A SOLUBLE FORM LINKED TO CHRONIC ASTHMA, AND TIGHT EPIGENETIC REGULATION INDICATE A LEVEL OF COMPLEXITY IN THE WAY ADAM33 INFLUENCES DISEASE PHENOTYPE. ITS RECENT ASSOCIATION WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE AS WELL AS WITH ASTHMA AND LUNG DEVELOPMENT POINTS TO FUNCTIONS RELATING TO AIRWAY WALL MODELING AND REMODELING AS A GENERAL MORPHOGENETIC REPAIR GENE RATHER THAN BEING RESTRICTED TO ASTHMA.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18  3931 25 LIVER INJURY AND THE ACTIVATION OF THE HEPATIC MYOFIBROBLASTS. LIVER FIBROSIS IS A WOUND HEALING PROCESS, THE END RESULT OF CHRONIC LIVER INJURY ELICITED BY DIFFERENT NOXIOUS STIMULI. ACTIVATED HEPATIC STELLATE CELLS OR MYOFIBROBLASTS AND PORTAL MYOFIBROBLASTS ARE CONSIDERED AS THE MAIN PRODUCERS OF THE EXTRACELLULAR MATRIX IN THE LIVER. UPON LIVER INJURY THE QUIESCENT STELLATE CELLS TRANSDIFFERENTIATE INTO MYOFIBROBLASTS A PROCESS HIGHLIGHTED BY THE LOSS OF VITAMIN A STORES, UPREGULATION OF INTERSTITIAL TYPE COLLAGENS, SMOOTH MUSCLE ALPHA ACTIN, MATRIX METALLOPROTEINASES, PROTEOGLYCANS, AND THE INDUCTION OF CELL SURVIVAL PATHWAYS. ACTIVATION OF HEPATIC STELLATE CELLS IS A RESULT OF A COMPLEX INTERPLAY BETWEEN THE PARENCHYMAL CELLS, IMMUNE CELLS, EXTRACELLULAR MATRIX MECHANICS AND EXTRAHEPATIC MILIEU SUCH AS THE GUT MICROBIOME. IN THIS REVIEW WE WILL FOCUS ON THE PATHOMECHANISM OF STELLATE CELL ACTIVATION FOLLOWING CHRONIC LIVER INJURY; WITH THE AIM OF IDENTIFYING POSSIBLE TREATMENT TARGETS FOR ANTI-FIBROGENIC AGENTS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19   543 23 ATRIAL FIBRILLATION IS ASSOCIATED WITH HYPERMETHYLATION IN HUMAN LEFT ATRIUM, AND TREATMENT WITH DECITABINE REDUCES ATRIAL TACHYARRHYTHMIAS IN SPONTANEOUSLY HYPERTENSIVE RATS. ATRIAL FIBRILLATION (AF) IS THE MOST COMMON CARDIAC ARRHYTHMIA. AS THE MOLECULAR MECHANISMS UNDERLYING THE PATHOLOGY ARE LARGELY UNKNOWN, THIS CARDIAC ARRHYTHMIA REMAINS DIFFICULT TO TREAT. TO IDENTIFY SPECIFIC MOLECULAR ACTORS INVOLVED IN AF, WE HAVE PERFORMED A TRANSCRIPTOMIC ANALYSIS ON LEFT ATRIUM (LA) FROM PATIENTS WITH VALVULAR HEART DISEASE WITH OR WITHOUT AF. WE SHOWED THAT 1627 GENES HAD ALTERED BASAL EXPRESSION LEVEL IN LA TISSUE OF AF PATIENTS COMPARED WITH THE CONTROL GROUP. THE SIGNIFICANTLY ENRICHED GENE ONTOLOGY BIOLOGICAL PROCESS "ANATOMICAL STRUCTURE MORPHOGENESIS" CONTAINED THE HIGHEST NUMBER OF GENES IN LINE WITH CHANGES IN STRUCTURE THAT OCCUR WHEN THE HUMAN HEART REMODELS FOLLOWING AF DEVELOPMENT (IE, LA DILATATION AND INTERSTITIAL FIBROSIS). WE THEN FOCUSED THE STUDY ON PITX2 (PAIRED-LIKE HOMEODOMAIN 2), BEING THE MOST ALTERED TRANSCRIPTION FACTOR IN LA FROM AF PATIENTS AND FROM WHICH COMPELLING EVIDENCE HAVE INDICATED THAT ITS REDUCED EXPRESSION CAN BE CONSIDERED AS A MARKER FOR THE DISEASE. IN ADDITION, ITS EXPRESSION WAS INVERSELY CORRELATED WITH LA SIZE. WE DEMONSTRATED THAT AF IS ASSOCIATED WITH PITX2 PROMOTER HYPERMETHYLATION BOTH IN HUMANS AND ARRHYTHMIC AGING SPONTANEOUSLY HYPERTENSIVE RATS. CHRONIC ADMINISTRATION OF A DNA METHYLATION INHIBITOR (IE, 5-AZA-2'-DEOXYCITIDINE) IMPROVED ECG ARRHYTHMIC PROFILES AND SUPEROXIDE DISMUTASE ACTIVITIES AND REDUCED FIBROSIS IN THE LEFT VENTRICLE OF SPONTANEOUSLY HYPERTENSIVE RATS. TAKEN TOGETHER, THESE DATA SUPPORT THE NOTION THAT AF IS ASSOCIATED WITH EPIGENETIC CHANGES IN LA AND PROVIDE A PROOF-OF-CONCEPT THAT HYPOMETHYLATING AGENTS HAVE TO BE CONSIDERED IN THE TREATMENT OF ATRIAL ARRHYTHMIAS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                       
20  2219 36 EPIGENETIC MODIFICATIONS IN HEPATIC STELLATE CELLS CONTRIBUTE TO LIVER FIBROSIS. LIVER FIBROSIS REPRESENTS THE FINAL COMMON PATHWAY OF VIRTUALLY ALL TYPES OF CHRONIC LIVER DISEASES, AND IT HAS BEEN A MAJOR PUBLIC HEALTH CONCERN. MANY GENES HAVE BEEN DEMONSTRATED TO BE INVOLVED IN THE PATHOGENESIS OF LIVER FIBROSIS, WHILE THE MECHANISMS UNDERLYING GENE REGULATION STILL NEEDS FURTHER RESEARCH. ON THE OTHER HAND, HEPATIC STELLATE CELLS (HSCS) ARE QUIESCENT CELLS IN THE PERISINUSOIDAL SPACE IN LIVER. HSCS FACILITATE HEPATOCYTES INTERACTIONS VIA RELEASING SOLUBLE INFLAMMATORY FACTORS AND PRODUCING EXTRACELLULAR MATRIX. HSCS CAN BE ACTIVATED IN RESPONSE TO LIVER INJURY, AND THEY DIFFERENTIATE TO MYOFIBROBLASTS, WHICH GREATLY CONTRIBUTE TO THE FIBROGENESIS PROCESS. VARIOUS EPIGENETIC PROCEDURES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND FORMATION OF PARTICULAR CHROMATIN STRUCTURE, PLAY CRUCIAL ROLES IN THE GENE TRANSCRIPTIONAL EXPRESSION IN HSCS, REGULATING VARIOUS VITAL PROCESSES. FOR INSTANCE, EPIGENETIC MODULATION ON THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPAR-GAMMA) GENE PROMOTER ACCOUNTS FOR HSC DIFFERENTIATION THROUGH INTERACTING PATHWAYS. ABERRANT EXPRESSION OF A SERIES OF HISTONES AND CHEMOKINES IN ACTIVATED HSCS CAN AGGRAVATE INFLAMMATION AND OXIDATIVE STRESS, WHICH IN TURN PROMOTES DIFFERENTIATION OF HSCS TO MYOFIBROBLASTS AND ENHANCES THE WHOLE FIBROGENESIS PROCESS. DEGRADATION OF EXTRACELLULAR MATRIX IS ALSO REGULATED THROUGH EPIGENETIC MODULATION ON MATRIX ASSOCIATED ENZYMES. MOREOVER, FIBROSIS-RELATED EPIGENETIC MODIFICATIONS IN THE PARENTAL GENERATION MAY BE INHERITED TO THEIR OFFSPRING. IN THIS REVIEW, WE FIRSTLY SUMMARIZE THE VITAL EPIGENETIC MODIFICATIONS OF FIBROSIS-RELATED GENES IN HSCS, AND HIGHLIGHT SPECIFIC NUCLEIC ACID SEQUENCES AND STRUCTURES IN GENE PROMOTERS AS IMPORTANT ACTION SITES, WHICH MAY PROVIDE INDICATORS FOR LIVER FIBROSIS DIAGNOSIS IN THE FUTURE.	2013