1 6758 141 WNT SIGNALING IN STEM CELL BIOLOGY AND REGENERATIVE MEDICINE. WNT FAMILY MEMBERS ARE SECRETED-TYPE GLYCOPROTEINS TO ORCHESTRATE EMBRYOGENESIS, TO MAINTAIN HOMEOSTASIS, AND TO INDUCE PATHOLOGICAL CONDITIONS. FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, FZD10, LRP5, LRP6, AND ROR2 ARE TRANSMEMBRANE RECEPTORS TRANSDUCING WNT SIGNALS BASED ON LIGAND-DEPENDENT PREFERENTIALITY FOR CAVEOLIN- OR CLATHRIN-MEDIATED ENDOCYTOSIS. WNT SIGNALS ARE TRANSDUCED TO CANONICAL PATHWAY FOR CELL FATE DETERMINATION, AND TO NON-CANONICAL PATHWAYS FOR REGULATION OF PLANAR CELL POLARITY, CELL ADHESION, AND MOTILITY. MYC, CCND1, AXIN2, FGF20, WISP1, JAG1, DKK1 AND GLUCAGON ARE TARGET GENES OF CANONICAL WNT SIGNALING CASCADE, WHILE CD44, VIMENTIN AND STX5 ARE TARGET GENES OF NON-CANONICAL WNT SIGNALING CASCADES. HOWEVER, TARGET GENES OF WNT SIGNALING CASCADES ARE DETERMINED IN A CONTEXT-DEPENDENT MANNER DUE TO EXPRESSION PROFILE OF TRANSCRIPTION FACTORS AND EPIGENETIC STATUS. WNT SIGNALING CASCADES NETWORK WITH NOTCH, FGF, BMP AND HEDGEHOG SIGNALING CASCADES TO REGULATE THE BALANCE OF STEM CELLS AND PROGENITOR CELLS. HERE WNT SIGNALING IN EMBRYONIC STEM CELLS, NEURAL STEM CELLS, MESENCHYMAL STEM CELLS, HEMATOPOIETIC STEM CELLS, AND INTESTINAL STEM CELLS WILL BE REVIEWED. WNT3, WNT5A AND WNT10B ARE EXPRESSED IN UNDIFFERENTIATED HUMAN EMBRYONIC STEM CELLS, WHILE WNT6, WNT8B AND WNT10B IN ENDODERM PRECURSOR CELLS. WNT6 IS EXPRESSED IN INTESTINAL CRYPT REGION FOR STEM OR PROGENITOR CELLS. TNF/ALPHA-WNT10B SIGNALING IS A NEGATIVE FEEDBACK LOOP TO MAINTAIN HOMEOSTASIS OF ADIPOSE TISSUE AND GASTROINTESTINAL MUCOSA WITH CHRONIC INFLAMMATION. RECOMBINANT WNT PROTEIN OR WNT MIMETIC (CIRCULAR PEPTIDE, SMALL MOLECULE COMPOUND, OR RNA APTAMER) IN COMBINATION WITH NOTCH MIMETIC, FGF PROTEIN, AND BMP PROTEIN OPENS A NEW WINDOW TO TISSUE ENGINEERING FOR REGENERATIVE MEDICINE. 2008 2 2754 23 EXPRESSION OF CAVEOLIN 1 IS ENHANCED BY DNA DEMETHYLATION DURING ADIPOCYTE DIFFERENTIATION. STATUS OF INSULIN SIGNALING. CAVEOLIN 1 (CAV-1) IS AN ESSENTIAL CONSTITUENT OF ADIPOCYTE CAVEOLAE WHICH BINDS THE BETA SUBUNIT OF THE INSULIN RECEPTOR (IR) AND IS IMPLICATED IN THE REGULATION OF INSULIN SIGNALING. WE HAVE FOUND THAT, DURING ADIPOCYTE DIFFERENTIATION OF 3T3-L1 CELLS THE PROMOTER, EXON 1 AND FIRST INTRON OF THE CAV-1 GENE UNDERGO A DEMETHYLATION PROCESS THAT IS ACCOMPANIED BY A STRONG INDUCTION OF CAV-1 EXPRESSION, INDICATING THAT EPIGENETIC MECHANISMS MUST HAVE A PIVOTAL ROLE IN THIS DIFFERENTIATION PROCESS. FURTHERMORE, IR, PKB-AKT AND GLUT-4 EXPRESSION ARE ALSO INCREASED DURING THE DIFFERENTIATION PROCESS SUGGESTING A COORDINATED REGULATION WITH CAV-1. ACTIVATION OF CAV-1 PROTEIN BY PHOSPHORYLATION ARISES DURING THE DIFFERENTIATION PROCESS, YET IN FULLY MATURE ADIPOCYTES INSULIN IS NO LONGER ABLE TO SIGNIFICANTLY INCREASE CAV-1 PHOSPHORYLATION. HOWEVER, THESE LONG-TERM DIFFERENTIATED CELLS ARE STILL ABLE TO RESPOND ADEQUATELY TO INSULIN, INCREASING IR AND PKB-AKT PHOSPHORYLATION AND GLUCOSE UPTAKE. THE ACTIVATION OF CAV-1 DURING THE ADIPOCYTE DIFFERENTIATION PROCESS COULD FACILITATE THE MAINTENANCE OF INSULIN SENSITIVITY BY THESE FULLY MATURE ADIPOCYTES ISOLATED FROM ADDITIONAL EXTERNAL STIMULI. HOWEVER, UNDER THE INFLUENCE OF PHYSIOLOGICAL CONDITIONS ASSOCIATED TO OBESITY, SUCH AS CHRONIC INFLAMMATION AND HYPOXIA, INSULIN SENSITIVITY WOULD FINALLY BE COMPROMISED. 2014 3 4482 16 MOLECULAR REGULATION AND CLINICAL SIGNIFICANCE OF CAVEOLIN-1 METHYLATION IN CHRONIC LUNG DISEASES. CHRONIC LUNG DISEASES REPRESENT A LARGELY GLOBAL BURDEN WHOSE PATHOGENESIS REMAINS LARGELY UNKNOWN. RESEARCH INCREASINGLY SUGGESTS THAT EPIGENETIC MODIFICATIONS, ESPECIALLY DNA METHYLATION, PLAY A MECHANISTIC ROLE IN CHRONIC LUNG DISEASES. DNA METHYLATION CAN AFFECT GENE EXPRESSION AND INDUCE VARIOUS DISEASES. OF THE CAVEOLAE IN PLASMA MEMBRANE OF CELL, CAVEOLIN-1 (CAV-1) IS A CRUCIAL STRUCTURAL CONSTITUENT INVOLVED IN MANY IMPORTANT LIFE ACTIVITIES. WITH THE INCREASINGLY ADVANCED PROGRESS OF GENOME-WIDE METHYLATION SEQUENCING TECHNOLOGIES, THE IMPORTANT IMPACT OF CAV-1 DNA METHYLATION HAS BEEN DISCOVERED. THE PRESENT REVIEW OVERVIEWS THE BIOLOGICAL CHARACTERS, FUNCTIONS, AND STRUCTURE OF CAV-1; EPIGENETIC MODIFICATIONS OF CAV-1 IN HEALTH AND DISEASE; EXPRESSION AND REGULATION OF CAV-1 DNA METHYLATION IN THE RESPIRATORY SYSTEM AND ITS SIGNIFICANCE; AS WELL AS CLINICAL POTENTIAL AS DISEASE-SPECIFIC BIOMARKER AND TARGETS FOR EARLY DIAGNOSIS AND THERAPY. 2020 4 3216 49 HEDGEHOG SIGNALING PATHWAY AND GASTROINTESTINAL STEM CELL SIGNALING NETWORK (REVIEW). HEDGEHOG, BMP/TGFBETA, FGF, WNT AND NOTCH SIGNALING PATHWAYS CONSTITUTE THE STEM CELL SIGNALING NETWORK, WHICH PLAYS A KEY ROLE IN A VARIETY OF PROCESSES, SUCH AS EMBRYOGENESIS, MAINTENANCE OF ADULT TISSUE HOMEOSTASIS, TISSUE REPAIR DURING CHRONIC PERSISTENT INFLAMMATION, AND CARCINOGENESIS. SONIC HEDGEHOG (SHH), INDIAN HEDGEHOG (IHH) AND DESERT HEDGEHOG (DHH) BIND TO PTCH1/PTCH OR PTCH2 RECEPTOR TO RELEASE SMOOTHENED (SMO) SIGNAL TRANSDUCER FROM PATCHED-DEPENDENT SUPPRESSION. SMO THEN ACTIVATES STK36 SERINE/THREONINE KINASE TO STABILIZE GLI FAMILY MEMBERS AND TO PHOSPHORYLATE SUFU FOR NUCLEAR ACCUMULATION OF GLI. HEDGEHOG SIGNALING ACTIVATION LEADS TO GLI-DEPENDENT TRANSCRIPTIONAL ACTIVATION OF TARGET GENES, SUCH AS GLI1, PTCH1, CCND2, FOXL1, JAG2 AND SFRP1. GLI1-DEPENDENT POSITIVE FEEDBACK LOOP COMBINED WITH PTCH1-DEPENDENT NEGATIVE FEEDBACK LOOP GIVES RISE TO TRANSIENT PROLIFERATION OF HEDGEHOG TARGET CELLS. IGUANA HOMOLOGS (DZIP1 AND DZIP1L) AND COSTAL-2 HOMOLOGS (KIF7 AND KIF27) ARE IDENTIFIED BY COMPARATIVE INTEGROMICS. SHH-DEPENDENT PARIETAL CELL PROLIFERATION IS IMPLICATED IN GASTRIC MUCOSAL REPAIR DURING CHRONIC HELICOBACTER PYLORI INFECTION. BMP-RUNX3 SIGNALING INDUCES IHH EXPRESSION IN SURFACE DIFFERENTIATED EPITHELIAL CELLS OF STOMACH AND INTESTINE. HEDGEHOG SIGNALS FROM EPITHELIAL CELLS THEN INDUCES FOXL1-MEDIATED BMP4 UPREGULATION IN MESENCHYMAL CELLS. HEDGEHOG SIGNALING IS FREQUENTLY ACTIVATED IN ESOPHAGEAL CANCER, GASTRIC CANCER AND PANCREATIC CANCER DUE TO TRANSCRIPTIONAL UPREGULATION OF HEDGEHOG LIGANDS AND EPIGENETIC SILENCING OF HHIP1/HHIP GENE, ENCODING THE HEDGEHOG INHIBITOR. HOWEVER, HEDGEHOG SIGNALING IS RARELY ACTIVATED IN COLORECTAL CANCER DUE TO NEGATIVE REGULATION BY THE CANONICAL WNT SIGNALING PATHWAY. HEDGEHOG SIGNALING MOLECULES OR TARGETS, SUCH AS SHH, IHH, HHIP1, PTCH1 AND GLI1, ARE APPLIED AS BIOMARKERS FOR CANCER DIAGNOSTICS, PROGNOSTICS AND THERAPEUTICS. SMALL-MOLECULE INHIBITORS FOR SMO OR STK36 ARE SUITABLE TO BE USED FOR TREATMENT OF HEDGEHOG-DEPENDENT CANCER. 2006 5 1730 46 DYSREGULATION OF STEM CELL SIGNALING NETWORK DUE TO GERMLINE MUTATION, SNP, HELICOBACTER PYLORI INFECTION, EPIGENETIC CHANGE AND GENETIC ALTERATION IN GASTRIC CANCER. GENETIC FACTORS, HELICOBACTER PYLORI INFECTION, SALT OVER-UPTAKE, DECREASED VEGETABLE/FRUIT CONSUMPTION, SMOKING, AND METABOLIC SYNDROME ARE RISK FACTORS OF HUMAN GASTRIC CANCER. GERMLINE MUTATIONS OF CDH1 GENE, AND SNPS OF PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 AND RUNX3 GENES ARE ASSOCIATED WITH GASTRIC CANCER. HELICOBACTER PYLORI ACTIVATES CAGA-SHP2-ERK AND PEPTIDOGLYCAN-NOD1-NFKAPPAB SIGNALING CASCADES IN GASTRIC EPITHELIAL CELLS USING TYPE IV SECRETION SYSTEM, AND ALSO TRAF6-MAP3K7-NFKAPPAB AND TRAF6-MAP3K7-AP-1 SIGNALING CASCADES IN EPITHELIAL AND IMMUNE CELLS THROUGH LIPOPOLYSACCHARIDE RECOGNITION BY TLR2 OR TLR4. IL-1BETA, IL-6, IL-8, TNFALPHA AND IFNGAMMA ARE ELEVATED IN GASTRIC MUCOSA WITH HELICOBACTER PYLORI INFECTION. IL-6 AND TNFALPHA INDUCE UPREGULATION OF WNT5A AND WNT10B, RESPECTIVELY. WNT SIGNALS ARE TRANSDUCED TO BETA-CATENIN-TCF/LEF, RHOA, JNK, PKC, NFAT, AND NLK SIGNALING CASCADES. WNT-BETA-CATENIN-TCF/LEF SIGNALING INDUCES UPREGULATION OF MYC, CCND1, WISP1, FGF20, JAG1 AND DKK1 GENES. NOTCH SIGNALS ARE TRANSDUCED TO CSL-NICD-MAML AND NFKAPPAB SIGNALING CASCADES. FGF SIGNALS ARE TRANSDUCED TO ERK, PI3K-AKT, PKC, AND NFAT SIGNALING CASCADES. HELICOBACTER PYLORI INFECTION INDUCES SHH UPREGULATION IN PARIETAL CELL LINEAGE, WHILE BMP SIGNALS INDUCE IHH UPREGULATION IN PIT CELL LINEAGE. HEDGEHOG SIGNALS INDUCE UPREGULATION OF GLI1, PTCH1, CCND2, FOXL1, JAG2 AND SFRP1 GENES. JAG1 AND JAG2 ACTIVATE NOTCH SIGNALING, WHILE DKK1 AND SFRP1 INHIBIT WNT SIGNALING. STEM CELL SIGNALING NETWORK, CONSISTING OF WNT, NOTCH, FGF, HEDGEHOG AND BMP SIGNALING PATHWAYS, IS ACTIVATED DURING CHRONIC HELICOBACTER PYLORI INFECTION. EPIGENETIC SILENCING OF SFRP1 GENE OCCURS IN THE EARLIER STAGE OF CARCINOGENESIS IN THE STOMACH, WHILE AMPLIFICATION AND OVEREXPRESSION OF FGFR2 GENE IN THE LATER STAGE. DYSREGULATION OF THE STEM CELL SIGNALING NETWORK DUE TO THE ACCUMULATION OF GERMLINE MUTATION, SNP, HELICOBACTER PYLORI INFECTION, EPIGENETIC CHANGE AND GENETIC ALTERATION GIVES RISE TO GASTRIC CANCER. SNP TYPING AND CUSTOM-MADE MICROARRAY ANALYSES ON GENES ENCODING STEM CELL SIGNALING MOLECULES COULD BE UTILIZED FOR THE PERSONALIZED MEDICINE. 2007 6 6756 44 WNT ANTAGONIST, SFRP1, IS HEDGEHOG SIGNALING TARGET. HEDGEHOG AND WNT SIGNALING PATHWAYS NETWORK TOGETHER DURING EMBRYOGENESIS AND CARCINOGENESIS. HEDGEHOG SIGNALING IN INTESTINAL EPITHELIUM REPRESSES CANONICAL WNT SIGNALING TO RESTRICT EXPRESSION OF WNT TARGET GENES TO STEM OR PROGENITOR CELLS; HOWEVER, THE MECHANISM REMAINS UNCLEAR. THE HEDGEHOG SIGNAL IS TRANSDUCED TO GLI FAMILY TRANSCRIPTION FACTORS THOUGH PATCHED RECEPTOR, SMOOTHENED SIGNAL TRANSDUCER, AND OTHER SIGNALING COMPONENTS, SUCH AS KIF27, KIF7, STK36, SUFU, AND DZIP1. HERE, WE SEARCHED FOR THE GLI-BINDING SITE WITHIN THE PROMOTER REGION OF GENES ENCODING SECRETED-TYPE WNT SIGNAL INHIBITORS, INCLUDING SFRP1, SFRP2, SFRP3, SFRP4, SFRP5, DKK1, DKK2, DKK3, DKK4, AND WIF1. THE GLI-BINDING SITE WAS IDENTIFIED WITHIN THE HUMAN SFRP1 PROMOTER BASED ON BIOINFORMATICS AND HUMAN INTELLIGENCE. THE CHIMPANZEE SFRP1 GENE WAS IDENTIFIED WITHIN THE NW_110515.1 GENOME SEQUENCE. THE GLI-BINDING SITE OF THE HUMAN SFRP1 PROMOTER WAS CONSERVED IN CHIMPANZEE SFRP1, MOUSE SFRP1, AND RAT SFRP1 PROMOTERS. SFRP1 IS THE EVOLUTIONARILY CONSERVED TARGET OF THE HEDGEHOG-GLI SIGNALING PATHWAY. EXPRESSION DOMAIN ANALYSES BASED ON TEXT MINING REVEALED THAT INDIAN HEDGEHOG (IHH), SFRP1, AND WNT6 ARE EXPRESSED IN DIFFERENTIATED INTESTINAL EPITHELIAL CELLS, MESENCHYMAL CELLS, AND STEM/PROGENITOR CELLS, RESPECTIVELY. HEDGEHOG IS SECRETED FROM DIFFERENTIATED EPITHELIAL CELLS TO INDUCE SFRP1 EXPRESSION IN MESENCHYMAL CELLS, WHICH KEEPS DIFFERENTIATED EPITHELIAL CELLS AWAY FROM THE EFFECTS OF CANONICAL WNT SIGNALING. THESE FACTS INDICATE THAT SFRP1 IS THE HEDGEHOG TARGET TO CONFINE CANONICAL WNT SIGNALING WITHIN STEM OR PROGENITOR CELLS. THEREFORE, EPIGENETIC CPG HYPERMETHYLATION OF THE SFRP1 PROMOTER DURING CHRONIC PERSISTENT INFLAMMATION AND AGING LEADS TO THE OCCURRENCE OF GASTROINTESTINAL CANCERS, SUCH AS COLORECTAL CANCER AND GASTRIC CANCER, THROUGH THE BREAKDOWN OF HEDGEHOG-DEPENDENT WNT SIGNAL INHIBITION. 2006 7 6662 23 UPREGULATION OF FZD5 IN EOSINOPHILIC CHRONIC RHINOSINUSITIS WITH NASAL POLYPS BY EPIGENETIC MODIFICATION. EOSINOPHILIC CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP) IS ONE OF THE MOST CHALLENGING PROBLEMS IN CLINICAL RHINOLOGY. FZD5 IS A RECEPTOR FOR WNT5A, AND ITS COMPLEX WITH WNT5A CONTRIBUTES TO ACTIVATING INFLAMMATION AND TISSUE MODIFICATION. NASAL POLYPS AND EOSINOPHIL/NON-EOSINOPHIL COUNTS ARE REPORTED TO BE DIRECTLY CORRELATED. THIS STUDY INVESTIGATED THE EXPRESSION AND DISTRIBUTION OF FZD5, AND THE ROLE OF EOSINOPHIL INFILTRATION AND FZD5 IN EOSINOPHILIC CRSWNP PATHOGENESIS. THE PROGNOSTIC ROLE OF EOSINOPHIL LEVELS WAS EVALUATED IN SEVEN PATIENTS WITH CRSWNP. FIFTEEN PATIENTS WITH CRS WERE CLASSIFIED BASED ON THE PERCENTAGE OF EOSINOPHILS IN NASAL POLYP TISSUE. METHYLATED GENES WERE DETECTED USING METHYL-CPG-BINDING DOMAIN SEQUENCING, AND QRT-PCR AND IMMUNOHISTOCHEMISTRY WERE USED TO DETECT FZD5 EXPRESSION IN NASAL POLYP TISSUE SAMPLES. THE RESULTS SHOWED THAT MRNA EXPRESSION OF FZD5 WAS UPREGULATED IN NASAL POLYPS. FZD5 EXPRESSION WAS SIGNIFICANTLY HIGHER IN NASAL POLYP SAMPLES FROM PATIENTS WITH EOSINOPHILIC CRSWNP THAN IN THOSE FROM PATIENTS WITH NON-EOSINOPHILIC CRSWNP, AS INDICATED BY IMMUNOHISTOCHEMISTRY. FURTHERMORE, INFLAMMATORY CYTOKINE LEVELS WERE HIGHER IN EOSINOPHILIC CRSWNP-DERIVED EPITHELIAL CELLS THAN IN NORMAL TISSUES. IN CONCLUSION, FZD5 EXPRESSION IN NASAL MUCOSAL EPITHELIAL CELLS IS CORRELATED WITH INFLAMMATORY CELLS AND MIGHT PLAY A ROLE IN THE PATHOGENESIS OF EOSINOPHILIC CRSWNP. 2019 8 4034 18 M6A METHYLATION PROMOTES WHITE-TO-BEIGE FAT TRANSITION BY FACILITATING HIF1A TRANSLATION. OBESITY MAINLY RESULTS FROM A CHRONIC ENERGY IMBALANCE. PROMOTING BROWNING OF WHITE ADIPOCYTES IS A PROMISING STRATEGY TO ENHANCE ENERGY EXPENDITURE AND COMBAT OBESITY. N6-METHYLADENOSINE (M6A), THE MOST ABUNDANT MRNA MODIFICATION IN EUKARYOTES, PLAYS AN IMPORTANT ROLE IN REGULATING ADIPOGENESIS. HOWEVER, WHETHER M6A REGULATES WHITE ADIPOCYTE BROWNING WAS UNKNOWN. HERE, WE REPORT THAT ADIPOSE TISSUE-SPECIFIC DELETION OF FTO, AN M6A DEMETHYLASE, PREDISPOSES MICE TO PREVENT HIGH-FAT DIET (HFD)-INDUCED OBESITY BY ENHANCING ENERGY EXPENDITURE. ADDITIONALLY, DELETION OF FTO IN VITRO PROMOTES THERMOGENESIS AND WHITE-TO-BEIGE ADIPOCYTE TRANSITION. MECHANISTICALLY, FTO DEFICIENCY INCREASES THE M6A LEVEL OF HIF1A MRNA, WHICH IS RECOGNIZED BY M6A-BINDING PROTEIN YTHDC2, FACILITATING MRNA TRANSLATION AND INCREASING HIF1A PROTEIN ABUNDANCE. HIF1A ACTIVATES THE TRANSCRIPTION OF THERMOGENIC GENES, INCLUDING PPAGGC1A, PRDM16, AND PPARG, THEREBY PROMOTING UCP1 EXPRESSION AND THE BROWNING PROCESS. COLLECTIVELY, THESE RESULTS UNVEIL AN EPIGENETIC MECHANISM BY WHICH M6A-FACILITATED HIF1A EXPRESSION CONTROLS BROWNING OF WHITE ADIPOCYTES AND THERMOGENESIS, PROVIDING A POTENTIAL TARGET TO COUNTERACT OBESITY AND METABOLIC DISEASE. 2021 9 1393 24 DIAGNOSTIC VALUE OF THE HYPOMETHYLATION OF THE WISP1 PROMOTER IN PATIENTS WITH HEPATOCELLULAR CARCINOMA ASSOCIATED WITH HEPATITIS B VIRUS. WNT1-INDUCIBLE SIGNALING PATHWAY PROTEIN 1 (WISP1) REGULATES CELL PROLIFERATION, DIFFERENTIATION, ADHESION, MIGRATION AND SURVIVAL. ABNORMAL WISP1 EXPRESSION IS ASSOCIATED WITH THE CARCINOGENESIS OF HEPATOCELLULAR CARCINOMA (HCC). ABERRANT DNA METHYLATION IS ONE OF THE MAJOR EPIGENETIC ALTERATIONS IN HCC. HOWEVER, THE METHYLATION STATUS OF THE WISP1 PROMOTER IS STILL UNCLEAR. WE THEREFORE AIMED TO DETERMINE THE METHYLATION STATUS OF THE WISP1 PROMOTER AND EVALUATE ITS CLINICAL VALUE IN HCC. THE STUDY ENROLLED 251 PARTICIPANTS, INCLUDING 123 PARTICIPANTS WITH HCC, 90 PARTICIPANTS WITH CHRONIC HEPATITIS B (CHB) AND 38 HEALTHY CONTROLS (HCS). WISP1 METHYLATION STATUS, MRNA LEVELS AND PLASMA SOLUBLE WISP1 WERE DETECTED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), QUANTITATIVE REAL-TIME PCR (RT-QPCR) AND ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RESPECTIVELY. WE FOUND THAT THE METHYLATION FREQUENCY OF WISP1 IN PATIENTS WITH HCC WAS SIGNIFICANTLY LOWER THAN THAT IN PATIENTS WITH CHB AND HCS, WHILE THE RELATIVE EXPRESSION LEVELS OF WISP1 MRNA WERE MARKEDLY HIGHER IN PATIENTS WITH HCC THAN IN PATIENTS WITH CHB AND HCS. FURTHERMORE, THE PLASMA SOLUBLE WISP1 IN PATIENTS WITH HCC WAS OBVIOUSLY LOWER THAN IN THAT IN PATIENTS WITH CHB AND HCS. ALPHA-FETOPROTEIN (AFP) IS A WIDELY RECOGNIZED BIOMARKER TO DIAGNOSE HCC WHICH LACKS ENOUGH SENSITIVITY AND SPECIFICITY. WISP1 PROMOTER METHYLATION STATUS COMBINED WITH AFP SIGNIFICANTLY IMPROVED THE DIAGNOSTIC ABILITY IN DISCRIMINATING HCC FROM CHB COMPARED WITH AFP OR WISP1 METHYLATION STATUS ALONE. IN CONCLUSION, HYPOMETHYLATION OF THE WISP1 GENE PROMOTER MAY SERVE AS A NONINVASIVE BIOMARKER FOR DETECTING HBV-ASSOCIATED HCC. 2020 10 2811 32 FGFR2-RELATED PATHOGENESIS AND FGFR2-TARGETED THERAPEUTICS (REVIEW). FGFR2 GENE AT HUMAN CHROMOSOME 10Q26 ENCODES FGFR2B AND FGFR2C ISOFORMS FUNCTIONING AS FGF RECEPTORS WITH DISTINCT EXPRESSION DOMAIN AND LIGAND SPECIFICITY. FGFR2 PLAYS ONCOGENIC AND ANTI-ONCOGENIC ROLES IN A CONTEXT-DEPENDENT MANNER. SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) WITHIN INTRON 2 OF FGFR2 GENE ARE ASSOCIATED WITH BREAST CANCER THROUGH ALLELIC FGFR2 UPREGULATION. MISSENSE MUTATIONS OR COPY NUMBER GAINS OF FGFR2 GENE OCCUR IN BREAST CANCER AND GASTRIC CANCER TO ACTIVATE FGFR2 SIGNALING. ABERRANT FGFR2 SIGNALING ACTIVATION INDUCES PROLIFERATION AND SURVIVAL OF TUMOR CELLS. THE CLASS SWITCH FROM FGFR2B TO FGFR2C OCCURS DURING PROGRESSION OF PROSTATE CANCER AND BLADDER CANCER BECAUSE OF SPLICEOSOME DYSREGULATION. IN ADDITION, EPIDERMAL FGFR2B KNOCKOUT MICE SHOW INCREASED SENSITIVITY TO CHEMICAL CARCINOGENESIS PARTLY DUE TO THE FAILURE OF NFE2L2 (NRF2)-MEDIATED DETOXIFICATION OF REACTIVE OXYGEN SPECIES (ROS). LOSS OF FGFR2B SIGNALING INDUCES EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) AND UNRULY ROS. FGFR2 SIGNALING DYSREGULATION DUE TO THE ACCUMULATION OF EPIGENETIC MODIFICATIONS AND GENETIC ALTERATIONS DURING CHRONIC INFLAMMATION, SMOKING, INCREASED CALORIC UPTAKE, AND DECREASED EXERCISE LEADS TO CARCINOGENESIS. PD173074, SU5402, AZD2171, AND KI23057 ARE SMALL-MOLECULE FGFR INHIBITORS. HUMAN ANTIBODY, PEPTIDE MIMETIC, RNA APTAMER, SIRNA, AND SYNTHETIC MICRORNA (MIRNA) ARE EMERGING TECHNOLOGIES TO BE APPLIED FOR CANCER THERAPEUTICS TARGETED TO FGFR2. BECAUSE NOVEL SEQUENCE TECHNOLOGY AND PETA-SCALE SUPER-COMPUTER ARE OPENING UP THE SEQUENCE ERA FOLLOWING THE GENOME ERA, PERSONALIZED MEDICINE PRESCRIBING TARGETED DRUGS BASED ON GERMLINE AND/OR SOMATIC GENOMIC INFORMATION IS COMING REALITY. APPLICATION OF FGFR2 INHIBITORS FOR CANCER TREATMENT IN PATIENTS WITH FGFR2 MUTATION OR GENE AMPLIFICATION IS BENEFICIAL; HOWEVER, THAT FOR CANCER PREVENTION IN PEOPLE WITH FGFR2 RISK ALLELE MIGHT BE DISADVANTAGEOUS DUE TO THE IMPEDIMENT OF A CYTOPROTECTIVE MECHANISM AGAINST OXIDATIVE STRESS. 2009 11 5332 18 PYRUVATE DEHYDROGENASE KINASE 1 AND 2 DEFICIENCY REDUCES HIGH-FAT DIET-INDUCED HYPERTROPHIC OBESITY AND INHIBITS THE DIFFERENTIATION OF PREADIPOCYTES INTO MATURE ADIPOCYTES. OBESITY IS NOW RECOGNIZED AS A DISEASE. THIS STUDY REVEALED A NOVEL ROLE FOR PYRUVATE DEHYDROGENASE KINASE (PDK) IN DIET-INDUCED HYPERTROPHIC OBESITY. MICE WITH GLOBAL OR ADIPOSE TISSUE-SPECIFIC PDK2 DEFICIENCY WERE PROTECTED AGAINST DIET-INDUCED OBESITY. THE WEIGHT OF ADIPOSE TISSUES AND THE SIZE OF ADIPOCYTES WERE REDUCED. ADIPOCYTE-SPECIFIC PDK2 DEFICIENCY SLIGHTLY INCREASED INSULIN SENSITIVITY IN HFD-FED MICE. IN STUDIES WITH 3T3-L1 PREADIPOCYTES, PDK2 AND PDK1 EXPRESSION WAS STRONGLY INCREASED DURING ADIPOGENESIS. EVIDENCE WAS FOUND FOR EPIGENETIC INDUCTION OF BOTH PDK1 AND PDK2. GAIN- AND LOSS-OF-FUNCTION STUDIES WITH 3T3-L1 CELLS REVEALED A CRITICAL ROLE FOR PDK1/2 IN ADIPOCYTE DIFFERENTIATION AND LIPID ACCUMULATION. PDK1/2 INDUCTION DURING DIFFERENTIATION WAS ALSO ACCOMPANIED BY INCREASED EXPRESSION OF HYPOXIA-INDUCIBLE FACTOR-1ALPHA (HIF1ALPHA) AND ENHANCED LACTATE PRODUCTION, BOTH OF WHICH WERE ABSENT IN THE CONTEXT OF PDK1/2 DEFICIENCY. EXOGENOUS LACTATE SUPPLEMENTATION INCREASED THE STABILITY OF HIF1ALPHA AND PROMOTED ADIPOGENESIS. PDK1/2 OVEREXPRESSION-MEDIATED ADIPOGENESIS WAS ABOLISHED BY HIF1ALPHA INHIBITION, SUGGESTING A ROLE FOR THE PDK-LACTATE-HIF1ALPHA AXIS DURING ADIPOGENESIS. IN HUMAN ADIPOSE TISSUE, THE EXPRESSION OF PDK1/2 WAS POSITIVELY CORRELATED WITH THAT OF THE ADIPOGENIC MARKER PPARGAMMA AND INVERSELY CORRELATED WITH OBESITY. SIMILARLY, PDK1/2 EXPRESSION IN MOUSE ADIPOSE TISSUE WAS DECREASED BY CHRONIC HIGH-FAT DIET FEEDING. WE CONCLUDE THAT PDK1 AND 2 ARE NOVEL REGULATORS OF ADIPOGENESIS THAT PLAY CRITICAL ROLES IN OBESITY. 2021 12 4296 22 MICRORNA-1 MODULATES CHONDROCYTE PHENOTYPE BY REGULATING FZD7 OF WNT/ BETA-CATENIN SIGNALING PATHWAY. OBJECTIVE: OSTEOARTHRITIS (OA) IS AN INCURABLE JOINT DISEASE CHARACTERIZED BY PRONOUNCED PAIN. MICRORNAS CONSTITUTE EPIGENETIC MECHANISMS THAT MAY AFFECT OA PROGRESSION BY CONTRIBUTING TO CHANGES IN CHONDROCYTE PHENOTYPE. THIS STUDY INVESTIGATES FOR THE FIRST TIME WHETHER THERE IS A LINK BETWEEN MIRNA-1 (MIR-1) AND OA PATHOGENESIS, AND THE MOLECULAR MECHANISMS INVOLVED. DESIGN: OA-ASSOCIATED GENE EXPRESSION, INCLUDING MMP-13, ADAMTS5, AND COL2A1 WAS COMPARED IN CHONDROCYTES FROM NON-OA AND OA CARTILAGE, AND IN SW1353 CELLS OVER- AND UNDEREXPRESSING MIR-1. BIOINFORMATICS AND LUCIFERASE REPORTER ASSAY WERE CONDUCTED TO CONFIRM WHETHER FZD7 WAS A TARGET OF MIR-1. THE EFFECTS OF MIR-1 ON FZD7 EXPRESSION AND DOWNSTREAM WNT/BETA-CATENIN SIGNALLING WERE INVESTIGATED. RESULTS: NON-OA AND OA CHONDROCYTES DIFFERED SIGNIFICANTLY IN THE EXPRESSION OF MIR-1 AND OA-ASSOCIATED GENES. MIR-1 OVER- AND UNDEREXPRESSION IN SW1353 CELLS, RESPECTIVELY, REDUCED AND ENHANCED GENE EXPRESSION ASSOCIATED WITH CARTILAGE CATABOLISM. FZD7, WHICH HAS AN IMPORTANT ROLE IN THE WNT/BETA-CATENIN SIGNALING PATHWAY, WAS SHOWN TO BE A POTENTIAL TARGET OF MIR-1. MIR-1 BINDING TO FZD7 INCREASED THE LEVELS OF PHOSPHORYLATED (INACTIVATED) BETA-CATENIN, THEREBY PREVENTING DOWNSTREAM BETA-CATENIN SIGNALING. CONCLUSIONS: INHIBITION OF WNT/BETA-CATENIN SIGNALING BY MIR-1 IN CHONDROCYTES MAY ATTENUATE THE EXPRESSION OF GENES THAT REGULATE THE ACTIVITY OF CATABOLIC ENZYMES. THIS FINDING MAY BE USEFUL FOR FUTURE INVESTIGATIONS OF MOLECULAR TARGETS FOR OA TREATMENT. 2021 13 5668 30 SFRP1 EXPRESSION REGULATES WNT SIGNALING IN CHRONIC MYELOID LEUKEMIA K562 CELLS. BACKGROUND: WNT SIGNALING CASCADES PLAY IMPORTANT ROLES IN CELL FATE DECISIONS AND THEIR DEREGULATION HAS BEEN DOCUMENTED IN MANY DISEASES, INCLUDING MALIGNANT TUMORS AND LEUKEMIA. ONE MECHANISM OF ABERRANT WNT SIGNALING IS THE SILENCING OF WNT INHIBITORS THROUGH EPIGENETIC MECHANISMS. THE SFRPS ARE ONE OF THE MOST STUDIED WNT INHIBITORS; AND THE SFRP1 LOSS IS KNOWN IN MANY HEMATOLOGICAL MALIGNANCIES. THEREFORE, WE AIMED TO COMPARE THE EXPRESSION OF WNT RELATED GENES IN THE PRESENCE AND ABSENCE OF SFRP1 IN A CHRONIC MYELOID LEUKEMIA (CML) CELL LINE. OBJECTIVE: IT IS IMPORTANT TO UNDERSTAND HOW SFRP1 AND SFRP1 PERFORM THEIR EFFECTS ON CML TO DESIGN NEW AGENTS AND STRATEGIES FOR RESISTANT AND ADVANCED FORMS OF CML. MATERIALS AND METHODS: WE USED K562 CELLS, WHICH NORMALLY DO NOT EXPRESS SFRP1 AND ITS SFRP1 EXPRESSING SUBCLONE K562S. TOTAL RNA WAS ISOLATED FROM K562 AND K562S CELL LINES AND CONVERTED TO CDNA. PCR ARRAY EXPERIMENTS WERE PERFORMED USING HUMAN WNT SIGNALING PATHWAY PLUS RT2 PROFILER KIT. WNT SIGNALING PATHWAY ACTIVATION WAS STUDIED BY WESTERN BLOT FOR DOWNSTREAM SIGNALING TARGETS. RESULTS: THE WNT3, LRP6, PRICKLE1 AND BTRC EXPRESSIONS WERE SIGNIFICANTLY DECREASED IN THE PRESENCE OF SFRP1; WHILE WNT5B INCREASED. THE SFRP1 EXPRESSION INHIBITED STABILIZATION OF TOTAL BETA-CATENIN PROTEIN AND DOWNSTREAM EFFECTOR PHOSPHORYLATION OF NONCANONICAL WNT/PCP SIGNALING; WHEREAS CA2+/PKC SIGNALING REMAINED ACTIVE. CONCLUSION: THE RESULTS SUGGEST THAT SFRP1 COULD BE A PROMISING THERAPEUTIC ANTICANCER AGENT. DEFINING THESE PATHWAY INTERACTIONS IS CRUCIAL FOR DESIGNING NEW AGENTS RESISTANT AND ADVANCED FORMS OF CML. 2022 14 6263 39 THE MULTIPLE WAYS WNT SIGNALING CONTRIBUTES TO ACUTE LEUKEMIA PATHOGENESIS. WNT PROTEINS CONSTITUTE A VERY CONSERVED FAMILY OF SECRETED GLYCOPROTEINS THAT ACT AS SHORT-RANGE LIGANDS FOR SIGNALING WITH CRITICAL ROLES IN HEMATOPOIESIS, EMBRYONIC DEVELOPMENT, AND TISSUE HOMEOSTASIS. THESE PROTEINS TRANSDUCE SIGNALS VIA THE CANONICAL PATHWAY, WHICH IS BETA-CATENIN-MEDIATED AND BETTER-CHARACTERIZED, OR VIA MORE DIVERSE NONCANONICAL PATHWAYS THAT ARE BETA-CATENIN INDEPENDENT AND COMPRISE THE PLANAR CELL POLARITY (PCP) PATHWAY AND THE WNT/CA(++) PATHWAYS. SEVERAL PROTEINS REGULATE WNT SIGNALING THROUGH A VARIETY OF SOPHISTICATED MECHANISMS. DISORDERS WITHIN THE PATHWAY CAN CONTRIBUTE TO VARIOUS HUMAN DISEASES, AND THE DYSREGULATION OF WNT PATHWAYS BY DIFFERENT MOLECULAR MECHANISMS IS IMPLICATED IN THE PATHOGENESIS OF MANY TYPES OF CANCER, INCLUDING THE HEMATOLOGICAL MALIGNANCIES. THE TYPES OF LEUKEMIA DIFFER CONSIDERABLY AND CAN BE SUBDIVIDED INTO CHRONIC, MYELOID OR LYMPHOCYTIC, AND ACUTE, MYELOID OR LYMPHOCYTIC, LEUKEMIA, ACCORDING TO THE DIFFERENTIATION STAGE OF THE PREDOMINANT CELLS, THE PROGENITOR LINEAGE, THE DIAGNOSTIC AGE STRATA, AND THE SPECIFIC MOLECULAR DRIVERS BEHIND THEIR DEVELOPMENT. HERE, WE REVIEW THE ROLE OF WNT SIGNALING IN NORMAL HEMATOPOIESIS AND DISCUSS IN DETAIL THE MULTIPLE WAYS CANONICAL WNT SIGNALING CAN BE DYSREGULATED IN ACUTE LEUKEMIA, INCLUDING ALTERATIONS IN GENE EXPRESSION AND PROTEIN LEVELS, EPIGENETIC REGULATION, AND MUTATIONS. FURTHERMORE, WE HIGHLIGHT THE DIFFERENT IMPACTS OF THESE ALTERATIONS, CONSIDERING THE DISTINCT FORMS OF THE DISEASE, AND THE THERAPEUTIC POTENTIAL OF TARGETING WNT SIGNALING. 2020 15 3875 20 KDM2A DEFICIENCY IN MACROPHAGES ENHANCES THERMOGENESIS TO PROTECT MICE AGAINST HFD-INDUCED OBESITY BY ENHANCING H3K36ME2 AT THE PPARG LOCUS. KDM2A CATALYZES H3K36ME2 DEMETHYLATION TO PLAY AN INTRIGUING EPIGENETIC REGULATORY ROLE IN CELL PROLIFERATION, DIFFERENTIATION, AND APOPTOSIS. HEREIN WE FOUND THAT MYELOID-SPECIFIC KNOCKOUT OF KDM2A (LYSM-CRE-KDM2A(F/F), KDM2A(-/-)) PROMOTED MACROPHAGE M2 PROGRAM BY REPROGRAMING METABOLIC HOMEOSTASIS THROUGH ENHANCING FATTY ACID UPTAKE AND LIPOLYSIS. KDM2A(-/-) INCREASED H3K36ME2 LEVELS AT THE PPARG LOCUS ALONG WITH AUGMENTED CHROMATIN ACCESSIBILITY AND STAT6 RECRUITMENT, WHICH RENDERED MACROPHAGES WITH PREFERENTIAL M2 POLARIZATION. THEREFORE, THE KDM2A(-/-) MICE WERE HIGHLY PROTECTED FROM HIGH-FAT DIET (HFD)-INDUCED OBESITY, INSULIN RESISTANCE, AND HEPATIC STEATOSIS, AND FEATURED BY THE REDUCED ACCUMULATION OF ADIPOSE TISSUE MACROPHAGES AND REPRESSED CHRONIC INFLAMMATION FOLLOWING HFD CHALLENGE. PARTICULARLY, KDM2A(-/-) MACROPHAGES PROVIDED A MICROENVIRONMENT IN FAVOR OF THERMOGENESIS. UPON HFD OR COLD CHALLENGE, THE KDM2A(-/-) MICE MANIFESTED HIGHER CAPACITY FOR INDUCING ADIPOSE BROWNING AND BEIGING TO PROMOTE ENERGY EXPENDITURE. COLLECTIVELY, OUR FINDINGS DEMONSTRATE THE IMPORTANCE OF KDM2A-MEDIATED H3K36 DEMETHYLATION IN ORCHESTRATING MACROPHAGE POLARIZATION, PROVIDING NOVEL INSIGHT THAT TARGETING KDM2A IN MACROPHAGES COULD BE A VIABLE THERAPEUTIC APPROACH AGAINST OBESITY AND INSULIN RESISTANCE. 2021 16 4521 36 MULTI?LAYERED PREVENTION AND TREATMENT OF CHRONIC INFLAMMATION, ORGAN FIBROSIS AND CANCER ASSOCIATED WITH CANONICAL WNT/BETA?CATENIN SIGNALING ACTIVATION (REVIEW). BETA?CATENIN/CTNNB1 IS AN INTRACELLULAR SCAFFOLD PROTEIN THAT INTERACTS WITH ADHESION MOLECULES (E?CADHERIN/CDH1, N?CADHERIN/CDH2, VE?CADHERIN/CDH5 AND ALPHA?CATENINS), TRANSMEMBRANE?TYPE MUCINS (MUC1/CD227 AND MUC16/CA125), SIGNALING REGULATORS (APC, AXIN1, AXIN2 AND NHERF1/EBP50) AND EPIGENETIC OR TRANSCRIPTIONAL REGULATORS (BCL9, BCL9L, CREBBP/CBP, EP300/P300, FOXM1, MED12, SMARCA4/BRG1 AND TCF/LEF). GAIN?OF?FUNCTION CTTNB1 MUTATIONS ARE DETECTED IN BLADDER CANCER, COLORECTAL CANCER, GASTRIC CANCER, LIVER CANCER, LUNG CANCER, PANCREATIC CANCER, PROSTATE CANCER AND UTERINE CANCER, WHEREAS LOSS?OF?FUNCTION CTNNB1 MUTATIONS ARE ALSO DETECTED IN HUMAN CANCER. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA AND ZNRF3 ARE REPRESENTATIVE BETA?CATENIN TARGET GENES. BETA?CATENIN SIGNALING IS INVOLVED IN MYOFIBROBLAST ACTIVATION AND SUBSEQUENT PULMONARY FIBROSIS, IN ADDITION TO OTHER TYPES OF FIBROSIS. BETA?CATENIN AND NF?KAPPAB SIGNALING ACTIVATION ARE INVOLVED IN FIELD CANCERIZATION IN THE STOMACH ASSOCIATED WITH HELICOBACTER PYLORI (H. PYLORI) INFECTION AND IN THE LIVER ASSOCIATED WITH HEPATITIS C VIRUS (HCV) INFECTION AND OTHER ETIOLOGIES. BETA?CATENIN?TARGETED THERAPEUTICS ARE FUNCTIONALLY CLASSIFIED INTO BETA?CATENIN INHIBITORS TARGETING UPSTREAM REGULATORS (AZ1366, ETC?159, G007?LK, GNF6231, IPAFRICEPT, NVP?TNKS656, ROSMANTUZUMAB, VANTICTUMAB, WNT?C59, WNT974 AND XAV939), BETA?CATENIN INHIBITORS TARGETING PROTEIN?PROTEIN INTERACTIONS (CGP049090, CWP232228, E7386, ICG?001, LF3 AND PRI?724), BETA?CATENIN INHIBITORS TARGETING EPIGENETIC REGULATORS (PKF118?310), BETA?CATENIN INHIBITORS TARGETING MEDIATOR COMPLEXES (CCT251545 AND CORTISTATIN A) AND BETA?CATENIN INHIBITORS TARGETING TRANSMEMBRANE?TYPE TRANSCRIPTIONAL OUTPUTS, INCLUDING CD44V6, FZD7 AND LGR5. ERADICATING H. PYLORI AND HCV IS THE OPTIMAL APPROACH FOR THE FIRST?LINE PREVENTION OF GASTRIC CANCER AND HEPATOCELLULAR CARCINOMA (HCC), RESPECTIVELY. HOWEVER, BETA?CATENIN INHIBITORS MAY BE APPLICABLE FOR THE PREVENTION OF ORGAN FIBROSIS, SECOND?LINE HCC PREVENTION AND TREATING BETA?CATENIN?DRIVEN CANCER. THE MULTI?LAYERED PREVENTION AND TREATMENT STRATEGY OF BETA?CATENIN?RELATED HUMAN DISEASES IS NECESSARY FOR THE PRACTICE OF PERSONALIZED MEDICINE AND IMPLEMENTATION OF PRECISION MEDICINE. 2018 17 3353 24 HISTONE DEMETHYLASES REGULATE ADIPOCYTE THERMOGENESIS. ADIPOCYTES PLAY A PIVOTAL ROLE IN THE REGULATION OF ENERGY METABOLISM. WHILE WHITE ADIPOCYTE STORES ENERGY, BROWN ADIPOCYTE DISSIPATES ENERGY BY PRODUCING HEAT. IN ADDITION, ANOTHER TYPE OF HEAT-PRODUCING ADIPOCYTE, BEIGE ADIPOCYTE, EMERGES IN WHITE ADIPOSE TISSUE IN RESPONSE TO CHRONIC COLDNESS. THIS PHENOTYPIC ADAPTATION TO THE COLD ENVIRONMENT IS CONSIDERED TO BE ATTRIBUTED TO THE EPIGENETIC MODIFICATIONS. HISTONE METHYLATION IS A CHEMICALLY STABLE EPIGENETIC MODIFICATION AND THUS A PROPER MECHANISM FOR LONG-LASTING CELLULAR MEMORY. SEVERAL HISTONE METHYL-MODIFYING ENZYMES SUCH AS EHMT1, JMJD1A, JMJD3, AND LSD1 ARE REPORTED TO BE INVOLVED IN THE BEIGE ADIPOSE CELL FATE DETERMINATION. AMONG THESE, A HISTONE DEMETHYLASE JMJD1A SENSES COLD ENVIRONMENT BY BEING PHOSPHORYLATED AT S265 IN RESPONSE TO BETA-ADRENERGIC RECEPTOR STIMULATION. PHOSPHORYLATED JMJD1A REGULATES BOTH ACUTE AND COLD THERMOGENESIS. UNDER ACUTE COLDNESS, PHOSPHORYLATED JMJD1A FORMS A COMPLEX WITH CHROMATIN REMODELER SWI/SNF AND DNA-BOUND PPARGAMMA, WHICH RECRUITS JMJD1A TO THE TARGET GENOMIC REGIONS IN BROWN ADIPOCYTE. THIS COMPLEX FORMATION, IN TURN, INDUCES THE EXPRESSION OF TARGET GENES BY BRINGING THE ENHANCER AND THE PROMOTER INTO CLOSE PROXIMITY. DURING CHRONIC COLDNESS, PHOSPHORYLATED JMJD1A REGULATES BEIGE ADIPOGENESIS THROUGH A TWO-STEP MECHANISM. IN THE FIRST STEP, PHOSPHORYLATED JMJD1A IS RECRUITED TO THE REGULATORY REGIONS OF TARGET GENES BY FORMING A COMPLEX WITH PRDM16, PGC1ALPHA, AND DNA-BOUND PPARGAMMA. IN THE SECOND STEP, JMJD1A DEMETHYLATES HISTONE H3K9ME2 AND INDUCES STABLE EXPRESSION OF BEIGE-SELECTIVE GENES. THE PHENOTYPIC ANALYSES OF JMJD1A-NULL MICE AND NON-PHOSPHORYLATED MUTANT S265A JMJD1A KNOCK-IN MICE INDICATE THAT JMJD1A IS A POTENTIAL THERAPEUTIC TARGET FOR THE TREATMENT OF OBESITY-RELATED DISEASES INCLUDING METABOLIC SYNDROME AND TYPE 2 DIABETES. 2018 18 5083 30 PICKING A BONE WITH WISP1 (CCN4): NEW STRATEGIES AGAINST DEGENERATIVE JOINT DISEASE. AS THE WORLD'S POPULATION CONTINUES TO AGE, IT IS ESTIMATED THAT DEGENERATIVE JOINT DISEASE DISORDERS SUCH AS OSTEOARTHRITIS WILL IMPACT AT LEAST 130 MILLION INDIVIDUALS THROUGHOUT THE GLOBE BY THE YEAR 2050. ADVANCED AGE, OBESITY, GENETICS, GENDER, BONE DENSITY, TRAUMA, AND A POOR LEVEL OF PHYSICAL ACTIVITY CAN LEAD TO THE ONSET AND PROGRESSION OF OSTEOARTHRITIS. HOWEVER, FACTORS THAT LEAD TO DEGENERATIVE JOINT DISEASE AND INVOLVE GENDER, GENETICS, EPIGENETIC MECHANISMS, AND ADVANCED AGE ARE NOT WITHIN THE CONTROL OF AN INDIVIDUAL. FURTHERMORE, CURRENT THERAPIES INCLUDING PAIN MANAGEMENT, IMPROVED NUTRITION, AND REGULAR PROGRAMS FOR EXERCISE DO NOT LEAD TO THE RESOLUTION OF OSTEOARTHRITIS. AS A RESULT, NEW AVENUES FOR TARGETING THE TREATMENT OF OSTEOARTHRITIS ARE DESPERATELY NEEDED. WNT1 INDUCIBLE SIGNALING PATHWAY PROTEIN 1 (WISP1), A MATRICELLULAR PROTEIN AND A DOWNSTREAM TARGET OF THE WINGLESS PATHWAY WNT1, IS ONE SUCH TARGET TO CONSIDER THAT GOVERNS CELLULAR PROTECTION, STEM CELL PROLIFERATION, AND TISSUE REGENERATION IN A NUMBER OF DISORDERS INCLUDING BONE DEGENERATION. HOWEVER, INCREASED WISP1 EXPRESSION ALSO HAS BEEN ASSOCIATED WITH THE PROGRESSION OF OSTEOARTHRITIS. WISP1 HAS AN INTRICATE RELATIONSHIP WITH A NUMBER OF PROLIFERATIVE AND PROTECTIVE PATHWAYS THAT INCLUDE PHOSPHOINOSITIDE 3-KINASE (PI 3-K), PROTEIN KINASE B (AKT), NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB), INTERLEUKIN -6 (IL-6), TRANSFORMING GROWTH FACTOR-BETA, MATRIX METALLOPROTEINASE, SMALL NON-CODING RIBONUCLEIC ACIDS (RNAS), SIRTUIN SILENT MATING TYPE INFORMATION REGULATION 2 HOMOLOG 1 (SACCHAROMYCES CEREVISIAE) (SIRT1), AND THE MECHANISTIC TARGET OF RAPAMYCIN (MTOR). TAKEN TOGETHER, THIS COMPLEX ASSOCIATION WISP1 HOLDS WITH THESE SIGNALING PATHWAYS NECESSITATES A FINE BIOLOGICAL REGULATION OF WISP1 ACTIVITY THAT CAN OFFSET THE PROGRESSION OF DEGENERATIVE JOINT DISEASE, BUT NOT LIMIT THE CELLULAR PROTECTIVE CAPABILITIES OF THE WISP1 PATHWAY. 2016 19 4867 23 OSSIFYING FIBROMA TUMOR STEM CELLS ARE MAINTAINED BY EPIGENETIC REGULATION OF A TSP1/TGF-BETA/SMAD3 AUTOCRINE LOOP. ABNORMAL STEM CELL FUNCTION MAKES A KNOWN CONTRIBUTION TO MANY MALIGNANT TUMORS, BUT THE ROLE OF STEM CELLS IN BENIGN TUMORS IS NOT WELL UNDERSTOOD. HERE, WE SHOW THAT OSSIFYING FIBROMA (OF) CONTAINS A STEM CELL POPULATION THAT RESEMBLES MESENCHYMAL STEM CELLS (OFMSCS) AND IS CAPABLE OF GENERATING OF-LIKE TUMOR XENOGRAFTS. MECHANISTICALLY, OFMSCS SHOW ENHANCED TGF-BETA SIGNALING THAT INDUCES ABERRANT PROLIFERATION AND DEFICIENT OSTEOGENESIS VIA NOTCH AND BMP SIGNALING PATHWAYS, RESPECTIVELY. THE ELEVATED TGF-BETA ACTIVITY IS TIGHTLY REGULATED BY JHDM1D-MEDIATED EPIGENETIC REGULATION OF THROMBOSPONDIN-1 (TSP1), FORMING A JHDM1D/TSP1/TGF-BETA/SMAD3 AUTOCRINE LOOP. INHIBITION OF TGF-BETA SIGNALING IN OFMSCS CAN RESCUE THEIR ABNORMAL OSTEOGENIC DIFFERENTIATION AND ELEVATED PROLIFERATION RATE. FURTHERMORE, CHRONIC ACTIVATION OF TGF-BETA CAN CONVERT NORMAL MSCS INTO OF-LIKE MSCS VIA ESTABLISHMENT OF THIS JHDM1D/TSP1/TGF-BETA/SMAD3 AUTOCRINE LOOP. THESE RESULTS REVEAL THAT EPIGENETIC REGULATION OF TGF-BETA SIGNALING IN MSCS GOVERNS THE BENIGN TUMOR PHENOTYPE IN OF AND HIGHLIGHT TGF-BETA SIGNALING AS A CANDIDATE THERAPEUTIC TARGET. 2013 20 202 21 ACTIVATION INDUCED CYTIDINE DEAMINASE: AN OLD FRIEND WITH NEW FACES. ACTIVATION INDUCED CYTIDINE DEAMINASE (AID) PROTEIN IS A MEMBER OF APOBEC FAMILY. AID CONVERTS CYTIDINE TO URACIL, WHICH IS A KEY STEP FOR SOMATIC HYPERMUTATION (SHM) AND CLASS SWITCH RECOMBINATION (CSR). AID ALSO PLAYS CRITICAL ROLES IN B CELL PRECURSOR STAGES, REMOVING POLYREACTIVE B CELLS FROM IMMUNE REPERTOIRE. SINCE THE MAIN FUNCTION OF AID IS INDUCING POINT MUTATIONS, DYSREGULATION CAN LEAD TO INCREASED MUTATION LOAD, TRANSLOCATIONS, DISTURBED GENOMIC INTEGRITY, AND LYMPHOMAGENESIS. AS SUCH, EXPRESSION OF AID AS WELL AS ITS FUNCTION IS CONTROLLED STRICTLY AT VARIOUS MOLECULAR STEPS. OTHER MEMBERS OF THE APOBEC FAMILY ALSO PLAY CRUCIAL ROLES DURING CARCINOGENESIS. CONSIDERING ALL THESE FUNCTIONS, AID REPRESENTS A BRIDGE, LINKING CHRONIC INFLAMMATION TO CARCINOGENESIS AND IMMUNE DEFICIENCIES TO AUTOIMMUNE MANIFESTATIONS. 2022