1 460 135 ARACHIDONIC ACID 15-LIPOXYGENASE: EFFECTS OF ITS EXPRESSION, METABOLITES, AND GENETIC AND EPIGENETIC VARIATIONS ON AIRWAY INFLAMMATION. ARACHIDONIC ACID 15-LIPOXYGENASE (ALOX15) IS AN ENZYME THAT CAN OXIDIZE POLYUNSATURATED FATTY ACIDS. ALOX15 IS STRONGLY EXPRESSED IN AIRWAY EPITHELIAL CELLS, WHERE IT CATALYZES THE CONVERSION OF ARACHIDONIC ACID TO 15-HYDROXYEICOSATETRAENOIC ACID (15-HETE) INVOLVED IN VARIOUS AIRWAY INFLAMMATORY DISEASES. INTERLEUKIN (IL)-4 AND IL-13 INDUCE ALOX15 EXPRESSION BY ACTIVATING JAK2 AND TYK2 KINASES AS WELL AS SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION (STATS) 1/3/5/6. ALOX15 UP-REGULATION AND SUBSEQUENT ASSOCIATION WITH PHOSPHATIDYLETHANOLAMINE-BINDING PROTEIN 1 (PEBP1) ACTIVATE THE MITOGEN-ACTIVATED EXTRACELLULAR SIGNAL-REGULATED KINASE (MEK)-EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) PATHWAY, THUS INDUCING EOSINOPHIL-MEDIATED AIRWAY INFLAMMATION. IN ADDITION, ALOX15 PLAYS A SIGNIFICANT ROLE IN PROMOTING THE MIGRATION OF IMMUNE CELLS, SUCH AS IMMATURE DENDRITIC CELLS, ACTIVATED T CELLS, AND MAST CELLS, AND AIRWAY REMODELING, INCLUDING GOBLET CELL DIFFERENTIATION. GENOME-WIDE ASSOCIATION STUDIES HAVE REVEALED MULTIPLE ALOX15 VARIANTS AND THEIR SIGNIFICANT CORRELATION WITH THE RISK OF DEVELOPING AIRWAY DISEASES. THE EPIGENETIC MODIFICATIONS OF THE ALOX15 GENE, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS, HAVE BEEN SHOWN TO CLOSELY RELATE WITH AIRWAY INFLAMMATION. THIS REVIEW SUMMARIZES THE ROLE OF ALOX15 IN DIFFERENT PHENOTYPES OF ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CHRONIC RHINOSINUSITIS, ASPIRIN-EXACERBATED RESPIRATORY DISEASE, AND NASAL POLYPS, SUGGESTING NEW TREATMENT STRATEGIES FOR THESE AIRWAY INFLAMMATORY DISEASES WITH COMPLEX ETIOLOGY AND POOR TREATMENT RESPONSE. 2021 2 2818 18 FIBROSIS UNDER ARREST. APPROXIMATELY 5% OF PEOPLE THAT ARE HOSPITALIZED FOR ANY REASON DEVELOP ACUTE KIDNEY FAILURE, WHICH, IN SOME CASES, PROGRESSES TO A CHRONIC CONDITION RESULTING IN FIBROSIS OF THE KIDNEY AND PERMANENT CHANGES IN THE ORGAN'S FUNCTION. TWO NEW STUDIES SUGGEST THAT CELL CYCLE ARREST OF EPITHELIAL CELLS AND EPIGENETIC MODIFICATIONS HAVE KEY ROLES IN THE SWITCH TO CHRONIC DISEASE (PAGES 535-543 AND 544-550). 2010 3 238 31 ADENOSINE KINASE: A KEY REGULATOR OF PURINERGIC PHYSIOLOGY. ADENOSINE (ADO) IS AN ESSENTIAL BIOMOLECULE FOR LIFE THAT PROVIDES CRITICAL REGULATION OF ENERGY UTILIZATION AND HOMEOSTASIS. ADENOSINE KINASE (ADK) IS AN EVOLUTIONARY ANCIENT RIBOKINASE DERIVED FROM BACTERIAL SUGAR KINASES THAT IS WIDELY EXPRESSED IN ALL FORMS OF LIFE, TISSUES AND ORGAN SYSTEMS THAT TIGHTLY REGULATES INTRACELLULAR AND EXTRACELLULAR ADO CONCENTRATIONS. THE FACILE ABILITY OF ADK TO ALTER ADO AVAILABILITY PROVIDES A "SITE AND EVENT" SPECIFICITY TO THE ENDOGENOUS PROTECTIVE EFFECTS OF ADO IN SITUATIONS OF CELLULAR STRESS. IN ADDITION TO MODULATING THE ABILITY OF ADO TO ACTIVATE ITS COGNATE RECEPTORS (P1 RECEPTORS), NUCLEAR ADK ISOFORM ACTIVITY HAS BEEN LINKED TO EPIGENETIC MECHANISMS BASED ON TRANSMETHYLATION PATHWAYS. PREVIOUS DRUG DISCOVERY RESEARCH HAS TARGETED ADK INHIBITION AS A THERAPEUTIC APPROACH TO MANAGE EPILEPSY, PAIN, AND INFLAMMATION. THESE EFFORTS GENERATED MULTIPLE CLASSES OF HIGHLY POTENT AND SELECTIVE INHIBITORS. HOWEVER, CLINICAL DEVELOPMENT OF EARLY ADK INHIBITORS WAS STOPPED DUE TO APPARENT MECHANISTIC TOXICITY AND THE LACK OF SUITABLE TRANSLATIONAL MARKERS. NEW INSIGHTS REGARDING THE POTENTIAL ROLE OF THE NUCLEAR ADK ISOFORM (ADK-LONG) IN THE EPIGENETIC MODULATION OF MALADAPTIVE DNA METHYLATION OFFERS THE POSSIBILITY OF IDENTIFYING NOVEL ADK-ISOFORM SELECTIVE INHIBITORS AND NEW INTERVENTIONAL STRATEGIES THAT ARE INDEPENDENT OF ADO RECEPTOR ACTIVATION. 2021 4 5511 27 RIBONUCLEASES IN TUMOR GROWTH. THIS REVIEW SUMMARIZES DATA ON AMBIGUOUS BIOLOGICAL FUNCTIONS OF RIBONUCLEASES (RNASES) AT TUMOR GROWTH. IN SOME CASES THE RAISED LEVEL OF ENZYME ACTIVITY IN BIOLOGICAL FLUIDS CAN BE REGARDED AS AN ADDITIONAL MARKER OF MALIGNANT GROWTH (PANCREAS CANCER, CHRONIC MYELOID LEUKEMIA, ETC.). AT THE SAME TIME THE ACTIVITY OF RNASES IS OFTEN LOWERED IN TUMOR TISSUE. HIGH SUBSTRATE SPECIFICITY OF PARTICULAR RNASES PROVIDES METABOLIC BALANCE BETWEEN VARIOUS KINDS OF RNAS WITH VARIOUS HALF-TIME EXCHANGE TURN. RNASES ARE THE IMPORTANT FACTORS OF EPIGENETIC REGULATION OF GENE ACTIVITY IN CELLS. THE ACTIVITY OF RNASES IS ADJUSTABLE BY INHIBITORS AND OTHER FACTORS, AND DEFINES TIME OF EXISTENCE OF DIFFERENT KINDS OF RNAS. RNASES (THE MODIFIED VARIANTS OF RNASE A, RNASES OF SEMEN FLUID OF THE CATTLE, RNASE OF AMPHIBIA OOCYTES) CAN BE USED AS ANTI-TUMOR THERAPEUTIC AGENTS. ON THE OTHER HAND, SOME INHIBITORS OF RNASES OF NATURAL OR SYNTHETIC ORIGIN WERE DEMONSTRATED TO BE PERSPECTIVE DRUGS THAT INHIBIT TUMOR GROWTH. 2009 5 35 24 A CHROMATIN ACTIVITY-BASED CHEMOPROTEOMIC APPROACH REVEALS A TRANSCRIPTIONAL REPRESSOME FOR GENE-SPECIFIC SILENCING. IMMUNE CELLS DEVELOP ENDOTOXIN TOLERANCE (ET) AFTER PROLONGED STIMULATION. ET INCREASES THE LEVEL OF A REPRESSION MARK H3K9ME2 IN THE TRANSCRIPTIONALLY SILENT CHROMATIN SPECIFICALLY ASSOCIATED WITH PRO-INFLAMMATORY GENES. HOWEVER, IT IS NOT CLEAR WHAT PROTEINS ARE FUNCTIONALLY INVOLVED IN THIS PROCESS. HERE WE SHOW THAT A NOVEL CHROMATIN ACTIVITY-BASED CHEMOPROTEOMIC (CHAC) APPROACH CAN DISSECT THE FUNCTIONAL CHROMATIN PROTEIN COMPLEXES THAT REGULATE ET-ASSOCIATED INFLAMMATION. USING UNC0638 THAT BINDS THE ENZYMATICALLY ACTIVE H3K9-SPECIFIC METHYLTRANSFERASE G9A/GLP, CHAC REVEALS THAT G9A IS CONSTITUTIVELY ACTIVE AT A G9A-DEPENDENT MEGA-DALTON REPRESSOME IN PRIMARY ENDOTOXIN-TOLERANT MACROPHAGES. G9A/GLP BROADLY IMPACTS THE ET-SPECIFIC REPROGRAMMING OF THE HISTONE CODE LANDSCAPE, CHROMATIN REMODELLING AND THE ACTIVITIES OF SELECT TRANSCRIPTION FACTORS. WE DISCOVER THAT THE G9A-DEPENDENT EPIGENETIC ENVIRONMENT PROMOTES THE TRANSCRIPTIONAL REPRESSION ACTIVITY OF C-MYC FOR GENE-SPECIFIC CO-REGULATION OF CHRONIC INFLAMMATION. CHAC MAY ALSO BE APPLICABLE TO DISSECT OTHER FUNCTIONAL PROTEIN COMPLEXES IN THE CONTEXT OF PHENOTYPIC CHROMATIN ARCHITECTURES. 2014 6 5601 32 RORALPHA IS CRUCIAL FOR ATTENUATED INFLAMMATORY RESPONSE TO MAINTAIN INTESTINAL HOMEOSTASIS. RETINOIC ACID-RELATED ORPHAN RECEPTOR ALPHA (RORALPHA) FUNCTIONS AS A TRANSCRIPTION FACTOR FOR VARIOUS BIOLOGICAL PROCESSES, INCLUDING CIRCADIAN RHYTHM, CANCER, AND METABOLISM. HERE, WE GENERATE INTESTINAL EPITHELIAL CELL (IEC)-SPECIFIC RORALPHA-DEFICIENT (RORALPHA(DELTAIEC)) MICE AND FIND THAT RORALPHA IS CRUCIAL FOR MAINTAINING INTESTINAL HOMEOSTASIS BY ATTENUATING NUCLEAR FACTOR KAPPAB (NF-KAPPAB) TRANSCRIPTIONAL ACTIVITY. RORALPHA(DELTAIEC) MICE EXHIBIT EXCESSIVE INTESTINAL INFLAMMATION AND HIGHLY ACTIVATED INFLAMMATORY RESPONSES IN THE DEXTRAN SULFATE SODIUM (DSS) MOUSE COLITIS MODEL. TRANSCRIPTOME ANALYSIS REVEALS THAT DELETION OF RORALPHA LEADS TO UP-REGULATION OF NF-KAPPAB TARGET GENES IN IECS. CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALS CORECRUITMENT OF RORALPHA AND HISTONE DEACETYLASE 3 (HDAC3) ON NF-KAPPAB TARGET PROMOTERS AND SUBSEQUENT DISMISSAL OF CREB BINDING PROTEIN (CBP) AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) FOR TRANSCRIPTIONAL REPRESSION. TOGETHER, WE DEMONSTRATE THAT RORALPHA/HDAC3-MEDIATED ATTENUATION OF NF-KAPPAB SIGNALING CONTROLS THE BALANCE OF INFLAMMATORY RESPONSES, AND THERAPEUTIC STRATEGIES TARGETING THIS EPIGENETIC REGULATION COULD BE BENEFICIAL TO THE TREATMENT OF CHRONIC INFLAMMATORY DISEASES, INCLUDING INFLAMMATORY BOWEL DISEASE (IBD). 2019 7 2080 33 EPIGENETIC DNA METHYLATION OF EBI3 MODULATES HUMAN INTERLEUKIN-35 FORMATION VIA NFKB SIGNALING: A PROMISING THERAPEUTIC OPTION IN ULCERATIVE COLITIS. ULCERATIVE COLITIS (UC), A SEVERE CHRONIC DISEASE WITH UNCLEAR ETIOLOGY THAT IS ASSOCIATED WITH INCREASED RISK FOR COLORECTAL CANCER, IS ACCOMPANIED BY DYSREGULATION OF CYTOKINES. EPSTEIN-BARR VIRUS-INDUCED GENE 3 (EBI3) ENCODES A SUBUNIT IN THE UNIQUE HETERODIMERIC IL-12 CYTOKINE FAMILY OF EITHER PRO- OR ANTI-INFLAMMATORY FUNCTION. AFTER HAVING RECENTLY DEMONSTRATED THAT UPREGULATION OF EBI3 BY HISTONE ACETYLATION ALLEVIATES DISEASE SYMPTOMS IN A DEXTRAN SULFATE SODIUM (DSS)-TREATED MOUSE MODEL OF CHRONIC COLITIS, WE NOW AIMED TO EXAMINE A POSSIBLE FURTHER EPIGENETIC REGULATION OF EBI3 BY DNA METHYLATION UNDER INFLAMMATORY CONDITIONS. TREATMENT WITH THE DNA METHYLTRANSFERASE INHIBITOR (DNMTI) DECITABINE (DAC) AND TNFALPHA LED TO SYNERGISTIC UPREGULATION OF EBI3 IN HUMAN COLON EPITHELIAL CELLS (HCEC). USE OF DIFFERENT SIGNALING PATHWAY INHIBITORS INDICATED NFKAPPAB SIGNALING WAS NECESSARY AND PROPORTIONAL TO THE SYNERGISTIC EBI3 INDUCTION. MALDI-TOF/MS AND HPLC-ESI-MS/MS ANALYSIS OF DAC/TNFALPHA-TREATED HCEC IDENTIFIED IL-12P35 AS THE MOST PROBABLE BINDING PARTNER TO FORM A FUNCTIONAL PROTEIN. EBI3/IL-12P35 HETERODIMERS (IL-35) INDUCE THEIR OWN GENE UPREGULATION, SOMETHING THAT WAS INDEED OBSERVED IN HCEC CULTURED WITH MEDIA FROM PREVIOUSLY DAC/TNFALPHA-TREATED HCEC. THESE RESULTS SUGGEST THAT UNDER INFLAMMATORY AND DEMETHYLATING CONDITIONS THE UPREGULATION OF EBI3 RESULTS IN THE FORMATION OF ANTI-INFLAMMATORY IL-35, WHICH MIGHT BE CONSIDERED AS A THERAPEUTIC TARGET IN COLITIS. 2021 8 5863 30 SUPPRESSION OF ALLERGIC ASTHMA BY LOSS OF FUNCTION OF MIZ1-MEDIATED TH1 SKEWING. ASTHMA IS THE MOST PREVALENT CHRONIC RESPIRATORY DISEASE WORLDWIDE. THERE IS CURRENTLY NO CURE, AND IT REMAINS AN IMPORTANT CAUSE OF MORBIDITY AND MORTALITY. HERE WE REPORT THAT LUNG-SPECIFIC LOSS OF FUNCTION OF THE TRANSCRIPTION FACTOR MIZ1 (C-MYC-INTERACTING ZINC FINGER PROTEIN-1) UPREGULATES THE PRO-T-HELPER CELL TYPE 1 CYTOKINE IL-12. UPREGULATION OF IL-12 IN TURN STIMULATES A TH1 RESPONSE, THEREBY COUNTERACTING T-HELPER CELL TYPE 2 RESPONSE AND PREVENTING THE ALLERGIC RESPONSE IN MOUSE MODELS OF HOUSE DUST MITE- AND OVA (OVALBUMIN)-INDUCED ASTHMA. USING TRANSGENIC MICE EXPRESSING CRE UNDER A CELL-SPECIFIC PROMOTER, WE DEMONSTRATE THAT MIZ1 ACTS IN LUNG EPITHELIAL CELLS AND DENDRITIC CELLS IN ASTHMA. CHROMATIN IMMUNOPRECIPITATION COUPLED WITH HIGH-THROUGHPUT DNA SEQUENCING OR QUANTITATIVE PCR REVEALS THE BINDING OF MIZ1 ON THE IL12 PROMOTER INDICATING DIRECT REPRESSION OF IL-12 BY MIZ1. IN ADDITION, HDAC1 (HISTONE DEACETYLASE 1) IS RECRUITED TO THE IL12 PROMOTER IN A MIZ1-DEPDENENT MANNER, SUGGESTING EPIGENETIC REPRESSION OF IL12 BY MIZ1. FURTHERMORE, MIZ1 IS UPREGULATED IN THE LUNGS OF ASTHMATIC MICE. OUR DATA TOGETHER SUGGEST THAT MIZ1 IS UPREGULATED DURING ASTHMA, WHICH IN TURN PROMOTES ASTHMA PATHOGENESIS BY PREVENTING TH1 SKEWING THROUGH THE TRANSCRIPTIONAL REPRESSION OF IL-12. 2022 9 768 39 CD47 (CLUSTER OF DIFFERENTIATION 47). CD47, ALSO KNOWN AS INTEGRIN-ASSOCIATED PROTEIN, IS A CONSTITUTIVELY AND UBIQUITOUSLY EXPRESSED TRANSMEMBRANE RECEPTOR. CD47 IS CONSERVED ACROSS AMNIOTES INCLUDING MAMMALS, REPTILES, AND BIRDS. EXPRESSION IS INCREASED IN MANY CANCERS AND, IN NON-MALIGNANT CELLS, BY STRESS AND WITH AGING. THE UP-REGULATION OF CD47 EXPRESSION IS GENERALLY EPIGENETIC, WHEREAS GENE AMPLIFICATION OCCURS WITH LOW FREQUENCY IN SOME CANCERS. CD47 IS A HIGH AFFINITY SIGNALING RECEPTOR FOR THE SECRETED PROTEIN THROMBOSPONDIN-1 (THBS1) AND THE COUNTER-RECEPTOR FOR SIGNAL REGULATORY PROTEIN-ALPHA (SIRPA, SIRPALPHA) AND SIRPGAMMA (SIRPG). CD47 INTERACTION WITH SIRPALPHA SERVES AS A MARKER OF SELF TO INNATE IMMUNE CELLS AND THEREBY PROTECTS CANCER CELLS FROM PHAGOCYTIC CLEARANCE. CONSEQUENTLY, HIGHER CD47 CORRELATES WITH A POOR PROGNOSIS IN SOME CANCERS, AND THERAPEUTIC BLOCKADE CAN SUPPRESS TUMOR GROWTH BY ENHANCING INNATE ANTITUMOR IMMUNITY. CD47 EXPRESSED ON CYTOTOXIC T CELLS, DENDRITIC CELLS, AND NK CELLS MEDIATES INHIBITORY THBS1 SIGNALING THAT FURTHER LIMITS ANTITUMOR IMMUNITY. CD47 LATERALLY ASSOCIATES WITH SEVERAL INTEGRINS AND THEREBY REGULATES CELL ADHESION AND MIGRATION. CD47 HAS ADDITIONAL LATERAL BINDING PARTNERS IN SPECIFIC CELL TYPES, AND LIGATION OF CD47 IN SOME CASES MODULATES THEIR FUNCTION. THBS1-CD47 SIGNALING IN NON-MALIGNANT CELLS INHIBITS NITRIC OXIDE/CGMP, CALCIUM, AND VEGF SIGNALING, MITOCHONDRIAL HOMEOSTASIS, STEM CELL MAINTENANCE, PROTECTIVE AUTOPHAGY, AND DNA DAMAGE RESPONSE, AND PROMOTES NADPH OXIDASE ACTIVITY. CD47 SIGNALING IS A PHYSIOLOGICAL REGULATOR OF PLATELET ACTIVATION, ANGIOGENESIS AND BLOOD FLOW. THBS1/CD47 SIGNALING IS FREQUENTLY DYSREGULATED IN CHRONIC DISEASES. 2021 10 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 11 669 29 BONE MARROW STROMAL CELL ANTIGEN-1 (CD157) REGULATED BY SPHINGOSINE KINASE 2 MEDIATES KIDNEY FIBROSIS. CHRONIC KIDNEY DISEASE IS A PROGRESSIVE DISEASE THAT MAY LEAD TO END-STAGE RENAL DISEASE. INTERSTITIAL FIBROSIS DEVELOPS AS THE DISEASE PROGRESSES. THERAPIES THAT FOCUS ON FIBROSIS TO DELAY OR REVERSE PROGRESSIVE RENAL FAILURE ARE LIMITED. WE AND OTHERS SHOWED THAT SPHINGOSINE KINASE 2-DEFICIENT MICE (SPHK2 (-/-)) DEVELOP LESS FIBROSIS IN MOUSE MODELS OF KIDNEY FIBROSIS. SPHINGOSINE KINASE2 (SPHK2), ONE OF TWO SPHINGOSINE KINASES THAT PRODUCE SPHINGOSINE 1-PHOSPHATE (S1P), IS PRIMARILY LOCATED IN THE NUCLEUS. S1P PRODUCED BY SPHK2 INHIBITS HISTONE DEACETYLASE (HDAC) AND CHANGES HISTONE ACETYLATION STATUS, WHICH CAN LEAD TO ALTERED TARGET GENE EXPRESSION. WE HYPOTHESIZED THAT SPHK2 EPIGENETICALLY REGULATES DOWNSTREAM GENES TO INDUCE FIBROSIS, AND WE PERFORMED A COMPREHENSIVE ANALYSIS USING THE COMBINATION OF RNA-SEQ AND CHIP-SEQ. BST1/CD157 WAS IDENTIFIED AS A GENE THAT IS REGULATED BY SPHK2 THROUGH A CHANGE IN HISTONE ACETYLATION LEVEL, AND BST1 (-/-) MICE WERE FOUND TO DEVELOP LESS RENAL FIBROSIS AFTER UNILATERAL ISCHEMIA-REPERFUSION INJURY, A MOUSE MODEL OF KIDNEY FIBROSIS. ALTHOUGH BST1 IS A CELL-SURFACE MOLECULE THAT HAS A WIDE VARIETY OF FUNCTIONS THROUGH ITS VARIED ENZYMATIC ACTIVITIES AND DOWNSTREAM INTRACELLULAR SIGNALING PATHWAYS, NO STUDIES ON THE ROLE OF BST1 IN KIDNEY DISEASES HAVE BEEN REPORTED PREVIOUSLY. IN THE CURRENT STUDY, WE DEMONSTRATED THAT BST1 IS A GENE THAT IS REGULATED BY SPHK2 THROUGH EPIGENETIC CHANGE AND IS CRITICAL IN KIDNEY FIBROSIS. 2022 12 5153 26 PPP2R2B HYPERMETHYLATION CAUSES ACQUIRED APOPTOSIS DEFICIENCY IN SYSTEMIC AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION CAUSES TARGET ORGAN DAMAGE IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES. THE FACTORS THAT ALLOW THIS PROTRACTED RESPONSE ARE POORLY UNDERSTOOD. WE ANALYZED THE TRANSCRIPTIONAL REGULATION OF PPP2R2B (B55SS), A MOLECULE NECESSARY FOR THE TERMINATION OF THE IMMUNE RESPONSE, IN PATIENTS WITH AUTOIMMUNE DISEASES. ALTERED EXPRESSION OF B55SS CONDITIONED RESISTANCE TO CYTOKINE WITHDRAWAL-INDUCED DEATH (CWID) IN PATIENTS WITH AUTOIMMUNE DISEASES. THE IMPAIRED UPREGULATION OF B55SS WAS CAUSED BY INFLAMMATION-DRIVEN HYPERMETHYLATION OF SPECIFIC CYTOSINES LOCATED WITHIN A REGULATORY ELEMENT OF PPP2R2B PREVENTING CTCF BINDING. THIS PHENOTYPE COULD BE INDUCED IN HEALTHY T CELLS BY EXPOSURE TO TNF-ALPHA. OUR RESULTS REVEAL A GENE WHOSE EXPRESSION IS AFFECTED BY AN ACQUIRED DEFECT, THROUGH AN EPIGENETIC MECHANISM, IN THE SETTING OF SYSTEMIC AUTOIMMUNITY. BECAUSE FAILURE TO REMOVE ACTIVATED T CELLS THROUGH CWID COULD CONTRIBUTE TO AUTOIMMUNE PATHOLOGY, THIS MECHANISM ILLUSTRATES A VICIOUS CYCLE THROUGH WHICH AUTOIMMUNE INFLAMMATION CONTRIBUTES TO ITS OWN PERPETUATION. 2019 13 3778 36 INTERFERING WITH ALTERNATIVELY ACTIVATED MACROPHAGES BY CSF-1R INHIBITION EXERTS THERAPEUTIC CAPACITY ON ALLERGIC AIRWAY INFLAMMATION. PURPOSE: ALLERGIC ASTHMA IS A CHRONIC INFLAMMATORY DISORDER WITH AIRWAY HYPERRESPONSIVENESS AND TISSUE REMODELING AS THE MAIN PATHOLOGICAL CHARACTERISTICS. THE ETIOLOGY OF ASTHMA IS RELATIVELY COMPLICATED, INVOLVING GENETIC SUSCEPTIBILITY, EPIGENETIC REGULATION, ENVIRONMENTAL FACTORS, AND IMMUNE IMBALANCE. COLONY STIMULATING FACTOR 1 RECEPTOR (CSF-1R), HIGHLY EXPRESSED IN MYELOID MONOCYTES, PLAYS AN IMPORTANT ROLE IN REGULATING INFLAMMATION. HOWEVER, THE PATHOLOGICAL ROLE OF CSF-1R AND THE THERAPEUTIC EFFECTS OF CSF-1R INHIBITOR IN ALLERGIC AIRWAY INFLAMMATION REMAIN INDISTINCT. METHODS: THE HOUSE DUST MITE (HDM)-TRIGGERED ALLERGIC AIRWAY INFLAMMATION MODEL WAS CONDUCTED TO FULLY UNCOVER THE EFFICACIES OF CSF-1R INHIBITION, AS ILLUSTRATED BY HISTOPATHOLOGICAL EXAMINATIONS, BIOCHEMICAL ANALYSIS, ELISA, RT-PCR, WESTERN BLOTTING ASSAY, IMMUNOFLUORESCENCE, AND FLOW CYTOMETRY. FURTHERMORE, BONE MARROW-DERIVED MACROPHAGES (BMDMS) WERE DIFFERENTIATED AND POLARIZED UPON IL-4/IL-13 INDUCTION TO CLARIFY THE UNDERLYING MECHANISMS OF CSF-1R INHIBITION. RESULTS: HEREIN, WE PRESENTED THAT THE EXPRESSION OF CSF-1R WAS INCREASED IN HDM-INDUCED EXPERIMENTAL ASTHMA AND INHIBITION OF CSF-1R DISPLAYED DRAMATIC EFFECTS ON THE DISEASE SEVERITY OF ASTHMA, REFERRING TO SUPPRESSING THE SECRETION OF ALLERGIC MEDIATORS, DYSFUNCTION OF AIRWAY EPITHELIUM, AND INFILTRATION OF INFLAMMATORY CELLS. FURTHERMORE, CSF-1R INHIBITOR COULD MARKEDLY RESTRAIN THE POLARIZATION AND EXPRESSION OF TRANSCRIPTIONAL FACTORS OF ALTERNATIVELY ACTIVATED MACROPHAGES (AAMS) IN THE PRESENCE OF IL-4/IL-13 AND REDUCE THE RECRUITMENT OF CSF-1R-DOMINANT MACROPHAGES, BOTH IN ACUTE AND CHRONIC ALLERGIC AIRWAY INFLAMMATION MODEL. CONCLUSION: COLLECTIVELY, OUR FINDINGS DEMONSTRATED THE MOLECULAR PATHOLOGICAL MECHANISM OF CSF-1R IN ALLERGIC AIRWAY DISEASES AND SUGGESTED THAT TARGETING CSF-1R MIGHT BE AN ALTERNATIVE INTERVENTION STRATEGY ON THE HOMEOSTASIS OF AIRWAY IMMUNE MICROENVIRONMENT IN ASTHMA. 2022 14 1013 39 CIGARETTE SMOKE-INDUCED INFLAMMATION: NLRP10-MEDIATED MECHANISMS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A PROGRESSIVE, LIFE-THREATENING DISEASE THAT CAUSES IRREVERSIBLE LUNG DAMAGE. CIGARETTE SMOKING IS THE CHIEF ETIOLOGIC FACTOR FOR THE COMMENCEMENT OF THIS CONDITION. DESPITE CONSTANT EFFORTS TO DEVELOP THERAPEUTIC INTERVENTIONS AND TO ASCERTAIN THE MOLECULAR MECHANISM LEADING TO THE PATHOPHYSIOLOGY OF THIS DISEASE, MUCH REMAINS UNKNOWN. HOWEVER, PATTERN RECOGNITION RECEPTORS (PRRS), I.E., TOLL-LIKE-RECEPTORS (TLRS) AND NOD-LIKE RECEPTORS (NLRS) ARE BELIEVED TO PLAY IMPORTANT ROLES IN COPD AND COULD SERVE AS EFFECTIVE THERAPEUTIC TARGETS. ALTHOUGH THE ROLE OF TLRS IN COPD HAS BEEN WELL STUDIED, THE IMPORTANCE OF NLRS HAS NOT YET BEEN EXPLORED IN DETAIL. THE NLR FAMILY MEMBER NLRP10 (AKA NOD8, PAN5, PYNOD) IS THE ONLY MEMBER OF THIS FAMILY OF PROTEINS THAT LACKS THE LEUCINE RICH REPEAT (LRR) DOMAIN RESPONSIBLE FOR DETECTION OF PATHOGEN AND DANGER-ASSOCIATED MOLECULAR PATTERNS (PAMPS/DAMPS). THEREFORE, INSTEAD OF FUNCTIONING AS A PRR, NLRP10 MAY HAVE A BROADER REGULATORY ROLE. TO ELUCIDATE THE ROLE OF NLRP10 IN SECONDHAND SMOKE (SHS)-INDUCED INFLAMMATION, WE EXPOSED C57BL/6 (WT) AND NLRP10-DEFICIENT MICE (NLRP10(-/-)) ON THE C57BL/6 BACKGROUND TO FILTERED AIR- OR SHS- FOR 6 WEEKS (ACUTE EXPOSURE) AND ASSESSED THE RESULTING MOLECULAR EVENTS. LEUKOCYTE RECRUITMENT IN SHS-EXPOSED NLRP10(-/-) MICE WAS FOUND TO BE SIGNIFICANTLY LOWER COMPARED TO SHS-EXPOSED WT MICE. IN ADDITION, WE OBSERVED AN IMPORTANT ROLE FOR NLRP10 IN SHS-MEDIATED CASPASE-1 ACTIVATION, CYTOKINE/CHEMOKINE PRODUCTION (IL-1BETA, IL-18, MCP-1 AND IL-17A), AND INDUCTION OF NF-KAPPAB AND MAPKS IN THE LUNGS OF C57BL/6 MICE. THE REDUCED INFLUX OF CD4(+)IL-17A(+) AND CD8(+)IL-17A(+) CELLS INTO THE LUNGS OF SHS-EXPOSED NLRP10(-/-) MICE AND IMPAIRED DIFFERENTIATION OF NLRP10(-/-) TH0 CELLS INTO TH17 CELLS (EX VIVO) PROVIDE INSIGHT INTO THE MECHANISTIC DETAILS UNDERLYING NLRP10-DEPENDENT IL-17 PRODUCTION. WE FURTHER SUBSTANTIATED OUR IN VIVO FINDINGS BY CHALLENGING HUMAN ALVEOLAR TYPE II EPITHELIAL CELLS (A549) TRANSFECTED WITH SCRAMBLED- OR NLRP10-SIRNA WITH CIGARETTE SMOKE EXTRACT (CSE). WE OBSERVED AN IMPORTANT ROLE OF NLRP10 IN CYTOKINE AND CHEMOKINE PRODUCTION AS WELL AS EXPRESSION OF NF-KAPPAB AND MAPKS IN CSE-EXPOSED A549 CELLS. FURTHERMORE, REPLENISHMENT OF A549 CELL CULTURE WITH RECOMBINANT IL-17A (RIL-17A) DURING NLRP10 KNOCKDOWN RESCUED CSE-INDUCED INFLAMMATORY RESPONSES. TO IDENTIFY UPSTREAM MEDIATORS OF NLRP10 REGULATION WE INVESTIGATED EPIGENETIC MARKERS WITHIN THE NLRP10 PROMOTER FOLLOWING CIGARETTE SMOKE EXPOSURE AND OBSERVED SIGNIFICANT CHANGES IN ACTIVE AS WELL AS REPRESSIVE GENE MARKERS ON HISTONE 3 AND HISTONE 4 USING BOTH IN VIVO AND IN VITRO STUDY MODELS. FURTHER, ALTERATIONS IN THE RESPECTIVE HISTONE ACETYL- AND METHYLTRANSFERASES (PCAF, SET1, ESET, SUV20H1) CORRELATED WELL WITH THE OBSERVED HISTONE MODIFICATIONS. OVERALL, OUR FINDINGS SUGGEST A NOVEL ROLE OF EPIGENETICALLY REGULATED NLRP10 IN TH17/IL-17 SIGNALING DURING CS EXPOSURE. 2018 15 1335 29 DERMAL FIBROBLASTS CULTURED FROM DONORS WITH TYPE 2 DIABETES MELLITUS RETAIN AN EPIGENETIC MEMORY ASSOCIATED WITH POOR WOUND HEALING RESPONSES. THE PREVALENCE OF TYPE 2 DIABETES MELLITUS (T2DM) IS ESCALATING GLOBALLY. PATIENTS SUFFER FROM MULTIPLE COMPLICATIONS INCLUDING THE DEVELOPMENT OF CHRONIC WOUNDS THAT CAN LEAD TO AMPUTATION. THESE WOUNDS ARE CHARACTERISED BY AN INFLAMMATORY ENVIRONMENT INCLUDING ELEVATED TUMOUR NECROSIS FACTOR ALPHA (TNF-ALPHA). DERMAL FIBROBLASTS (DF) ARE CRITICAL FOR EFFECTIVE WOUND HEALING, SO WE SOUGHT TO ESTABLISH WHETHER THERE WERE ANY DIFFERENCES IN DF CULTURED FROM T2DM DONORS OR THOSE WITHOUT DIABETES (ND-DF). ND- AND T2DM-DF WHEN CULTURED SIMILARLY IN VITRO SECRETED COMPARABLE CONCENTRATIONS OF TNF-ALPHA. FUNCTIONALLY, PRE-TREATMENT WITH TNF-ALPHA REDUCED THE PROLIFERATION OF ND-DF AND TRANSIENTLY ALTERED ND-DF MORPHOLOGY; HOWEVER, T2DM-DF WERE RESISTANT TO THESE TNF-ALPHA INDUCED CHANGES. IN CONTRAST, TNF-ALPHA INHIBITED ND- AND T2DM-DF MIGRATION AND MATRIX METALLOPROTEASE EXPRESSION TO THE SAME DEGREE, ALTHOUGH T2DM-DF EXPRESSED SIGNIFICANTLY HIGHER LEVELS OF TISSUE INHIBITOR OF METALLOPROTEASES (TIMP)-2. FINALLY, TNF-ALPHA SIGNIFICANTLY INCREASED THE SECRETION OF PRO-INFLAMMATORY CYTOKINES (INCLUDING CCL2, CXCL1 AND SERPINE1) IN ND-DF, WHILST THIS EFFECT IN T2DM-DF WAS BLUNTED, PRESUMABLY DUE TO THE TENDENCY TO HIGHER BASELINE PRO-INFLAMMATORY CYTOKINE EXPRESSION OBSERVED IN THIS CELL TYPE. COLLECTIVELY, THESE DATA DEMONSTRATE THAT T2DM-DF EXHIBIT A SELECTIVE LOSS OF RESPONSIVENESS TO TNF-ALPHA, PARTICULARLY REGARDING PROLIFERATIVE AND SECRETORY FUNCTIONS. THIS HIGHLIGHTS IMPORTANT PHENOTYPIC CHANGES IN T2DM-DF THAT MAY EXPLAIN THE SUSCEPTIBILITY TO CHRONIC WOUNDS IN THESE PATIENTS. 2021 16 1950 35 EPIGENETIC ACTIVATION OF TENSIN 4 PROMOTES GASTRIC CANCER PROGRESSION. GASTRIC CANCER (GC) IS A COMPLEX DISEASE INFLUENCED BY MULTIPLE GENETIC AND EPIGENETIC FACTORS. CHRONIC INFLAMMATION CAUSED BY HELICOBACTER PYLORI INFECTION AND DIETARY RISK FACTORS CAN RESULT IN THE ACCUMULATION OF ABERRANT DNA METHYLATION IN GASTRIC MUCOSA, WHICH PROMOTES GC DEVELOPMENT. TENSIN 4 (TNS4), A MEMBER OF THE TENSIN FAMILY OF PROTEINS, IS LOCALIZED TO FOCAL ADHESION SITES, WHICH CONNECT THE EXTRACELLULAR MATRIX AND CYTOSKELETAL NETWORK. WE IDENTIFIED UPREGULATION OF TNS4 IN GC USING QUANTITATIVE REVERSE TRANSCRIPTION PCR WITH 174 PAIRED SAMPLES OF GC TUMORS AND ADJACENT NORMAL TISSUES. TRANSCRIPTIONAL ACTIVATION OF TNS4 OCCURRED EVEN DURING THE EARLY STAGE OF TUMOR DEVELOPMENT. TNS4 DEPLETION IN GC CELL LINES THAT EXPRESSED HIGH TO MODERATE LEVELS OF TNS4, I.E., SNU-601, KATO III, AND MKN74, REDUCED CELL PROLIFERATION AND MIGRATION, WHEREAS ECTOPIC EXPRESSION OF TNS4 IN THOSE LINES THAT EXPRESSED LOWER LEVELS OF TNS4, I.E., SNU-638, MKN1, AND MKN45 INCREASED COLONY FORMATION AND CELL MIGRATION. THE PROMOTER REGION OF TNS4 WAS HYPOMETHYLATED IN GC CELL LINES THAT SHOWED UPREGULATION OF TNS4. WE ALSO FOUND A SIGNIFICANT NEGATIVE CORRELATION BETWEEN TNS4 EXPRESSION AND CPG METHYLATION IN 250 GC TUMORS BASED ON THE CANCER GENOME ATLAS (TCGA) DATA. THIS STUDY ELUCIDATES THE EPIGENETIC MECHANISM OF TNS4 ACTIVATION AND FUNCTIONAL ROLES OF TNS4 IN GC DEVELOPMENT AND PROGRESSION AND SUGGESTS A POSSIBLE APPROACH FOR FUTURE GC TREATMENTS. 2023 17 6636 41 UNRAVELING A NEW PLAYER IN MULTIPLE SCLEROSIS PATHOGENESIS: THE RNA-BINDING PROTEIN HUR. BACKGROUND: ELAV-LIKE PROTEINS ARE A SMALL FAMILY OF RNA-BINDING PROTEINS THAT ARE FUNDAMENTAL PLAYERS IN POST-TRANSCRIPTIONAL MECHANISMS AND ARE INVOLVED IN THE PATHOGENESIS OF NEUROLOGIC AND PSYCHIATRIC DISORDERS. HUR, THE UBIQUITOUSLY EXPRESSED MEMBER OF THE FAMILY, IS ALSO IMPLICATED IN SUSTAINING INFLAMMATION AND INFLAMMATORY DISEASES, SUPPORTING THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES. INFLAMMATION PLAYS A CENTRAL ROLE IN MULTIPLE SCLEROSIS (MS), WHICH REPRESENTS THE MOST COMMON CAUSE OF PERMANENT PHYSICAL DISABILITY IN YOUNG ADULTS. MS IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING THE CENTRAL NERVOUS SYSTEM, WITH A COMPLEX AETIOLOGY INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. NO DATA ARE AVAILABLE ON THE POTENTIAL ENTANGLEMENT OF HUR IN MS PATHOGENESIS IN PATIENTS. IN THE PRESENT WORK, WE AIMED AT EXPLORING HUR PROTEIN LEVELS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM MS PATIENTS, COMPARED TO HEALTHY CONTROLS. TO FURTHER ELUCIDATE THE POSSIBLE INVOLVEMENT OF HUR IN MS, WE ALSO INVESTIGATED THE RELATIONSHIP BETWEEN THIS SPECIFIC RNA-BINDING PROTEIN AND HSP70-2 PROTEIN, ALSO CONSIDERING THE HSP70-2 RS1061581 POLYMORPHISM, GIVEN THAT HSP70-2 MRNA HAS BEEN REPORTED AS A HUR TARGET AND THIS SPECIFIC POLYMORPHISM TO BE ASSOCIATED WITH MS RISK. METHODS: ALLELES AND GENOTYPES FOR HSP70-2 RS1061581 POLYMORPHISM WERE ASSESSED, BY USING A POLYMERASE CHAIN REACTION-RESTRICTION FRAGMENT LENGTH POLYMORPHISM, FOLLOWED BY DIGESTION WITH RESTRICTION ENZYME, IN MS PATIENTS AND HEALTHY CONTROLS. PBMCS FROM A SUBGROUP OF PATIENTS AND CONTROLS WERE USED TO EVALUATE HUR AND HSP70-2 PROTEIN CONTENT BY WESTERN BLOT. RESULTS: PBMCS FROM 52 MS PATIENTS HAD A LOWER HUR AND HIGHER HSP70-2 PROTEIN CONTENT COMPARED TO 43 HEALTHY CONTROLS. AN INCREASE OF 100 UNITS OF HUR SIGNIFICANTLY DECREASED THE RISK OF DEVELOPING MS BY 9.8% (OR: 0.902, 95% CI: 0.83-0.98), CONTROLLING FOR HSP70-2 PROTEIN EXPRESSION, HSP70-2 RS1061581 GENOTYPE, AGE AND SEX. MOREOVER, HOLDING HUR LEVELS, AN INCREASE OF 100 UNITS OF HSP70-2 PROTEIN SIGNIFICANTLY INCREASED THE MS RISK BY 18.1% (OR: 1.181, 95% CI: 1.03-1.36) AND THE GENETIC SUSCEPTIBILITY OF DEVELOPING MS FOR HSP70-2 RS1061581 GG CARRIERS IS CONFIRMED. OF INTEREST, MS PATIENTS WITH A MODERATE TO SEVERE FORM OF MS (MSSS >/= 3) SHOWED A TREND TOWARDS A REDUCTION OF HUR PROTEIN LEVELS COMPARED TO PATIENTS WITH MILD DISEASE SEVERITY (MSSS < 3). CONCLUSIONS: HUR PROTEIN LEVELS ARE REDUCED IN MS PATIENTS COMPARED TO HEALTHY SUBJECTS, AND THE PROTEIN AMOUNT MAY CONTINUE TO DECLINE WITH DISEASE PROGRESSION, SUGGESTING A PUTATIVE ROLE OF THIS RNA-BINDING PROTEIN. MOREOVER, OUR RESULTS SUGGEST THAT MS PATHOLOGY MAY HAVE DISRUPTED THE LINK BETWEEN HUR AND ITS TARGET TRANSCRIPT HSP70-2. IT WILL BE IMPORTANT TO FURTHER EXPLORE THE EXACT ROLE OF HUR IN MS, CONSIDERING THE COMPLEX INTERPLAY WITH OTHER RNA-BINDING FACTORS AND TARGET MRNAS. 2020 18 3074 28 GENOME-WIDE DNA METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INORGANIC NANOPARTICLES IN HUMAN KIDNEY CELLS AFTER CHRONIC EXPOSURE. THE UNIQUE PHYSICOCHEMICAL PROPERTIES MAKE INORGANIC NANOPARTICLES (INPS) AN EXCITING TOOL IN DIAGNOSIS AND DISEASE MANAGEMENT. HOWEVER, AS INPS ARE RELATIVELY DIFFICULT TO FULLY DEGRADE AND EXCRETE, THEIR UNINTENDED ACCUMULATION IN THE TISSUE MIGHT RESULT IN ADVERSE HEALTH EFFECTS. HEREIN, WE PROVIDE A METHYLOME-TRANSCRIPTOME FRAMEWORK FOR CHRONIC EFFECTS OF INPS, COMMONLY USED IN BIOMEDICAL APPLICATIONS, IN HUMAN KIDNEY TH-1 CELLS. RENAL CLEARANCE IS ONE OF THE MOST IMPORTANT ROUTES OF NANOPARTICLE EXCRETION; THEREFORE, A DETAILED EVALUATION OF NANOPARTICLE-MEDIATED NEPHROTOXICITY IS AN IMPORTANT TASK. INTEGRATED ANALYSIS OF METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INPS (PEG-AUNPS, FE(3)O(4)NPS, SIO(2)NPS, AND TIO(2)NPS) REVEALED SIGNIFICANTLY DEREGULATED GENES WITH FUNCTIONAL CLASSIFICATION IN IMMUNE RESPONSE, DNA DAMAGE, AND CANCER-RELATED PATHWAYS. ALTHOUGH MOST DEREGULATED GENES WERE UNIQUE TO INDIVIDUAL INPS, A RELATIVELY HIGH PROPORTION OF THEM ENCODED THE TRANSCRIPTION FACTORS. INTERESTINGLY, FOS HYPERMETHYLATION INVERSELY CORRELATING WITH GENE EXPRESSION WAS ASSOCIATED WITH ALL INPS EXPOSURES. OUR STUDY EMPHASIZES THE NEED FOR A MORE COMPREHENSIVE INVESTIGATION OF INPS' BIOLOGICAL SAFETY, ESPECIALLY AFTER CHRONIC EXPOSURE. 2022 19 1449 23 DIRECT LINEAGE REPROGRAMMING FOR INDUCED KERATINOCYTE STEM CELLS: A POTENTIAL APPROACH FOR SKIN REPAIR. SEVERE TRAUMA OR CHRONIC WOUNDS CAN DEPLETE THE KERATINOCYTE STEM CELLS (KSCS) PRESENT IN THE EPIDERMAL BASAL LAYER OR INHIBIT THEIR MIGRATION LEADING TO COMPROMISED WOUND HEALING. SUPPLEMENTING KSCS IS THE KEY TO SOLUTION WHILE LINEAGE REPROGRAMMING PROVIDES A NEW APPROACH TO ACQUIRING KSCS. THROUGH DIRECT LINEAGE REPROGRAMMING, INDUCED KSCS (IKSCS) CAN BE PRODUCED FROM SOMATIC CELLS, WHICH EXHIBIT GREAT APPLICATION POTENTIAL. TWO STRATEGIES ARE CURRENTLY BEING USED TO DIRECTLY GENERATE IKSCS, LINEAGE TRANSCRIPTION FACTOR (TF)-MEDIATED AND PLURIPOTENCY FACTORS-MEDIATED. THIS REVIEW FOCUSES ON LINEAGE TF-MEDIATED DIRECT REPROGRAMMING AND DESCRIBES THE CONVERSION PROCESS ALONG WITH THE UNDERLYING EPIGENETIC MECHANISMS. IT ALSO DISCUSSES OTHER POTENTIAL INDUCTION STRATEGIES TO GENERATE IKSCS AND CHALLENGES ASSOCIATED WITH IN SITU REPROGRAMMING FOR SKIN REPAIR. 2023 20 142 41 ABERRANT DNA METHYLATION OF PHOSPHODIESTERASE [CORRECTED] 4D ALTERS AIRWAY SMOOTH MUSCLE CELL PHENOTYPES. AIRWAY HYPERRESPONSIVENESS (AHR) IS A HALLMARK FEATURE IN ASTHMA CHARACTERIZED BY EXAGGERATED AIRWAY CONTRACTILE RESPONSE TO STIMULI DUE TO INCREASED AIRWAY SENSITIVITY AND CHRONIC AIRWAY REMODELING. WE HAVE PREVIOUSLY SHOWN THAT ALLERGEN-INDUCED AHR IN MICE IS ASSOCIATED WITH ABERRANT DNA METHYLATION IN THE LUNG GENOME, SUGGESTING THAT AHR COULD BE EPIGENETICALLY REGULATED, AND THESE CHANGES MIGHT PREDISPOSE THE ANIMALS TO ASTHMA. PREVIOUS STUDIES DEMONSTRATED THAT OVEREXPRESSION OF PHOSPHODIESTERASE 4D (PDE4D) IS ASSOCIATED WITH INCREASED AHR. HOWEVER, EPIGENETIC REGULATION OF THIS GENE IN ASTHMATIC AIRWAY SMOOTH MUSCLE CELLS (ASMCS) HAS NOT BEEN EXAMINED. IN THIS STUDY, WE AIMED TO EXAMINE THE RELATIONSHIP BETWEEN EPIGENETIC REGULATION OF PDE4D AND ASMC PHENOTYPES. WE IDENTIFIED CPG SITE-SPECIFIC HYPOMETHYLATION AT PDE4D PROMOTER IN HUMAN ASTHMATIC ASMCS. WE NEXT USED METHYLATED OLIGONUCLEOTIDES TO INTRODUCE CPG SITE-SPECIFIC METHYLATION AT PDE4D PROMOTER AND EXAMINED ITS EFFECT ON ASMCS. WE SHOWED THAT PDE4D METHYLATION DECREASED CELL PROLIFERATION AND MIGRATION OF ASTHMATIC ASMCS. WE FURTHER ELUCIDATED THAT METHYLATED PDE4D DECREASED PDE4D EXPRESSION IN ASTHMATIC ASMCS, INCREASED CAMP LEVEL, AND INHIBITED THE ABERRANT INCREASE IN CA(2+) LEVEL. MOREOVER, PDE4D METHYLATION REDUCED THE PHOSPHORYLATION LEVEL OF DOWNSTREAM EFFECTORS OF CA(2+) SIGNALING, INCLUDING MYOSIN LIGHT CHAIN KINASE AND P38. TAKEN TOGETHER, OUR FINDINGS DEMONSTRATE THAT GENE-SPECIFIC EPIGENETIC CHANGES MAY PREDISPOSE ASMCS TO ASTHMA THROUGH ALTERATIONS IN CELL PHENOTYPES. MODULATION OF ASMC PHENOTYPES BY METHYLATED PDE4D OLIGONUCLEOTIDES CAN REVERSE THE ABERRANT ASMC FUNCTIONS TO NORMAL PHENOTYPES. THIS HAS PROVIDED NEW INSIGHT TO THE DEVELOPMENT OF NOVEL THERAPEUTIC OPTIONS FOR THIS DEBILITATIVE DISEASE. 2016