1 5454 98 REPURPOSING BELINOSTAT FOR ALLEVIATION OF ATOPIC DERMATITIS. ATOPIC DERMATITIS (AD) IS A HIGHLY PREVALENT CHRONIC INFLAMMATORY SKIN DISEASE THAT IS CHARACTERIZED BY INTENSE PRURITUS, SERIOUSLY AFFECTING PATIENTS' QUALITY OF LIFE. ITS PATHOPHYSIOLOGY, WHICH INVOLVES BOTH THE ADAPTIVE AND INNATE IMMUNE RESPONSES AS WELL AS SKIN BARRIER DEFECTS, IS STILL POORLY UNDERSTOOD. WE RECENTLY IDENTIFIED A MICRORNA, MIR-335, AS A KEY DRIVER OF KERATINOCYTE DIFFERENTIATION AND CORNIFICATION, WHICH IS ESSENTIAL FOR THE ESTABLISHMENT OF A HEALTHY SKIN BARRIER. HOWEVER, EXPRESSION OF MIR-335 IS LOST IN AD, LEADING TO BARRIER DEFECT. WE FURTHER DEMONSTRATED HOW BELINOSTAT, A HISTONE DEACETYLASE INHIBITOR, CAN EFFECTIVELY RESTORE MIR-335 AND RESOLVE THE BARRIER DEFECT IN A DRY SKIN MODEL. HERE, IN THIS COMMENTARY, WE HIGHLIGHT THE ROLE OF BELINOSTAT IN THE TREATMENT OF AD AND DISCUSS THE NEED FOR MORE RESEARCH INTO CROSSTALK BETWEEN EPIGENETIC AND NON-CODING RNA-BASED REGULATION, AS WELL AS POSSIBLE THERAPEUTIC STRATEGIES TARGETING THE EPIGENOME. 2021 2 3104 34 GENOMIC, EPIGENOMIC, TRANSCRIPTOMIC, PROTEOMIC AND METABOLOMIC APPROACHES IN ATOPIC DERMATITIS. ATOPIC DERMATITIS (AD) IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH A HIGH PREVALENCE IN THE DEVELOPED COUNTRIES. IT IS ASSOCIATED WITH ATOPIC AND NON-ATOPIC DISEASES, AND ITS CLOSE CORRELATION WITH ATOPIC COMORBIDITIES HAS BEEN GENETICALLY DEMONSTRATED. ONE OF THE MAIN ROLES OF GENETIC STUDIES IS TO COMPREHEND THE DEFECTS OF THE CUTANEOUS BARRIER DUE TO FILAGGRIN DEFICIT AND EPIDERMAL SPONGIOSIS. RECENTLY, EPIGENETIC STUDIES STARTED TO ANALYZE THE INFLUENCE OF THE ENVIRONMENTAL FACTORS ON GENE EXPRESSION. THE EPIGENOME IS CONSIDERED TO BE A SUPERIOR SECOND CODE THAT CONTROLS THE GENOME, WHICH INCLUDES ALTERATIONS OF THE CHROMATIN. THE EPIGENETIC CHANGES DO NOT ALTER THE GENETIC CODE, HOWEVER, CHANGES IN THE CHROMATIN STRUCTURE COULD ACTIVATE OR INHIBIT THE TRANSCRIPTION PROCESS OF CERTAIN GENES AND CONSEQUENTLY, THE TRANSLATION PROCESS OF THE NEW MRNA INTO A POLYPEPTIDE CHAIN. IN-DEPTH ANALYSIS OF THE TRANSCRIPTOMIC, METABOLOMIC AND PROTEOMIC STUDIES ALLOW TO UNRAVEL DETAILED MECHANISMS THAT CAUSE AD. THE EXTRACELLULAR SPACE AND LIPID METABOLISM ARE ASSOCIATED WITH AD THAT IS INDEPENDENT OF THE FILAGGRIN EXPRESSION. ON THE OTHER HAND, AROUND 45 PROTEINS ARE CONSIDERED AS THE PRINCIPAL COMPONENTS IN THE ATOPIC SKIN. MOREOVER, GENETIC STUDIES BASED ON THE DISRUPTED CUTANEOUS BARRIER CAN LEAD TO THE DEVELOPMENT OF NEW TREATMENTS TARGETING THE CUTANEOUS BARRIER OR CUTANEOUS INFLAMMATION. UNFORTUNATELY, AT PRESENT, THERE ARE NO TARGET THERAPIES THAT FOCUS ON THE EPIGENETIC PROCESS OF AD. HOWEVER, IN THE FUTURE, MIR-143 COULD BE AN IMPORTANT OBJECTIVE FOR NEW THERAPIES, AS IT TARGETS THE MIR-335:SOX AXIS, THEREBY RESTORING THE MIR-335 EXPRESSION, AND REPAIRING THE CUTANEOUS BARRIER DEFECTS. 2023 3 845 27 CHILDHOOD ATOPIC DERMATITIS: CURRENT DEVELOPMENTS, TREATMENT APPROACHES, AND FUTURE EXPECTATIONS. ATOPIC DERMATITIS (AD) IS THE MOST COMMON CHRONIC INFLAMMATORY SKIN DISORDER OF CHILDHOOD. UNDERLYING FACTORS THAT CONTRIBUTE TO AD ARE IMPAIRED EPITHELIAL BARRIER, ALTERATIONS IN THE LIPID COMPOSITION OF THE SKIN, IMMUNOLOGICAL IMBALANCE INCLUDING INCREASED TH2/TH1 RATIO, PROINFLAMMATORY CYTOKINES, DECREASED T REGULATORY CELLS, GENETIC MUTATIONS, AND EPIGENETIC ALTERATIONS. ATOPIC DERMATITIS IS A MULTIFACTORIAL DISEASE WITH A PARTICULARLY COMPLICATED PATHOPHYSIOLOGY. DISCOVERIES TO DATE MAY BE CONSIDERED THE TIP OF THE ICEBERG, AND THE INCREASING NUMBER OF STUDIES IN THIS FIELD INDICATE THAT THERE ARE MANY POINTS TO BE ELUCIDATED IN AD PATHOPHYSIOLOGY. IN THIS REVIEW, WE AIMED TO ILLUSTRATE THE CURRENT UNDERSTANDING OF THE UNDERLYING PATHOGENIC MECHANISMS IN AD, TO EVALUATE AVAILABLE TREATMENT OPTIONS WITH A FOCUS ON RECENTLY DISCOVERED THERAPEUTIC AGENTS, AND TO DETERMINE THE PERSONAL, FAMILIAL, AND ECONOMIC BURDENS OF THE DISEASE, WHICH ARE FREQUENTLY NEGLECTED ISSUES IN AD. CURRENTLY AVAILABLE THERAPIES ONLY PROVIDE TRANSIENT SOLUTIONS AND CANNOT FULLY CURE THE DISEASE. HOWEVER, ADVANCES IN THE UNDERSTANDING OF THE PATHOGENIC MECHANISMS OF THE DISEASE HAVE LED TO THE PRODUCTION OF NEW TREATMENT OPTIONS, WHILE ONGOING DRUG TRIALS ALSO HAVE HAD PROMISING RESULTS. 2019 4 2064 31 EPIGENETIC CONTROL OF INFLAMMATION IN ATOPIC DERMATITIS. ATOPIC DERMATITIS (AD), ALSO KNOWN AS ATOPIC ECZEMA, IS A COMMON BUT ALSO COMPLEX CHRONIC, ITCHY SKIN CONDITION WITH UNDERLYING INFLAMMATION OF THE SKIN. THIS SKIN AILMENT IS PREVALENT WORLDWIDE AND AFFECTS PEOPLE OF ALL AGES, PARTICULARLY CHILDREN BELOW FIVE YEARS OF AGE. THE ITCHING AND RESULTING RASHES IN AD PATIENTS ARE OFTEN THE RESULT OF INFLAMMATORY SIGNALS, THUS NECESSITATING A CLOSER LOOK AT THE INFLAMMATION-REGULATING MECHANISMS FOR PUTATIVE RELIEF, CARE AND THERAPY. SEVERAL CHEMICAL- AS WELL AS GENETICALLY-INDUCED ANIMAL MODELS HAVE ESTABLISHED THE IMPORTANCE OF TARGETING PRO-INFLAMMATORY AD MICROENVIRONMENT. EPIGENETIC MECHANISMS ARE GAINING ATTENTION TOWARDS A BETTER UNDERSTANDING OF THE ONSET AS WELL AS THE PROGRESSION OF INFLAMMATION. SEVERAL PHYSIOLOGICAL PROCESSES WITH IMPLICATIONS IN PATHOPHYSIOLOGY OF AD, SUCH AS, BARRIER DYSFUNCTION EITHER DUE TO REDUCED FILAGGRIN / HUMAN BETA-DEFENSINS OR ALTERED MICROBIOME, REPROGRAMING OF FC RECEPTORS WITH RESULTING OVEREXPRESSION OF HIGH AFFINITY IGE RECEPTORS, ELEVATED EOSINOPHIL NUMBERS OR THE ELEVATED IL-22 PRODUCTION BY CD4 + T CELLS HAVE UNDERLYING EPIGENETIC MECHANISMS THAT INCLUDE DIFFERENTIAL PROMOTER METHYLATION AND/OR REGULATION BY NON-CODING RNAS. REVERSING THESE EPIGENETIC CHANGES HAS BEEN VERIFIED TO REDUCE INFLAMMATORY BURDEN THROUGH ALTERED SECRETION OF CYTOKINES IL-6, IL-4, IL-13, IL-17, IL-22 ETC, WITH BENEFIT AGAINST AD PROGRESSION IN EXPERIMENTAL MODELS. A THOROUGH UNDERSTANDING OF EPIGENETIC REMODELING OF INFLAMMATION IN AD HAS THE POTENTIAL OF OPENING AVENUES FOR NOVEL DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC OPTIONS. 2023 5 1172 32 CONTRIBUTION OF THE ENVIRONMENT, EPIGENETIC MECHANISMS AND NON-CODING RNAS IN PSORIASIS. DESPITE THE INCREASING RESEARCH AND CLINICAL INTEREST IN THE PREDISPOSITION OF PSORIASIS, A CHRONIC INFLAMMATORY SKIN DISEASE, THE MULTITUDE OF GENETIC AND ENVIRONMENTAL FACTORS INVOLVED IN ITS PATHOGENESIS REMAIN UNCLEAR. THIS COMPLEXITY IS FURTHER EXACERBATED BY THE SEVERAL CELL TYPES THAT ARE IMPLICATED IN PSORIASIS'S PROGRESSION, INCLUDING KERATINOCYTES, MELANOCYTES AND VARIOUS IMMUNE CELL TYPES. THE OBSERVED INTERACTIONS BETWEEN THE GENETIC SUBSTRATE AND THE ENVIRONMENT LEAD TO EPIGENETIC ALTERATIONS THAT DIRECTLY OR INDIRECTLY AFFECT GENE EXPRESSION. CHANGES IN DNA METHYLATION AND HISTONE MODIFICATIONS THAT ALTER DNA-BINDING SITE ACCESSIBILITY, AS WELL AS NON-CODING RNAS IMPLICATED IN THE POST-TRANSCRIPTIONAL REGULATION, ARE MECHANISMS OF GENE TRANSCRIPTIONAL ACTIVITY MODIFICATION AND THEREFORE AFFECT THE PATHWAYS INVOLVED IN THE PATHOGENESIS OF PSORIASIS. IN THIS REVIEW, WE SUMMARIZE THE RESEARCH CONDUCTED ON THE ENVIRONMENTAL FACTORS CONTRIBUTING TO THE DISEASE ONSET, EPIGENETIC MODIFICATIONS AND NON-CODING RNAS EXHIBITING DEREGULATION IN PSORIASIS, AND WE FURTHER CATEGORIZE THEM BASED ON THE UNDER-STUDY CELL TYPES. WE ALSO ASSESS THE RECENT LITERATURE CONSIDERING THERAPEUTIC APPLICATIONS TARGETING MOLECULES THAT COMPROMISE THE EPIGENOME, AS A WAY TO SUPPRESS THE INFLAMMATORY CUTANEOUS CASCADE. 2022 6 2591 36 EPIGENETICS OF PSORIASIS. PSORIASIS IS A CHRONIC AND RECURRENT INFLAMMATORY SKIN DISEASE, INVOLVING THE RAPID PROLIFERATION AND ABNORMAL DIFFERENTIATION OF KERATINOCYTES AND ACTIVATION OF T CELLS. IT IS GENERALLY ACCEPTED THAT THE CENTRAL PATHOGENESIS OF PSORIASIS IS A T CELL-DOMINANT IMMUNE DISORDER AFFECTED BY MULTIPLE FACTORS INCLUDING GENETIC SUSCEPTIBILITY, ENVIRONMENTAL FACTORS, INNATE AND ADAPTIVE IMMUNE RESPONSES, ETC. HOWEVER, THE EXACT ETIOLOGY IS LARGELY UNKNOWN. IN RECENT YEARS, EPIGENETIC INVOLVEMENTS, SUCH AS THE DNA METHYLATION, CHROMATIN MODIFICATIONS, AND NONCODING RNA REGULATION ARE REPORTED TO BE CRITICAL FOR THE PATHOGENESIS OF PSORIASIS. HOWEVER, THE INTERPLAY BETWEEN THESE FACTORS HAS ONLY RECENTLY BEEN STARTED TO BE UNRAVELED. NOTABLY, INHIBITORS OF ENZYMES THAT WORK IN EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLTRANSFERASES AND HISTONE DEACETYLASES, ARE BEGINNING TO APPEAR IN THE CLINICAL SETTING TO RESTORE NORMAL EPIGENETIC PATTERNS (GENERALI ET AL. IN J AUTOIMMUN 83:51-61, 2017), PROVIDING NOVEL THERAPEUTIC POTENTIAL AS NOVEL TREATMENT TARGETS FOR PSORIASIS. INDEED, MEDICATIONS PREVIOUSLY USED TO TREAT AUTOIMMUNE DISEASES HAVE LATER BEEN DISCOVERED TO EXERT THEIR ACTION VIA EPIGENETIC MECHANISMS. HEREIN, WE REVIEW THE FINDINGS ON EPIGENETICS ASSOCIATED WITH PSORIASIS, AND DISCUSS FUTURE PERSPECTIVES IN THIS FIELD. 2020 7 4872 34 OUTSIDE-IN HYPOTHESIS REVISITED: THE ROLE OF MICROBIAL, EPITHELIAL, AND IMMUNE INTERACTIONS. OBJECTIVE: OUR UNDERSTANDING OF THE ORIGIN OF ALLERGIC DISEASES HAS INCREASED IN RECENT YEARS, HIGHLIGHTING THE IMPORTANCE OF MICROBIAL DYSBIOSIS AND EPITHELIAL BARRIER DYSFUNCTION IN AFFECTED TISSUES. EXPLORING THE MICROBIAL-EPITHELIAL-IMMUNE CROSSTALK UNDERLYING THE MECHANISMS OF ALLERGIC DISEASES WILL ALLOW THE DEVELOPMENT OF NOVEL PREVENTION AND TREATMENT STRATEGIES FOR ALLERGIC DISEASES. DATA SOURCES: THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN MICROBIAL, EPITHELIAL, AND IMMUNE INTERACTIONS IN ATOPIC DERMATITIS, ALLERGIC RHINITIS, CHRONIC RHINOSINUSITIS, AND ASTHMA. STUDY SELECTIONS: WE PERFORMED A LITERATURE SEARCH, IDENTIFYING RELEVANT RECENT PRIMARY ARTICLES AND REVIEW ARTICLES. RESULTS: DYNAMIC CROSSTALK BETWEEN THE ENVIRONMENTAL FACTORS AND MICROBIAL, EPITHELIAL, AND IMMUNE CELLS IN THE DEVELOPMENT OF ATOPIC DERMATITIS, ALLERGIC RHINITIS, CHRONIC RHINOSINUSITIS, AND ASTHMA UNDERLIES THE PATHOGENESIS OF THESE DISEASES. THERE IS SUBSTANTIAL EVIDENCE IN THE LITERATURE SUGGESTING THAT ENVIRONMENTAL FACTORS DIRECTLY AFFECT BARRIER FUNCTION OF THE EPITHELIUM. IN ADDITION, T-HELPER 2 (T(H)2) CELLS, TYPE 2 INNATE LYMPHOID CELLS, AND THEIR CYTOKINE INTERLEUKIN 13 (IL-13) DAMAGE SKIN AND LUNG BARRIERS. THE EFFECTS OF ENVIRONMENTAL FACTORS MAY AT LEAST IN PART BE MEDIATED BY EPIGENETIC MECHANISMS. HISTONE DEACETYLASE ACTIVATION BY TYPE 2 IMMUNE RESPONSE HAS A MAJOR EFFECT ON LEAKY BARRIERS AND BLOCKING OF HISTONE DEACETYLASE ACTIVITY CORRECTS THE DEFECTIVE BARRIER IN HUMAN AIR-LIQUID INTERFACE CULTURES AND MOUSE MODELS OF ALLERGIC ASTHMA WITH RHINITIS. WE ALSO PRESENT AND DISCUSS A NOVEL DEVICE TO DETECT AND MONITOR SKIN BARRIER DYSFUNCTION, WHICH PROVIDES AN OPPORTUNITY TO RAPIDLY AND ROBUSTLY ASSESS DISEASE SEVERITY. CONCLUSION: A COMPLEX INTERPLAY BETWEEN ENVIRONMENTAL FACTORS, EPITHELIUM, AND THE IMMUNE SYSTEM IS INVOLVED IN THE DEVELOPMENT OF SYSTEMIC ALLERGIC DISEASES. 2020 8 2070 24 EPIGENETIC CONTROL OF SKIN IMMUNITY. EPIGENETICS HAS BEEN WELL UNDERSTOOD FOR ITS ROLE IN CELL DEVELOPMENT; HOWEVER, IT IS NOW KNOWN TO REGULATE MANY PROCESSES INVOLVED IN IMMUNE CELL ACTIVATION IN A VARIETY OF CELLS. THE SKIN MAINTAINS HOMEOSTASIS VIA CROSSTALK BETWEEN IMMUNE AND NON-IMMUNE CELLS. DISRUPTION OF NORMAL EPIGENETIC REGULATION IN THESE CELLS MAY ALTER THE TRANSCRIPTION OF IMMUNE-REGULATORY FACTORS AND AFFECT THE IMMUNOLOGICAL BALANCE IN THE SKIN. THIS REVIEW SUMMARIZES RECENT EVIDENCE FOR THE EPIGENETIC REGULATION OF SKIN IMMUNITY. MUCH OF WHAT IS KNOWN ABOUT EPIGENETIC INVOLVEMENT IN SKIN IMMUNITY IS ASSOCIATED WITH DNA METHYLATION. THIS REVIEW FOCUSES ON EPIGENETIC REGULATION OF HISTONE MODIFICATION AND CHROMATIN REMODELING AND DESCRIBES THEIR ROLE IN THE TRANSCRIPTIONAL REGULATION OF IMMUNE-REGULATORY FACTORS. WHILE MUCH IS STILL UNKNOWN REGARDING THE REGULATION OF SKIN IMMUNITY VIA HISTONE MODIFICATION OR CHROMATIN REMODELING, THESE PROCESSES MAY UNDERLIE THE PATHOGENESIS OF CHRONIC CUTANEOUS IMMUNE DISORDERS. 2023 9 6643 32 UNRAVELLING THE COMPLEX GENETIC BACKGROUND OF ATOPIC DERMATITIS: FROM GENETIC ASSOCIATION RESULTS TOWARDS NOVEL THERAPEUTIC STRATEGIES. ATOPIC DERMATITIS (AD) IS A CHRONIC INFLAMMATORY SKIN DISEASE ARISING FROM COMPLEX INTERACTION BETWEEN GENETIC AND ENVIRONMENTAL FACTORS. AS THE STARTING POINT OF THE SO-CALLED "ATOPIC MARCH", E.G. THE PROGRESSION TOWARDS ALLERGIC ASTHMA IN SOME BUT NOT ALL AFFECTED CHILDREN, AD HAS COME INTO FOCUS FOR POTENTIAL DISEASE-MODIFYING STRATEGIES. TO ELUCIDATE THE GENETIC FACTORS INFLUENCING AD DEVELOPMENT, LINKAGE, ASSOCIATION AS WELL AS GENOME-WIDE ASSOCIATION STUDIES HAVE BEEN PERFORMED OVER THE LAST TWO DECADES. THE RESULTS SUGGEST THAT BESIDES VARIATION IN IMMUNE-MEDIATED PATHWAYS, AN INTACT SKIN BARRIER FUNCTION PLAYS A KEY ROLE IN AD DEVELOPMENT. MUTATIONS IN THE GENE ENCODING FILAGGRIN, A MAJOR STRUCTURAL PROTEIN IN THE EPIDERMIS, HAVE BEEN CONSISTENTLY ASSOCIATED WITH AD, ESPECIALLY THE EARLY-ONSET PERSISTENT FORM OF DISEASE, AND ARE REGARDED AS THE MOST SIGNIFICANT KNOWN RISK FACTOR FOR AD DEVELOPMENT TO DATE. ADDITIONALLY, VARIATION IN SOME OTHER GENES INVOLVED IN SKIN INTEGRITY AND BARRIER FUNCTION HAVE SHOWN ASSOCIATION WITH AD. HOWEVER, THE KNOWN GENETIC RISK FACTORS CAN ONLY EXPLAIN A SMALL PART OF THE HERITABILITY AT THE MOMENT. WHOLE-EXOME OR WHOLE-GENOME SEQUENCING STUDIES HAVE NOT BEEN REPORTED YET, BUT WILL PROBABLY SOON EVALUATE THE INFLUENCE OF RARE VARIATIONS FOR AD DEVELOPMENT. ADDITIONALLY, LARGE MULTI-CENTRE STUDIES COMPREHENSIVELY INCORPORATING GENE-GENE AND GENE-ENVIRONMENT INTERACTIONS AS WELL AS EPIGENETIC MECHANISMS MIGHT FURTHER ELUCIDATE THE GENETIC FACTORS UNDERLYING AD PATHOGENESIS AND, THUS, OPEN THE WAY FOR A MORE INDIVIDUALIZED TREATMENT IN THE FUTURE. 2015 10 6624 34 UNDERSTANDING PSORIASIS: ROLE OF MIRNAS. PSORIASIS IS A CHRONIC, IMMUNE-MEDIATED INFLAMMATORY SKIN DISEASE, WITH A MULTIFACTORIAL ETIOLOGY AND IMPORTANT IMMUNOLOGIC, GENETIC AND ENVIRONMENTAL COMPONENTS. PSORIASIS VULGARIS REPRESENTS ITS MOST COMMON FORM, WITH A VARIABLE PREVALENCE ACROSS THE GLOBE. ALTHOUGH ITS PATHOGENESIS REMAINS TO BE FULLY ELUCIDATED, A LACK OF BALANCE IN THE EPIGENETIC NETWORK HAS BEEN SHOWN TO TRIGGER CERTAIN ELEMENTS OF THIS DISEASE, POSSIBLY ALTERING ITS OUTCOME. MICRORNAS ARE SMALL NON-CODING RNA MOLECULES INVOLVED IN RNA-SILENCING AND THE POST-TRANSCRIPTIONAL REGULATION OF GENE EXPRESSION, WHICH ALSO APPEAR TO MEDIATE THE IMMUNE DYSFUNCTION IN PSORIASIS. ALTHOUGH MICRORNA RESEARCH IS A NEW FIELD IN DERMATOLOGY AND PSORIASIS, THERE IS RAPIDLY ACCUMULATING EVIDENCE FOR ITS MAJOR CONTRIBUTION IN THE PATHOGENESIS OF CHRONIC INFLAMMATORY CONDITIONS, INCLUDING PSORIASIS AND OTHER DERMATOLOGICAL DISORDERS. FURTHERMORE, CIRCULATING MIRNAS IDENTIFIED IN PATIENTS' BLOOD SAMPLES HAVE BEEN IDENTIFIED AS PROMISING BIOMARKERS OF DIAGNOSIS, PROGNOSIS OR TREATMENT RESPONSE. EXTENDED INVESTIGATIONS IN THIS FIELD ARE REQUIRED, AS UNTIL NOW, THE EXACT INVOLVEMENT OF MIRNAS IN PSORIASIS HAVE REMAINED TO BE ENTIRELY ELUCIDATED. THIS SHORT REVIEW HIGHLIGHTS A NUMBER OF THE ROLES OF MIRNAS FOUND IN DIFFERENT STAGES OF PSORIASIS. 2018 11 3703 30 INFLAMMATORY SIGNALLING AS MEDIATOR OF EPIGENETIC MODULATION IN TISSUE-SPECIFIC CHRONIC INFLAMMATION. RECENT SUCCESSES OF THERAPEUTIC INTERVENTION IN CHRONIC INFLAMMATORY DISEASES USING EPIGENETIC MODIFIERS SUCH AS HISTONE DEACETYLASE INHIBITORS AND INHIBITORS OF DNA METHYLATION SUGGEST THAT EPIGENETIC REPROGRAMMING PLAYS A ROLE IN THE AETIOLOGY OF THESE DISEASES. THE EPIGENETIC SIGNATURE OF A GIVEN IMMUNE CELL IS REFLECTED IN THE HISTORY OF MODIFICATIONS FROM DIFFERENT SIGNALS THE CELL HAS BEEN SUBJECTED TO DURING DIFFERENTIATION. LIKE OTHER CELLS, DIFFERENTIATING IMMUNE CELLS ARE DEPENDENT ON A COMPLEX COMBINATION OF INTER- AND INTRACELL SIGNALLING AS WELL AS TRANSCRIPTION MACHINERIES TO MODULATE THEIR EPIGENOMES IN ORDER TO MEDIATE DIFFERENTIATION. DESPITE EXTENSIVE RESEARCH INTO THESE PROCESSES, THE LINK BETWEEN CELLULAR SIGNALLING AND EPIGENETIC MODULATION REMAINS POORLY UNDERSTOOD. HERE, WE REVIEW RECENT PROGRESS AND DISCUSS KEY FACTORS DRIVING EPIGENETIC MODULATION IN CHRONIC INFLAMMATION. 2009 12 2333 27 EPIGENETIC REGULATION OF INFLAMMATION: THE METABOLOMICS CONNECTION. EPIGENETIC FACTORS ARE CONSIDERED THE REGULATOR OF COMPLEX MACHINERY BEHIND INFLAMMATORY DISORDERS AND SIGNIFICANTLY CONTRIBUTED TO THE EXPRESSION OF INFLAMMATION-ASSOCIATED GENES. EPIGENETIC MODIFICATIONS MODULATE VARIATION IN THE EXPRESSION PATTERN OF TARGET GENES WITHOUT AFFECTING THE DNA SEQUENCE. THE CURRENT KNOWLEDGE OF EPIGENETIC RESEARCH FOCUSED ON THEIR ROLE IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES THAT CAUSES MORBIDITY AND MORTALITY WORLDWIDE. INFLAMMATORY DISEASES ARE CATEGORIZED AS ACUTE AND CHRONIC BASED ON THE DISEASE SEVERITY AND ARE REGULATED BY THE EXPRESSION PATTERN OF VARIOUS GENES. HENCE, UNDERSTANDING THE ROLE OF EPIGENETIC MODIFICATIONS DURING INFLAMMATION PROGRESSION WILL CONTRIBUTE TO THE DISEASE OUTCOMES AND THERAPEUTIC APPROACHES. THIS REVIEW ALSO FOCUSES ON THE METABOLOMICS APPROACH ASSOCIATED WITH THE STUDY OF INFLAMMATORY DISORDERS. INFLAMMATORY RESPONSES AND METABOLIC REGULATION ARE HIGHLY INTEGRATED AND VARIOUS ADVANCED TECHNIQUES ARE ADOPTED TO STUDY THE METABOLIC SIGNATURE MOLECULES. HERE WE DISCUSS SEVERAL METABOLOMICS APPROACHES USED TO LINK INFLAMMATORY DISORDERS AND EPIGENETIC CHANGES. WE PROPOSED THAT DECIPHERING THE MECHANISM BEHIND THE INFLAMMATION-METABOLISM LOOP MAY HAVE IMMENSE IMPORTANCE IN BIOMARKERS RESEARCH AND MAY ACT AS A PRINCIPAL COMPONENT IN DRUG DISCOVERY AS WELL AS THERAPEUTIC APPLICATIONS. 2022 13 6340 25 THE ROLE OF EPIGENETIC FACTORS IN PSORIASIS. PSORIASIS IS A CHRONIC, SYSTEMIC, IMMUNE-MEDIATED DISEASE WITH AN INCIDENCE OF APPROXIMATELY 2%. THE PATHOGENESIS OF THE DISEASE IS COMPLEX AND NOT YET FULLY UNDERSTOOD. GENETIC FACTORS PLAY A SIGNIFICANT ROLE IN THE PATHOGENESIS OF THE DISEASE. IN PREDISPOSED INDIVIDUALS, MULTIPLE TRIGGER FACTORS MAY CONTRIBUTE TO DISEASE ONSET AND EXACERBATIONS OF SYMPTOMS. ENVIRONMENTAL FACTORS (STRESS, INFECTIONS, CERTAIN MEDICATIONS, NICOTINISM, ALCOHOL, OBESITY) PLAY A SIGNIFICANT ROLE IN THE PATHOGENESIS OF PSORIASIS. IN ADDITION, EPIGENETIC MECHANISMS ARE CONSIDERED RESULT IN MODULATION OF INDIVIDUAL GENE EXPRESSION AND AN INCREASED LIKELIHOOD OF THE DISEASE. STUDIES HIGHLIGHT THE SIGNIFICANT ROLE OF EPIGENETIC FACTORS IN THE ETIOLOGY AND PATHOGENESIS OF PSORIASIS. EPIGENETIC MECHANISMS IN PSORIASIS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS. EPIGENETIC MECHANISMS INDUCE GENE EXPRESSION CHANGES UNDER THE INFLUENCE OF CHEMICAL MODIFICATIONS OF DNA AND HISTONES, WHICH ALTER CHROMATIN STRUCTURE AND ACTIVATE TRANSCRIPTION FACTORS OF SELECTED GENES, THUS LEADING TO TRANSLATION OF NEW MRNA WITHOUT AFFECTING THE DNA SEQUENCE. EPIGENETIC FACTORS CAN REGULATE GENE EXPRESSION AT THE TRANSCRIPTIONAL (VIA HISTONE MODIFICATION, DNA METHYLATION) AND POSTTRANSCRIPTIONAL LEVELS (VIA MICRORNAS AND LONG NON-CODING RNAS). THIS STUDY AIMS TO PRESENT AND DISCUSS THE DIFFERENT EPIGENETIC MECHANISMS IN PSORIASIS BASED ON A REVIEW OF THE AVAILABLE LITERATURE. 2021 14 4961 34 PATHOGENESIS OF PSORIASIS IN THE "OMIC" ERA. PART II. GENETIC, GENOMIC AND EPIGENETIC CHANGES IN PSORIASIS. PSORIASIS IS A MULTIFACTORIAL DISEASE IN WHICH GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS REGULATING GENE EXPRESSION PLAY A KEY ROLE. IN THE "GENOMIC ERA", GENOME-WIDE ASSOCIATION STUDIES TOGETHER WITH TARGET GENOTYPING PLATFORMS PERFORMED IN DIFFERENT ETHNIC POPULATIONS HAVE FOUND MORE THAN 50 GENETIC SUSCEPTIBLE MARKERS ASSOCIATED WITH THE RISK OF PSORIASIS WHICH HAVE BEEN IDENTIFIED SO FAR. UP TILL NOW, THE STRONGEST ASSOCIATION WITH THE RISK OF THE DISEASE HAS BEEN PROVED FOR HLA-C*06 GENE. THE MAJORITY OF OTHER PSORIASIS RISK SNPS ARE SITUATED NEAR THE GENES ENCODING MOLECULES INVOLVED IN ADAPTIVE AND INNATE IMMUNITY, AND SKIN BARRIER FUNCTION. MANY CONTEMPORARY STUDIES INDICATE THAT THE EPIGENETIC CHANGES: HISTONE MODIFICATION, PROMOTER METHYLATIONS, LONG NON-CODING AND MICRO-RNA HYPEREXPRESSION ARE CONSIDERED AS FACTORS CONTRIBUTING TO PSORIASIS PATHOGENESIS AS THEY REGULATE ABNORMAL KERATINOCYTE DIFFERENTIATION AND PROLIFERATION, ABERRANT KERATINOCYTES - INFLAMMATORY CELLS COMMUNICATION, NEOANGIOGENESIS AND CHRONIC INFLAMMATION. THE CIRCULATING MIRNAS DETECTED IN THE BLOOD MAY BECOME SPECIFIC MARKERS IN THE DIAGNOSIS, PROGNOSIS AND RESPONSE TO THE TREATMENT OF THE DISEASE. THE INHIBITION OF EXPRESSION IN SELECTED MIRNAS MAY BE A NEW PROMISING THERAPY OPTION FOR PATIENTS WITH PSORIASIS. 2020 15 6131 32 THE EPIGENETIC REGULATION OF WOUND HEALING. SIGNIFICANCE: EPIGENETIC REGULATORY MECHANISMS ARE ESSENTIAL FOR EPIDERMAL HOMEOSTASIS AND CONTRIBUTE TO THE PATHOGENESIS OF MANY SKIN DISEASES, INCLUDING SKIN CANCER AND PSORIASIS. HOWEVER, WHILE THE EPIGENETIC REGULATION OF EPIDERMAL HOMEOSTASIS IS NOW BECOMING ACTIVE AREA OF RESEARCH, THE EPIGENETIC MECHANISMS CONTROLLING THE WOUND HEALING RESPONSE REMAIN RELATIVELY UNTOUCHED. RECENT ADVANCES: SUBSTANTIAL PROGRESS ACHIEVED WITHIN THE LAST TWO DECADES IN UNDERSTANDING EPIGENETIC MECHANISMS CONTROLLING GENE EXPRESSION ALLOWED DEFINING SEVERAL LEVELS, INCLUDING COVALENT DNA AND HISTONE MODIFICATIONS, ATP-DEPENDENT AND HIGHER-ORDER CHROMATIN CHROMATIN REMODELING, AS WELL AS NONCODING RNA- AND MICRORNA-DEPENDENT REGULATION. RESEARCH PERTAINED OVER THE LAST FEW YEARS SUGGESTS THAT EPIGENETIC REGULATORY MECHANISMS PLAY A PIVOTAL ROLE IN THE REGULATION OF SKIN REGENERATION AND CONTROL AN EXECUTION OF REPARATIVE GENE EXPRESSION PROGRAMS IN BOTH SKIN EPITHELIUM AND MESENCHYME. CRITICAL ISSUES: EPIGENETIC REGULATORS APPEAR TO BE INHERENTLY INVOLVED IN THE PROCESSES OF SKIN REPAIR, AND ARE ABLE TO DYNAMICALLY REGULATE KERATINOCYTE PROLIFERATION, DIFFERENTIATION, AND MIGRATION, TOGETHER WITH INFLUENCING DERMAL REGENERATION AND NEOANGIOGENESIS. THIS IS ACHIEVED THROUGH A SERIES OF COMPLEX REGULATORY MECHANISMS THAT ARE ABLE TO BOTH STIMULATE AND REPRESS GENE ACTIVATION TO TRANSIENTLY ALTER CELLULAR PHENOTYPE AND BEHAVIOR, AND INTERACT WITH GROWTH FACTOR ACTIVITY. FUTURE DIRECTIONS: UNDERSTANDING THE MOLECULAR BASIS OF EPIGENETIC REGULATION IS A PRIORITY AS IT REPRESENTS POTENTIAL THERAPEUTIC TARGETS FOR THE TREATMENT OF BOTH ACUTE AND CHRONIC SKIN CONDITIONS. FUTURE RESEARCH IS, THEREFORE, IMPERATIVE TO HELP DISTINGUISH EPIGENETIC MODULATING DRUGS THAT CAN BE USED TO IMPROVE WOUND HEALING. 2014 16 2578 33 EPIGENETICS OF INFLAMMATORY BOWEL DISEASES. INFLAMMATORY BOWEL DISEASES ARE MULTIFACTORIAL, CHRONIC, CONTINUOUS, RELAPSING, AND IMMUNE-MEDIATED DISEASES OF THE GASTROINTESTINAL TRACT. IT HAS BEEN BELIEVED THAT MECHANISMS UNDERLYING INFLAMMATORY BOWEL DISEASES INCLUDE GENETIC PREDISPOSITION, ENVIRONMENTAL FACTORS, AND ALTERED IMMUNE RESPONSE TO THE GUT MICROBIOME. THE EPIGENETIC MODULATION TAKES PLACE VIA CHROMATIN MODIFICATIONS, INCLUDING PHOSPHORYLATION, ACETYLATION, METHYLATION, SUMOYLATION, AND UBIQUITINATION. THE METHYLATION LEVELS OF COLONIC TISSUE WERE FOUND WELL CORRELATED TO BLOOD SAMPLES IN INFLAMMATORY BOWEL DISEASES. MOREOVER, THE METHYLATION LEVEL OF SPECIFIC GENES WAS DIFFERENT BETWEEN CROHN'S DISEASE AND ULCERATIVE COLITIS. IT HAS BEEN SHOWN THAT THE ENZYMES AFFECTING HISTONE MODIFICATIONS LIKE HISTONE DEACETYLASES AND HISTONE ACETYLTRANSFERASES DO NOT ACT SOLELY ON HISTONES BUT ALSO AFFECT THE ACETYLATION OF MANY PROTEINS SUCH AS P53 AND STAT3. IT HAS BEEN ALREADY SHOWN THAT A NONSELECTIVE HISTONE DEACETYLASE INHIBITOR, VORINOSTAT (SAHA), WHICH IS CURRENTLY BEING USED IN SEVERAL CANCER TREATMENTS, SHOWED ANTI-INFLAMMATORY ACTIVITIES IN MOUSE MODELS. AMONG EPIGENETIC ALTERATIONS, LONG NON-CODING RNAS AND MICRORNAS PLAY SIGNIFICANT ROLES IN T-CELL MATURATION, DIFFERENTIATION, ACTIVATION, AND SENILITY. THE LONG NON-CODING RNA AND MICRORNA EXPRESSION PROFILES CAN PERFECTLY SEPARATE INFLAMMATORY BOWEL DISEASE PATIENTS FROM HEALTHY CONTROLS AND ARE REMARKED AS BIOMARKERS OF INFLAMMATORY BOWEL DISEASES. OVERALL, MANY STUDIES HAVE SHOWN THAT EPIGENETIC INHIBITORS CAN TARGET SIGNIFICANT SIGNAL PATHWAYS IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASES, AND THE IMPACT OF EPIGENETIC INHIBITORS IS BEING STUDIED IN CLINICAL TRIALS. IN CONCLUSION, EXPLORING MORE EPIGENETIC PATHWAYS REGARDING INFLAMMATORY BOWEL DISEASE PATHOGENESIS WILL HELP US TO DISCOVER THERAPEUTIC TARGETS AND NEW DRUGS AND AGENTS TARGETING MIRNAS IN INFLAMMATORY BOWEL DISEASES. IN GENERAL, DISCOVERING EPIGENETIC TARGETS COULD IMPROVE THE DIAGNOSIS AND TREATMENT OF INFLAMMATORY BOWEL DISEASES. 2023 17 2550 30 EPIGENETICS IN OSTEOARTHRITIS: POTENTIAL OF HDAC INHIBITORS AS THERAPEUTICS. OSTEOARTHRITIS (OA) IS THE MOST COMMON JOINT DISEASE AND THE LEADING CAUSE OF CHRONIC DISABILITY IN MIDDLE-AGED AND OLDER POPULATIONS WORLDWIDE. THE DEVELOPMENT OF DISEASE MODIFYING THERAPY FOR OA IS IN ITS INFANCY LARGELY BECAUSE THE REGULATORY MECHANISMS FOR THE MOLECULAR EFFECTORS OF OA PATHOGENESIS ARE POORLY UNDERSTOOD. RECENT STUDIES IDENTIFIED EPIGENETIC EVENTS AS A CRITICAL REGULATOR OF MOLECULAR PLAYERS INVOLVED IN THE INDUCTION AND DEVELOPMENT OF OA. EPIGENETIC MECHANISMS INCLUDE DNA METHYLATION, NON-CODING RNA AND HISTONE MODIFICATIONS. THE AIM OF THIS REVIEW IS TO BRIEFLY HIGHLIGHT THE RECENT ADVANCES IN THE EPIGENETICS OF CARTILAGE AND POTENTIAL OF HDACS (HISTONE DEACETYLASES) INHIBITORS IN THE THERAPEUTIC MANAGEMENT OF OA. WE SUMMARIZE THE RECENT STUDIES UTILIZING HDAC INHIBITORS AS POTENTIAL THERAPEUTICS FOR INHIBITING DISEASE PROGRESSION AND PREVENTING THE CARTILAGE DESTRUCTION IN OA. HDACS CONTROL NORMAL CARTILAGE DEVELOPMENT AND HOMEOSTASIS AND UNDERSTANDING THE IMPACT OF HDACS INHIBITORS ON THE DISEASE PATHOGENESIS IS OF INTEREST BECAUSE OF ITS IMPORTANCE IN AFFECTING OVERALL CARTILAGE HEALTH AND HOMEOSTASIS. THESE FINDINGS ALSO SHED NEW LIGHT ON CARTILAGE DISEASE PATHOPHYSIOLOGY AND PROVIDE SUBSTANTIAL EVIDENCE THAT HDACS MAY BE POTENTIAL NOVEL THERAPEUTIC TARGETS IN OA. 2018 18 2532 30 EPIGENETICS IN ATHEROSCLEROSIS AND INFLAMMATION. ATHEROSCLEROSIS IS A MULTIFACTORIAL DISEASE WITH A SEVERE BURDEN ON WESTERN SOCIETY. RECENT INSIGHTS INTO THE PATHOGENESIS OF ATHEROSCLEROSIS UNDERSCORE THE IMPORTANCE OF CHRONIC INFLAMMATION IN BOTH THE INITIATION AND PROGRESSION OF VASCULAR REMODELLING. EXPRESSION OF IMMUNOREGULATORY MOLECULES BY VASCULAR WALL COMPONENTS WITHIN THE ATHEROSCLEROTIC LESIONS IS ACCORDINGLY THOUGHT TO CONTRIBUTE TO THE ONGOING INFLAMMATORY PROCESS. BESIDES GENE REGULATORY PROTEINS (TRANSCRIPTION FACTORS), EPIGENETIC MECHANISMS ALSO PLAY AN ESSENTIAL AND FUNDAMENTAL ROLE IN THE TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION. THESE EPIGENETIC MECHANISMS CHANGE THE ACCESSIBILITY OF CHROMATIN BY DNA METHYLATION AND HISTONE MODIFICATIONS. EPIGENETIC MODULATORS ARE THUS CRITICALLY INVOLVED IN THE REGULATION OF VASCULAR, IMMUNE AND TISSUE-SPECIFIC GENE EXPRESSION WITHIN THE ATHEROSCLEROTIC LESION. IMPORTANTLY, EPIGENETIC PROCESSES ARE REVERSIBLE AND MAY PROVIDE AN EXCELLENT THERAPEUTIC TARGET. THE CONCEPT OF EPIGENETIC REGULATION IS GRADUALLY BEING RECOGNIZED AS AN IMPORTANT FACTOR IN THE PATHOGENESIS OF ATHEROSCLEROSIS. RECENT RESEARCH PROVIDES AN ESSENTIAL LINK BETWEEN INFLAMMATION AND REPROGRAMMING OF THE EPIGENOME. IN THIS REVIEW WE THEREFORE DISCUSS THE BASIS OF EPIGENETIC REGULATION - AND THE CONTRIBUTION THEREOF IN THE REGULATION OF INFLAMMATORY PROCESSES IN GENERAL AND DURING ATHEROSCLEROSIS IN PARTICULAR. MOREOVER WE HIGHLIGHT POTENTIAL THERAPEUTIC INTERVENTIONS BASED ON EPIGENETIC MECHANISMS. 2010 19 6447 26 THERAPEUTIC PROSPECTS FOR EPIGENETIC MODULATION. INTRODUCTION: EPIGENETICS DESCRIBES THE PHENOMENON OF HERITABLE CHANGES IN GENE REGULATION GOVERNED BY NON-MENDELIAN PROCESSES, PRIMARILY THROUGH BIOCHEMICAL MODIFICATIONS TO CHROMATIN THAT OCCUR DURING CELL DIFFERENTIATION AND DEVELOPMENT. ABNORMAL LEVELS OF DNA AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. DRUGS THAT TARGET THE PROTEINS CONTROLLING THESE CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS WITH SINGLE TARGET PHARMACOLOGIES THAT ARE SUSCEPTIBLE TO BIOCHEMICAL PATHWAY DEGENERACY. AREAS COVERED: THIS ARTICLE REVIEWS RESEARCH CHARACTERIZING DYSREGULATION OF EPIGENETIC PROCESSES IN CANCER, IMMUNO-INFLAMMATORY, PSYCHIATRIC, NEUROLOGICAL, METABOLIC AND VIROLOGY DISEASE AREAS, AND SUMMARIZES RECENT DEVELOPMENTS IN IDENTIFYING SMALL MOLECULE MODULATORS THAT ARE BEING USED TO INFORM TARGET DISCOVERY AND INITIATE DRUG DISCOVERY PROJECTS. EXPERT OPINION: THERE ARE NUMEROUS POTENTIAL OPPORTUNITIES FOR EPIGENETIC MODULATORS IN TREATING A WIDE RANGE OF CHRONIC DISEASES; HOWEVER, THE FIELD IS COMPLEX, INVOLVING > 300 PROTEINS, AND MUCH WORK IS STILL REQUIRED TO PROVIDE TOOLS TO UNRAVEL THE FUNCTIONS OF INDIVIDUAL PROTEINS, PARTICULARLY IN VIVO. THIS GROUNDWORK IS ESSENTIAL TO ALLOW THE DRUG DISCOVERY COMMUNITY TO FOCUS ON THOSE EPIGENETIC PROTEINS MOST LIKELY TO BE SUITABLE TARGETS FOR SAFE, EFFICACIOUS NEW THERAPIES. 2011 20 3038 25 GENOME ENGINEERING FOR OSTEOARTHRITIS: FROM DESIGNER CELLS TO DISEASE-MODIFYING DRUGS. BACKGROUND: OSTEOARTHRITIS (OA) IS A HIGHLY PREVALENT DEGENERATIVE JOINT DISEASE INVOLVING JOINT CARTILAGE AND ITS SURROUNDING TISSUES. OA IS THE LEADING CAUSE OF PAIN AND DISABILITY WORLDWIDE. AT PRESENT, THERE ARE NO DISEASE-MODIFYING OA DRUGS, AND THE PRIMARY THERAPIES INCLUDE EXERCISE AND NONSTEROIDAL ANTI-INFLAMMATORY DRUGS UNTIL TOTAL JOINT REPLACEMENT AT THE END-STAGE OF THE DISEASE. METHODS: IN THIS REVIEW, WE SUMMARIZED THE CURRENT STATE OF KNOWLEDGE IN GENETIC AND EPIGENETIC ASSOCIATIONS AND RISK FACTORS FOR OA AND THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. RESULTS: GENOME-WIDE ASSOCIATION STUDIES AND ANALYSIS OF EPIGENETIC MODIFICATIONS (SUCH AS MIRNA EXPRESSION, DNA METHYLATION AND HISTONE MODIFICATIONS) CONDUCTED ACROSS VARIOUS POPULATIONS SUPPORT THE NOTION THAT THERE IS A GENETIC BASIS FOR CERTAIN SUBSETS OF OA PATHOGENESIS. CONCLUSION: WITH RECENT ADVANCES IN THE DEVELOPMENT OF GENOME EDITING TECHNOLOGIES SUCH AS THE CRISPR-CAS9 SYSTEM, THESE GENETIC AND EPIGENETIC ALTERNATIONS IN OA CAN BE USED AS PLATFORMS FROM WHICH POTENTIAL BIOMARKERS FOR THE DIAGNOSIS, PROGNOSIS, DRUG RESPONSE, AND DEVELOPMENT OF POTENTIAL PERSONALIZED THERAPEUTIC TARGETS FOR OA CAN BE APPROACHED. FURTHERMORE, GENOME EDITING HAS ALLOWED THE DEVELOPMENT OF "DESIGNER" CELLS, WHEREBY THE RECEPTORS, GENE REGULATORY NETWORKS, OR TRANSGENES CAN BE MODIFIED AS A BASIS FOR NEW CELL-BASED THERAPIES. 2019