1 857 124 CHROMATIN ARCHITECTURE REVEALS CELL TYPE-SPECIFIC TARGET GENES FOR KIDNEY DISEASE RISK VARIANTS. BACKGROUND: CELL TYPE-SPECIFIC TRANSCRIPTIONAL PROGRAMMING RESULTS FROM THE COMBINATORIAL INTERPLAY BETWEEN THE REPERTOIRE OF ACTIVE REGULATORY ELEMENTS. DISEASE-ASSOCIATED VARIANTS DISRUPT SUCH PROGRAMMING, LEADING TO ALTERED EXPRESSION OF DOWNSTREAM REGULATED GENES AND THE ONSET OF PATHOLOGICAL STATES. HOWEVER, DUE TO THE NON-LINEAR REGULATORY PROPERTIES OF NON-CODING ELEMENTS SUCH AS ENHANCERS, WHICH CAN ACTIVATE TRANSCRIPTION AT LONG DISTANCES AND IN A NON-DIRECTIONAL WAY, THE IDENTIFICATION OF CAUSAL VARIANTS AND THEIR TARGET GENES REMAINS CHALLENGING. HERE, WE PROVIDE A MULTI-OMICS ANALYSIS TO IDENTIFY REGULATORY ELEMENTS ASSOCIATED WITH FUNCTIONAL KIDNEY DISEASE VARIANTS, AND DOWNSTREAM REGULATED GENES. RESULTS: IN ORDER TO UNDERSTAND THE GENETIC RISK OF KIDNEY DISEASES, WE GENERATED A COMPREHENSIVE DATASET OF THE CHROMATIN LANDSCAPE OF HUMAN KIDNEY TUBULE CELLS, INCLUDING TRANSCRIPTION-CENTERED 3D CHROMATIN ORGANIZATION, HISTONE MODIFICATIONS DISTRIBUTION AND TRANSCRIPTOME WITH HICHIP, CHIP-SEQ AND RNA-SEQ. WE IDENTIFIED GENOME-WIDE FUNCTIONAL ELEMENTS AND THOUSANDS OF INTERACTIONS BETWEEN THE DISTAL ELEMENTS AND TARGET GENES. THE RESULTS REVEALED THAT RISK VARIANTS FOR RENAL TUMOR AND CHRONIC KIDNEY DISEASE WERE ENRICHED IN KIDNEY TUBULE CELLS. WE FURTHER PINPOINTED THE TARGET GENES FOR THE VARIANTS AND VALIDATED TWO TARGET GENES BY CRISPR/CAS9 GENOME EDITING TECHNIQUES IN ZEBRAFISH, DEMONSTRATING THAT SLC34A1 AND MTX1 WERE INDISPENSABLE GENES TO MAINTAIN KIDNEY FUNCTION. CONCLUSIONS: OUR RESULTS PROVIDE A VALUABLE MULTI-OMICS RESOURCE ON THE CHROMATIN LANDSCAPE OF HUMAN KIDNEY TUBULE CELLS AND ESTABLISH A BIOINFORMATIC PIPELINE IN DISSECTING FUNCTIONS OF KIDNEY DISEASE-ASSOCIATED VARIANTS BASED ON CELL TYPE-SPECIFIC EPIGENOME. 2021 2 1269 40 CYTOSINE METHYLATION CHANGES IN ENHANCER REGIONS OF CORE PRO-FIBROTIC GENES CHARACTERIZE KIDNEY FIBROSIS DEVELOPMENT. BACKGROUND: ONE IN ELEVEN PEOPLE IS AFFECTED BY CHRONIC KIDNEY DISEASE, A CONDITION CHARACTERIZED BY KIDNEY FIBROSIS AND PROGRESSIVE LOSS OF KIDNEY FUNCTION. EPIDEMIOLOGICAL STUDIES INDICATE THAT ADVERSE INTRAUTERINE AND POSTNATAL ENVIRONMENTS HAVE A LONG-LASTING ROLE IN CHRONIC KIDNEY DISEASE DEVELOPMENT. EPIGENETIC INFORMATION REPRESENTS A PLAUSIBLE CARRIER FOR MEDIATING THIS PROGRAMMING EFFECT. HERE WE DEMONSTRATE THAT GENOME-WIDE CYTOSINE METHYLATION PATTERNS OF HEALTHY AND CHRONIC KIDNEY DISEASE TUBULE SAMPLES OBTAINED FROM PATIENTS SHOW SIGNIFICANT DIFFERENCES. RESULTS: WE IDENTIFY DIFFERENTIALLY METHYLATED REGIONS AND VALIDATE THESE IN A LARGE REPLICATION DATASET. THE DIFFERENTIALLY METHYLATED REGIONS ARE RARELY OBSERVED ON PROMOTERS, BUT MOSTLY OVERLAP WITH PUTATIVE ENHANCER REGIONS, AND THEY ARE ENRICHED IN CONSENSUS BINDING SEQUENCES FOR IMPORTANT RENAL TRANSCRIPTION FACTORS. THIS INDICATES THEIR IMPORTANCE IN GENE EXPRESSION REGULATION. A CORE SET OF GENES THAT ARE KNOWN TO BE RELATED TO KIDNEY FIBROSIS, INCLUDING GENES ENCODING COLLAGENS, SHOW CYTOSINE METHYLATION CHANGES CORRELATING WITH DOWNSTREAM TRANSCRIPT LEVELS. CONCLUSIONS: OUR REPORT RAISES THE POSSIBILITY THAT EPIGENETIC DYSREGULATION PLAYS A ROLE IN CHRONIC KIDNEY DISEASE DEVELOPMENT VIA INFLUENCING CORE PRO-FIBROTIC PATHWAYS AND CAN AID THE DEVELOPMENT OF NOVEL BIOMARKERS AND FUTURE THERAPEUTICS. 2013 3 4228 22 METHYLATION OF INFLAMMATORY CELLS IN LUNG DISEASES. THIS CHAPTER OVERVIEWS ROLES OF DNA METHYLATION IN INFLAMMATORY CELL BIOLOGY WITH THE FOCUSES ON LYMPHOCYTES AND MACROPHAGES/MONOCYTES IN LUNG DISEASES, ALTHOUGH THE MOLECULAR MECHANISMS BY WHICH TARGET GENES ARE METHYLATED AND REGULATED IN LUNG DISEASES REMAIN UNCLEAR. MOST OF EPIGENETIC STUDIES ON DNA METHYLATION OF TARGET GENES IN LUNG DISEASES MAINLY DEMONSTRATED THE CORRELATION OF DNA METHYLATION OF TARGET GENES WITH THE LEVELS OF OTHER CORRESPONDING FACTORS, WITH THE SPECIFICITY OF CLINICAL PHENOMES, AND WITH THE SEVERITY OF LUNG DISEASES. THERE IS AN URGENT NEED TO IDENTIFY AND VALIDATE THE SPECIFICITY AND REGULATORY MECHANISMS OF INFLAMMATORY CELL EPIGENETICS IN DEPTH. THE EPIGENETIC HETEROGENEITY AMONG DIFFERENT SUBSETS OF T CELLS AND AMONG PROMOTERS OR NON-PROMOTERS OF TARGET GENES SHOULD BE FURTHERMORE CLARIFIED IN ACUTE OR CHRONIC LUNG DISEASES AND CANCERS. THE HYPER/HYPO-METHYLATION AND MODIFICATIONS OF CHROMOSOL AND EXTRACHROMOSOMAL DNA MAY RESULT IN ALTERNATIONS IN PROTEINS WITHIN INFLAMMATORY CELLS, WHICH CAN BE IDENTIFIED AS DISEASE-SPECIFIC BIOMARKERS AND THERAPEUTIC TARGETS. 2020 4 3826 37 INVESTIGATION OF EPIGENETICS IN KIDNEY CELL BIOLOGY. EPIGENETICS IS THE STUDY OF HERITABLE CHANGES IN DNA OR ITS ASSOCIATED PROTEINS EXCEPT MUTATIONS IN GENE SEQUENCE. EPIGENETIC REGULATION PLAYS FUNDAMENTAL ROLES IN THE PROCESSES OF KIDNEY CELL BIOLOGY THROUGH THE ACTION OF DNA METHYLATION, CHROMATIN MODIFICATIONS VIA EPIGENETIC REGULATORS AND INTERACTION VIA TRANSCRIPTION FACTORS, AND NONCODING RNA SPECIES. KIDNEY DISEASES, INCLUDING ACUTE KIDNEY INJURY, CHRONIC KIDNEY DISEASE, NEPHRITIC AND NEPHROTIC SYNDROMES, PYELONEPHRITIS AND POLYCYSTIC KIDNEY DISEASES ARE DRIVEN BY ABERRANT ACTIVITY IN NUMEROUS SIGNALING PATHWAYS IN EVEN INDIVIDUAL KIDNEY CELL. EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION, HISTONE ACETYLATION AND METHYLATION, NONCODING RNAS, AND PROTEIN POSTTRANSLATIONAL MODIFICATIONS, COULD DISRUPT ESSENTIAL PATHWAYS THAT PROTECT THE RENAL CELLS FROM UNCONTROLLED GROWTH, APOPTOSIS AND ESTABLISHMENT OF OTHER RENAL ASSOCIATED SYNDROMES, WHICH HAVE BEEN RECOGNIZED AS ONE OF THE CRITICAL MECHANISMS FOR REGULATING FUNCTIONAL CHANGES THAT DRIVE AND MAINTAIN THE KIDNEY DISEASE PHENOTYPE. IN THIS CHAPTER, WE BRIEFLY SUMMARIZE THE EPIGENETIC MECHANISMS IN KIDNEY CELL BIOLOGY AND EPIGENETIC BASIS OF KIDNEY DEVELOPMENT, AND INTRODUCE EPIGENETIC TECHNIQUES THAT CAN BE USED IN INVESTIGATING THE MOLECULAR MECHANISM OF KIDNEY CELL BIOLOGY AND KIDNEYS DISEASES, PRIMARILY FOCUSING ON THE INTEGRATION OF DNA METHYLATION AND CHROMATIN IMMUNOPRECIPITATION TECHNOLOGIES INTO KIDNEY DISEASE ASSOCIATED STUDIES. FUTURE STUDIES USING THESE EMERGING TECHNOLOGIES WILL ELUCIDATE HOW ALTERATIONS IN THE RENAL CELL EPIGENOME COOPERATE WITH GENETIC ABERRATIONS FOR KIDNEY DISEASE INITIATION AND PROGRESSION. INCORPORATING EPIGENOMIC TESTING INTO THE CLINICAL RESEARCH IS ESSENTIAL TO FUTURE STUDIES WITH EPIGENETICS BIOMARKERS AND PRECISION MEDICINE USING EMERGING EPIGENETIC THERAPIES. 2019 5 6431 35 THE USE OF TARGETED NEXT GENERATION SEQUENCING TO EXPLORE CANDIDATE REGULATORS OF TGF-BETA1'S IMPACT ON KIDNEY CELLS. AIMS/HYPOTHESIS: TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA1) PLAYS AN IMPORTANT REGULATORY ROLE IN THE PROGRESSION OF CHRONIC KIDNEY FAILURE. FURTHER, DAMAGE TO KIDNEY GLOMERULAR MESANGIAL CELLS IS CENTRAL TO THE PROGRESSION OF DIABETIC NEPHROPATHY. THE AIM OF THIS STUDY WAS TO EXPLORE THE GENETIC ASSOCIATIONS BETWEEN MRNA, MICRORNA, AND EPIGENETICS IN MESANGIAL CELLS IN RESPONSE TO TGF-BETA1. METHODS: THE REGULATORY EFFECTS OF TGF-BETA1 ON MESANGIAL CELLS WERE INVESTIGATED AT DIFFERENT MOLECULAR LEVELS BY TREATING MESANGIAL CELLS WITH TGF-BETA1 FOR 3 DAYS FOLLOWED BY GENOME-WIDE MIRNA, RNA, DNA METHYLATION, AND H3K27ME3 EXPRESSION PROFILING USING NEXT GENERATION SEQUENCING (NGS). RESULTS: OUR RESULTS PROVIDE THE FIRST COMPREHENSIVE, COMPUTATIONALLY INTEGRATED REPORT OF RNA-SEQ, MIRNA-SEQ, AND EPIGENOMIC ANALYSES ACROSS ALL GENETIC VARIATIONS, CONFIRMING THE OCCURRENCE OF DNA METHYLATION AND H3K27ME3 IN RESPONSE TO TGF-BETA1. OUR FINDINGS SHOW THAT THE EXPRESSION OF KLF7 AND GJA4 ARE INVOLVED IN TGF-BETA1 REGULATED DNA METHYLATION. OUR DATA ALSO PROVIDE EVIDENCE OF THE ASSOCIATION BETWEEN EPIGENETIC CHANGES AND THE EXPRESSION OF GENES CLOSELY RELATED TO TGF-BETA1 REGULATION. CONCLUSION: THIS STUDY HAS ADVANCED OUR CURRENT KNOWLEDGE OF MECHANISMS THAT CONTRIBUTE TO THE EXPRESSION OF TGF-BETA1-REGULATED GENES INVOLVED IN THE PATHOGENESIS OF KIDNEY DISEASE. THE MOLECULAR UNDERPINNINGS OF TGF-BETA1 STIMULATION OF KIDNEY CELLS WAS DETERMINED, THEREBY PROVIDING A ROBUST PLATFORM FOR FURTHER TARGET EXPLORATION. 2018 6 6533 35 TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES ASSOCIATED WITH SEVERE ASTHMA. THE 10% OF PATIENTS WITH THE MOST SEVERE ASTHMA ARE RESPONSIBLE FOR A LARGE PART OF HEALTHCARE EXPENDITURE AND MORBIDITY. UNDERSTANDING THE PROCESSES INVOLVED IS KEY IF NEW THERAPEUTIC APPROACHES ARE TO BE DEVELOPED. EVIDENCE IS ACCUMULATING THAT CHRONIC DISEASES SUCH AS ASTHMA ARE ASSOCIATED WITH TEMPORAL AND SPATIAL ALTERATIONS IN THE PATTERN OF INFLAMMATORY GENE EXPRESSION WITHIN THE AIRWAYS. EXPRESSION OF THESE GENES CAN BE REGULATED BY TRANSCRIPTIONAL, POSTTRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS. IT IS WELL ESTABLISHED THAT BINDING OF ACTIVATED TRANSCRIPTION FACTORS TO SPECIFIC INDUCIBLE GENE PROMOTER SITES IS TIGHTLY CONTROLLED BY CHROMATIN STATE AS A RESULT OF HISTONE MODIFICATIONS, PARTICULARLY THE BALANCE BETWEEN HISTONE ACETYLATION AND DEACETYLATION [1]. THE INTERACTION BETWEEN TRANSCRIPTION FACTORS AND THE PROMOTER IS KEY TO THE DIVERSIFICATION OF GENE EXPRESSION IN A TIME DEPENDENT MANNER LEADING TO ALTERED GENE EXPRESSION PROFILES. ALTERATIONS OF THE ACCESSIBILITY OF TRANSCRIPTION FACTORS TO THE DNA CAN HAVE RESIDING EFFECTS UPON GENE TRANSCRIPTION. THIS REVIEW WILL FOCUS ON THE REGULATION OF SEVERAL GROUPS OF KEY GENES WHICH ARE INVOLVED IN CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA DRAWING MAINLY FROM OUR EXPERIENCE OF STUDYING THESE PROCESSES IN AIRWAY SMOOTH MUSCLE CELLS. AN OVERVIEW IS SHOWN IN FIGURE 1. 2011 7 1562 28 DNA METHYLATION OF ENHANCER ELEMENTS IN MYELOID NEOPLASMS: THINK OUTSIDE THE PROMOTERS? GENE REGULATION THROUGH DNA METHYLATION IS A WELL DESCRIBED PHENOMENON THAT HAS A PROMINENT ROLE IN PHYSIOLOGICAL AND PATHOLOGICAL CELL-STATES. THIS EPIGENETIC MODIFICATION IS USUALLY GROUPED IN REGIONS DENOMINATED CPG ISLANDS, WHICH FREQUENTLY CO-LOCALIZE WITH GENE PROMOTERS, SILENCING THE TRANSCRIPTION OF THOSE GENES. RECENT GENOME-WIDE DNA METHYLATION STUDIES HAVE CHALLENGED THIS PARADIGM, DEMONSTRATING THAT DNA METHYLATION OF REGULATORY REGIONS OUTSIDE PROMOTERS IS ABLE TO INFLUENCE CELL-TYPE SPECIFIC GENE EXPRESSION PROGRAMS UNDER PHYSIOLOGIC OR PATHOLOGIC CONDITIONS. COUPLING GENOME-WIDE DNA METHYLATION ASSAYS WITH HISTONE MARK ANNOTATION HAS ALLOWED FOR THE IDENTIFICATION OF SPECIFIC EPIGENOMIC CHANGES THAT AFFECT ENHANCER REGULATORY REGIONS, REVEALING AN ADDITIONAL LAYER OF COMPLEXITY TO THE EPIGENETIC REGULATION OF GENE EXPRESSION. IN THIS REVIEW, WE SUMMARIZE THE NOVEL EVIDENCE FOR THE MOLECULAR AND BIOLOGICAL REGULATION OF DNA METHYLATION IN ENHANCER REGIONS AND THE DYNAMISM OF THESE CHANGES CONTRIBUTING TO THE FINE-TUNING OF GENE EXPRESSION. WE ALSO ANALYZE THE CONTRIBUTION OF ENHANCER DNA METHYLATION ON THE EXPRESSION OF RELEVANT GENES IN ACUTE MYELOID LEUKEMIA AND CHRONIC MYELOPROLIFERATIVE NEOPLASMS. THE CHARACTERIZATION OF THE ABERRANT ENHANCER DNA METHYLATION PROVIDES NOT ONLY A NOVEL PATHOGENIC MECHANISM FOR DIFFERENT TUMORS BUT ALSO HIGHLIGHTS NOVEL POTENTIAL THERAPEUTIC TARGETS FOR MYELOID DERIVED NEOPLASMS. 2019 8 2873 28 FUNCTIONAL METHYLOME ANALYSIS OF HUMAN DIABETIC KIDNEY DISEASE. IN PATIENTS WITH DIABETES MELLITUS, POOR METABOLIC CONTROL HAS A LONG-LASTING IMPACT ON KIDNEY DISEASE DEVELOPMENT. EPIGENETIC CHANGES, INCLUDING CYTOSINE METHYLATION, HAVE BEEN PROPOSED AS POTENTIAL MEDIATORS OF THE LONG-LASTING EFFECT OF ADVERSE METABOLIC EVENTS. OUR UNDERSTANDING OF THE PRESENCE AND CONTRIBUTION OF METHYLATION CHANGES TO DISEASE DEVELOPMENT IS LIMITED BECAUSE OF THE LACK OF COMPREHENSIVE BASE-RESOLUTION METHYLOME INFORMATION OF HUMAN KIDNEY TISSUE SAMPLES AND SITE-SPECIFIC METHYLATION EDITING. BASE RESOLUTION, WHOLE-GENOME BISULFITE SEQUENCING METHYLOME MAPS OF HUMAN DIABETIC KIDNEY DISEASE (DKD) TUBULE SAMPLES, AND ASSOCIATED GENE EXPRESSION MEASURED BY RNA SEQUENCING HIGHLIGHTED WIDESPREAD METHYLATION CHANGES IN DKD. PATHWAY ANALYSIS HIGHLIGHTED COORDINATED (METHYLATION AND GENE EXPRESSION) CHANGES IN IMMUNE SIGNALING, INCLUDING TUMOR NECROSIS FACTOR ALPHA (TNF). CHANGES IN TNF METHYLATION CORRELATED WITH KIDNEY FUNCTION DECLINE. DCAS9-TET1-BASED LOWERING OF THE CYTOSINE METHYLATION LEVEL OF THE TNF DIFFERENTIALLY METHYLATED REGION RESULTED IN AN INCREASE IN THE TNF TRANSCRIPT LEVEL, INDICATING THAT METHYLATION OF THIS LOCUS PLAYS AN IMPORTANT ROLE IN CONTROLLING TNF EXPRESSION. INCREASING THE TNF LEVEL IN DIABETIC MICE INCREASED DISEASE SEVERITY, SUCH AS ALBUMINURIA. IN SUMMARY, OUR RESULTS INDICATE WIDESPREAD METHYLATION DIFFERENCES IN DKD KIDNEYS AND HIGHLIGHTS EPIGENETIC CHANGES IN THE TNF LOCUS AND ITS CONTRIBUTION TO THE DEVELOPMENT OF NEPHROPATHY IN PATIENTS WITH DIABETES MELLITUS. 2019 9 1604 33 DNA METHYLATION SUSTAINS "INFLAMED" MEMORY OF PERIPHERAL IMMUNE CELLS AGGRAVATING KIDNEY INFLAMMATORY RESPONSE IN CHRONIC KIDNEY DISEASE. THE INCIDENCE OF CHRONIC KIDNEY DISEASE (CKD) HAS RAPIDLY INCREASED IN THE PAST DECADES. A PROGRESSIVE LOSS OF KIDNEY FUNCTION CHARACTERIZES A PART OF CKD EVEN WITH INTENSIVE SUPPORTIVE TREATMENT. IRRESPECTIVE OF ITS ETIOLOGY, CKD PROGRESSION IS GENERALLY ACCOMPANIED WITH THE DEVELOPMENT OF CHRONIC KIDNEY INFLAMMATION THAT IS PATHOLOGICALLY FEATURED BY THE LOW-GRADE BUT CHRONIC ACTIVATION OF RECRUITED IMMUNE CELLS. CUMULATIVE EVIDENCE SUPPORT THAT ABERRANT DNA METHYLATION PATTERN OF DIVERSE PERIPHERAL IMMUNE CELLS, INCLUDING T CELLS AND MONOCYTES, IS CLOSELY ASSOCIATED WITH CKD DEVELOPMENT IN MANY CHRONIC DISEASE SETTINGS. THE CHANGE OF DNA METHYLATION PROFILE CAN SUSTAIN FOR A LONG TIME AND AFFECT THE FUTURE GENES EXPRESSION IN THE CIRCULATING IMMUNE CELLS EVEN AFTER THEY MIGRATE FROM THE CIRCULATION INTO THE INVOLVED KIDNEY. IT IS OF CLINICAL INTEREST TO REVEAL THE UNDERLYING MECHANISM OF HOW ALTERED DNA METHYLATION REGULATES THE INTENSITY AND THE TIME LENGTH OF THE INFLAMMATORY RESPONSE IN THE RECRUITED EFFECTOR CELLS. WE AND OTHERS RECENTLY DEMONSTRATED THAT ALTERED DNA METHYLATION OCCURS IN PERIPHERAL IMMUNE CELLS AND PROFOUNDLY CONTRIBUTES TO CKD DEVELOPMENT IN SYSTEMIC CHRONIC DISEASES, SUCH AS DIABETES AND HYPERTENSION. THIS REVIEW WILL SUMMARIZE THE CURRENT FINDINGS ABOUT THE INFLUENCE OF ABERRANT DNA METHYLATION ON CIRCULATING IMMUNE CELLS AND HOW IT POTENTIALLY DETERMINES THE OUTCOME OF CKD. 2021 10 347 36 ALTERED DNA METHYLATION IN KIDNEY DISEASE: USEFUL MARKERS AND THERAPEUTIC TARGETS. RECENT STUDIES HAVE DEMONSTRATED THE ASSOCIATION OF ALTERED EPIGENOMES WITH LIFESTYLE-RELATED DISEASES. EPIGENETIC REGULATION PROMOTES BIOLOGICAL PLASTICITY IN RESPONSE TO ENVIRONMENTAL CHANGES, AND SUCH PLASTICITY MAY CAUSE A 'MEMORY EFFECT', A SUSTAINED EFFECT OF TRANSIENT TREATMENT OR AN INSULT IN THE COURSE OF LIFESTYLE-RELATED DISEASES. WE INVESTIGATED THE SIGNIFICANCE OF EPIGENETIC CHANGES IN SEVERAL GENES REQUIRED FOR RENAL INTEGRITY, INCLUDING THE NEPHRIN GENE IN PODOCYTES, AND THE SUSTAINED ANTI-PROTEINURIC EFFECT, FOCUSING ON THE TRANSCRIPTION FACTOR KRUPPEL-LIKE FACTOR 4 (KLF4). WE FURTHER REPORTED THE ROLE OF THE DNA REPAIR FACTOR LYSINE-ACETYL TRANSFERASE 5 (KAT5), WHICH ACTS COORDINATELY WITH KLF4, IN PODOCYTE INJURY CAUSED BY A HYPERGLYCEMIC STATE THROUGH THE ACCELERATION OF DNA DAMAGE AND EPIGENETIC ALTERATION. IN CONTRAST, KAT5 IN PROXIMAL TUBULAR CELLS PREVENTS ACUTE KIDNEY INJURY VIA GLOMERULAR FILTRATION REGULATION BY AN EPIGENETIC MECHANISM AS WELL AS PROMOTION OF DNA REPAIR, INDICATING THE CELL TYPE-SPECIFIC ACTION AND ROLES OF DNA REPAIR FACTORS. THIS REVIEW SUMMARIZES EPIGENETIC ALTERATIONS IN KIDNEY DISEASES, ESPECIALLY DNA METHYLATION, AND THEIR UTILITY AS MARKERS AND POTENTIAL THERAPEUTIC TARGETS. FOCUSING ON TRANSCRIPTION FACTORS OR DNA DAMAGE REPAIR FACTORS ASSOCIATED WITH EPIGENETIC CHANGES MAY BE MEANINGFUL DUE TO THEIR CELL-SPECIFIC EXPRESSION OR ACTION. WE BELIEVE THAT A BETTER UNDERSTANDING OF EPIGENETIC ALTERATIONS IN THE KIDNEY WILL LEAD TO THE DEVELOPMENT OF A NOVEL STRATEGY FOR CHRONIC KIDNEY DISEASE (CKD) TREATMENT. 2022 11 462 31 ARE ALTERATIONS IN DNA METHYLATION RELATED TO CKD DEVELOPMENT? THE MODIFICATIONS IN GENOMIC DNA METHYLATION ARE INVOLVED IN THE REGULATION OF NORMAL AND PATHOLOGICAL CELLULAR PROCESSES. THE EPIGENETIC REGULATION STIMULATES BIOLOGICAL PLASTICITY AS AN ADAPTIVE RESPONSE TO VARIATIONS IN ENVIRONMENTAL FACTORS. THE ROLE OF EPIGENETIC CHANGES IS VITAL FOR THE DEVELOPMENT OF SOME DISEASES, INCLUDING ATHEROGENESIS, CANCERS, AND CHRONIC KIDNEY DISEASE (CKD). THE RESULTS OF STUDIES PRESENTED IN THIS REVIEW HAVE SUGGESTED THAT ALTERED DNA METHYLATION CAN MODULATE THE EXPRESSION OF PRO-INFLAMMATORY AND PRO-FIBROTIC GENES, AS WELL THOSE ESSENTIAL FOR KIDNEY DEVELOPMENT AND FUNCTION, THUS STIMULATING RENAL DISEASE PROGRESSION. ABNORMALLY INCREASED HOMOCYSTEINE, HYPOXIA, AND INFLAMMATION HAVE BEEN SUGGESTED TO ALTER EPIGENETIC REGULATION OF GENE EXPRESSION IN CKD. STUDIES OF RENAL SAMPLES HAVE DEMONSTRATED THE RELATIONSHIP BETWEEN VARIATIONS IN DNA METHYLATION AND FIBROSIS AND VARIATIONS IN ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) IN HUMAN CKD. THE UNRAVELLING OF THE GENETIC-EPIGENETIC PROFILE WOULD ENHANCE OUR UNDERSTANDING OF PROCESSES UNDERLYING THE DEVELOPMENT OF CKD. THE UNDERSTANDING OF MULTIFACETED RELATIONSHIP BETWEEN DNA METHYLATION, GENES EXPRESSION, AND DISEASE DEVELOPMENT AND PROGRESSION COULD IMPROVE THE ABILITY TO IDENTIFY INDIVIDUALS AT RISK OF CKD AND ENABLE THE CHOICE OF APPROPRIATE DISEASE MANAGEMENT. 2022 12 3308 30 HIGH-RESOLUTION TRANSCRIPTOMIC AND EPIGENETIC PROFILING IDENTIFIES NOVEL REGULATORS OF COPD. PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE STILL WAITING FOR CURATIVE TREATMENTS. CONSIDERING ITS ENVIRONMENTAL CAUSE, WE HYPOTHESIZED THAT COPD WILL BE ASSOCIATED WITH ALTERED EPIGENETIC SIGNALING IN LUNG CELLS. WE GENERATED GENOME-WIDE DNA METHYLATION MAPS AT SINGLE CPG RESOLUTION OF PRIMARY HUMAN LUNG FIBROBLASTS (HLFS) ACROSS COPD STAGES. WE SHOW THAT THE EPIGENETIC LANDSCAPE IS CHANGED EARLY IN COPD, WITH DNA METHYLATION CHANGES OCCURRING PREDOMINANTLY IN REGULATORY REGIONS. RNA SEQUENCING OF MATCHED FIBROBLASTS DEMONSTRATED DYSREGULATION OF GENES INVOLVED IN PROLIFERATION, DNA REPAIR, AND EXTRACELLULAR MATRIX ORGANIZATION. DATA INTEGRATION IDENTIFIED 110 CANDIDATE REGULATORS OF DISEASE PHENOTYPES THAT WERE LINKED TO FIBROBLAST REPAIR PROCESSES USING PHENOTYPIC SCREENS. OUR STUDY PROVIDES HIGH-RESOLUTION MULTI-OMIC MAPS OF HLFS ACROSS COPD STAGES. WE REVEAL NOVEL TRANSCRIPTOMIC AND EPIGENETIC SIGNATURES ASSOCIATED WITH COPD ONSET AND PROGRESSION AND IDENTIFY NEW CANDIDATE REGULATORS INVOLVED IN THE PATHOGENESIS OF CHRONIC LUNG DISEASES. THE PRESENCE OF VARIOUS EPIGENETIC FACTORS AMONG THE CANDIDATES DEMONSTRATES THAT EPIGENETIC REGULATION IN COPD IS AN EXCITING RESEARCH FIELD THAT HOLDS PROMISE FOR NOVEL THERAPEUTIC AVENUES FOR PATIENTS. 2023 13 1508 39 DNA METHYLATION AND MRNA AND MICRORNA EXPRESSION OF SLE CD4+ T CELLS CORRELATE WITH DISEASE PHENOTYPE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS AN AUTOIMMUNE DISEASE WELL KNOWN FOR ITS CLINICAL HETEROGENEITY, AND ITS ETIOLOGY SECONDARY TO A CROSS-TALK INVOLVING GENETIC PREDISPOSITION AND ENVIRONMENTAL STIMULI. ALTHOUGH GENOME-WIDE ANALYSIS HAS CONTRIBUTED GREATLY TO OUR UNDERSTANDING OF THE GENETIC BASIS OF SLE, THERE IS INCREASING EVIDENCE FOR A ROLE OF EPIGENETICS. INDEED, RECENT DATA HAVE DEMONSTRATED THAT IN PATIENTS WITH SLE, THERE ARE STRIKING ALTERATIONS OF DNA METHYLATION, HISTONE MODIFICATIONS, AND DEREGULATED MICRORNA EXPRESSION, THE SUM OF WHICH CONTRIBUTE TO OVER-EXPRESSION OF SELECT AUTOIMMUNE-RELATED GENES AND LOSS OF TOLERANCE. TO ADDRESS THIS ISSUE AT THE LEVEL OF CLINICAL PHENOTYPE, WE PERFORMED DNA METHYLATION, MRNA AND MICRORNA EXPRESSION SCREENING USING HIGH-THROUGHPUT SEQUENCING OF PURIFIED CD4+ T CELLS FROM PATIENTS WITH SLE, COMPARED TO AGE AND SEX MATCHED CONTROLS. IN PARTICULAR, WE STUDIED 42 PATIENTS WITH SLE AND DIVIDED THIS GROUP INTO THREE CLINICAL PHENOTYPES: A) THE PRESENCE OF SKIN LESIONS WITHOUT SIGNS OF SYSTEMIC PATHOLOGY; B) SKIN LESIONS BUT ALSO CHRONIC RENAL PATHOLOGY; AND C) SKIN LESIONS, CHRONIC RENAL PATHOLOGY AND POLYARTICULAR DISEASE. INTERESTINGLY, AND AS EXPECTED, SEQUENCING DATA REVEALED CHANGES IN DNA METHYLATION IN SLE COMPARED TO CONTROLS. HOWEVER, AND MORE IMPORTANTLY, ALTHOUGH THERE WERE COMMON METHYLATION CHANGES FOUND IN ALL GROUPS OF SLE COMPARED TO CONTROLS, THERE WAS SPECIFIC DNA METHYLATION CHANGES THAT CORRELATED WITH CLINICAL PHENOTYPE. THESE INCLUDED CHANGES IN THE NOVEL KEY TARGET GENES NLRP2, CD300LB AND S1PR3, AS WELL AS CHANGES IN THE CRITICAL PATHWAYS, INCLUDING THE ADHERENS JUNCTION AND LEUKOCYTE TRANSENDOTHELIAL MIGRATION. WE ALSO NOTED THAT A SIGNIFICANT PROPORTION OF GENES UNDERGOING DNA METHYLATION CHANGES WERE INVERSELY CORRELATED WITH GENE EXPRESSION AND THAT MIRNA SCREENING REVEALED THE EXISTENCE OF SUBSETS WITH CHANGES IN EXPRESSION. INTEGRATED ANALYSIS OF THIS DATA HIGHLIGHTS SPECIFIC SETS OF MIRNAS CONTROLLED BY DNA METHYLATION, AND GENES THAT ARE ALTERED BY METHYLATION AND TARGETED BY MIRNAS. IN CONCLUSION, OUR FINDINGS SUGGEST SELECT EPIGENETIC MECHANISMS THAT CONTRIBUTE TO CLINICAL PHENOTYPES AND FURTHER SHED LIGHT ON A NEW VENUE FOR BASIC SLE RESEARCH. 2014 14 2033 29 EPIGENETIC CHANGES IN SOLID AND HEMATOPOIETIC TUMORS. THERE ARE THREE CONNECTED MOLECULAR MECHANISMS OF EPIGENETIC CELLULAR MEMORY IN MAMMALIAN CELLS: DNA METHYLATION, HISTONE MODIFICATIONS, AND RNA INTERFERENCE. THE FIRST TWO HAVE NOW BEEN FIRMLY LINKED TO NEOPLASTIC TRANSFORMATION. HYPERMETHYLATION OF CPG-RICH PROMOTERS TRIGGERS LOCAL HISTONE CODE MODIFICATIONS RESULTING IN A CELLULAR CAMOUFLAGE MECHANISM THAT SEQUESTERS GENE PROMOTERS AWAY FROM TRANSCRIPTION FACTORS AND RESULTS IN STABLE SILENCING. THIS NORMALLY RESTRICTED MECHANISM IS UBIQUITOUSLY USED IN CANCER TO SILENCE HUNDREDS OF GENES, AMONG WHICH SOME CRITICALLY CONTRIBUTE TO THE NEOPLASTIC PHENOTYPE. VIRTUALLY EVERY PATHWAY IMPORTANT TO CANCER FORMATION IS AFFECTED BY THIS PROCESS. METHYLATION PROFILING OF HUMAN CANCERS REVEALS TISSUE-SPECIFIC EPIGENETIC SIGNATURES, AS WELL AS TUMOR-SPECIFIC SIGNATURES, REFLECTING IN PARTICULAR THE PRESENCE OF EPIGENETIC INSTABILITY IN A SUBSET OF CANCERS AFFECTED BY THE CPG ISLAND METHYLATOR PHENOTYPE. GENERALLY, METHYLATION PATTERNS CAN BE TRACED TO A TISSUE-SPECIFIC, PROLIFERATION-DEPENDENT ACCUMULATION OF ABERRANT PROMOTER METHYLATION IN AGING TISSUES, A PROCESS THAT CAN BE ACCELERATED BY CHRONIC INFLAMMATION AND LESS WELL-DEFINED MECHANISMS INCLUDING, POSSIBLY, DIET AND GENETIC PREDISPOSITION. THE EPIGENETIC MACHINERY CAN ALSO BE ALTERED IN CANCER BY SPECIFIC LESIONS IN EPIGENETIC EFFECTOR GENES, OR BY ABERRANT RECRUITMENT OF THESE GENES BY MUTANT TRANSCRIPTION FACTORS AND COACTIVATORS. EPIGENETIC PATTERNS ARE PROVING CLINICALLY USEFUL IN HUMAN ONCOLOGY VIA RISK ASSESSMENT, EARLY DETECTION, AND PROGNOSTIC CLASSIFICATION. PHARMACOLOGIC MANIPULATION OF THESE PATTERNS-EPIGENETIC THERAPY-IS ALSO POISED TO CHANGE THE WAY WE TREAT CANCER IN THE CLINIC. 2005 15 2541 34 EPIGENETICS IN KIDNEY DEVELOPMENT AND RENAL DISEASE. THE STUDY OF EPIGENETICS IS INTIMATELY LINKED AND INSEPARABLE FROM DEVELOPMENTAL BIOLOGY. MANY OF THE GENES THAT IMPRINT EPIGENETIC INFORMATION ON CHROMATIN FUNCTION DURING THE SPECIFICATION OF CELL LINEAGES IN THE DEVELOPING EMBRYO. THESE INCLUDE THE HISTONE METHYLTRANSFERASES AND THEIR COFACTORS OF THE POLYCOMB AND TRITHORAX GENE FAMILIES. HOW HISTONE METHYLATION IS ESTABLISHED AND WHAT REGULATES THE TISSUE AND LOCUS SPECIFICITY OF HISTONE METHYLATION IS AN EMERGING AREA OF RESEARCH. THE EMBRYONIC KIDNEY IS USED AS A MODEL TO UNDERSTAND HOW DNA-BINDING PROTEINS CAN SPECIFY CELL LINEAGES AND HOW SUCH PROTEINS INTERACT DIRECTLY WITH THE HISTONE METHYLATION MACHINERY TO GENERATE A UNIQUE EPIGENOME FOR PARTICULAR TISSUES AND CELL TYPES. IN ADULT TISSUES, HISTONE METHYLATION MARKS MUST BE MAINTAINED FOR NORMAL GENE EXPRESSION PATTERNS. IN CHRONIC AND ACUTE RENAL DISEASE, EPIGENETIC MARKS ARE BEING CHARACTERIZED AND CORRELATED WITH THE ESTABLISHMENT OF METABOLIC MEMORY, IN PART TO EXPLAIN THE PERSISTENCE OF PATHOLOGIES EVEN WHEN OPTIMAL TREATMENT MODALITIES ARE USED. THUS, THE STATE OF THE EPIGENOME IN ADULT CELLS MUST BE CONSIDERED WHEN ATTEMPTING TO ALLEVIATE OR ALTER GENE EXPRESSION PATTERNS IN DISEASE. 2015 16 2542 31 EPIGENETICS IN KIDNEY DISEASES. EPIGENETICS EXAMINES HERITABLE CHANGES IN DNA AND ITS ASSOCIATED PROTEINS EXCEPT MUTATIONS IN GENE SEQUENCE. EPIGENETIC REGULATION PLAYS FUNDAMENTAL ROLES IN KIDNEY CELL BIOLOGY THROUGH THE ACTION OF DNA METHYLATION, CHROMATIN MODIFICATION VIA EPIGENETIC REGULATORS AND NON-CODING RNA SPECIES. KIDNEY DISEASES, INCLUDING ACUTE KIDNEY INJURY, CHRONIC KIDNEY DISEASE, DIABETIC KIDNEY DISEASE AND RENAL FIBROSIS ARE MULTISTEP PROCESSES ASSOCIATED WITH NUMEROUS MOLECULAR ALTERATIONS EVEN IN INDIVIDUAL KIDNEY CELLS. EPIGENETIC ALTERATIONS, INCLUDING ANOMALOUS DNA METHYLATION, ABERRANT HISTONE ALTERATIONS AND CHANGES OF MICRORNA EXPRESSION ALL CONTRIBUTE TO KIDNEY PATHOGENESIS. THESE CHANGES ALTER THE GENOME-WIDE EPIGENETIC SIGNATURES AND DISRUPT ESSENTIAL PATHWAYS THAT PROTECT RENAL CELLS FROM UNCONTROLLED GROWTH, APOPTOSIS AND DEVELOPMENT OF OTHER RENAL ASSOCIATED SYNDROMES. MOLECULAR CHANGES IMPACT CELLULAR FUNCTION WITHIN KIDNEY CELLS AND ITS MICROENVIRONMENT TO DRIVE AND MAINTAIN DISEASE PHENOTYPE. IN THIS CHAPTER, WE BRIEFLY SUMMARIZE EPIGENETIC MECHANISMS IN FOUR KIDNEY DISEASES INCLUDING ACUTE KIDNEY INJURY, CHRONIC KIDNEY DISEASE, DIABETIC KIDNEY DISEASE AND RENAL FIBROSIS. WE PRIMARILY FOCUS ON CURRENT KNOWLEDGE ABOUT THE GENOME-WIDE PROFILING OF DNA METHYLATION AND HISTONE MODIFICATION, AND EPIGENETIC REGULATION ON SPECIFIC GENE(S) IN THE PATHOPHYSIOLOGY OF THESE DISEASES AND THE TRANSLATIONAL POTENTIAL OF IDENTIFYING NEW BIOMARKERS AND TREATMENT FOR PREVENTION AND THERAPY. INCORPORATING EPIGENOMIC TESTING INTO CLINICAL RESEARCH IS ESSENTIAL TO ELUCIDATE NOVEL EPIGENETIC BIOMARKERS AND DEVELOP PRECISION MEDICINE USING EMERGING THERAPIES. 2021 17 4250 27 METHYLATION-DEMETHYLATION DYNAMICS: IMPLICATIONS OF CHANGES IN ACUTE KIDNEY INJURY. OVER THE YEARS, THE EPIGENETIC LANDSCAPE HAS GROWN INCREASINGLY COMPLEX. UNTIL RECENTLY, METHYLATION OF DNA AND HISTONES WAS CONSIDERED ONE OF THE MOST IMPORTANT EPIGENETIC MODIFICATIONS. HOWEVER, WITH THE DISCOVERY OF ENZYMES INVOLVED IN THE DEMETHYLATION PROCESS, SEVERAL EXCITING PROSPECTS HAVE EMERGED THAT FOCUS ON THE DYNAMIC REGULATION OF METHYLATION AND ITS CRUCIAL ROLE IN DEVELOPMENT AND DISEASE. AN INTERPLAY OF THE METHYLATION-DEMETHYLATION MACHINERY CONTROLS THE PROCESS OF GENE EXPRESSION. SINCE ACUTE KIDNEY INJURY (AKI), A MAJOR RISK FACTOR FOR CHRONIC KIDNEY DISEASE AND DEATH, IS CHARACTERISED BY ABERRANT EXPRESSION OF GENES, UNDERSTANDING THE DYNAMICS OF METHYLATION AND DEMETHYLATION WILL PROVIDE NEW INSIGHTS INTO THE INTRICACIES OF THE DISEASE. RESEARCH ON EPIGENETICS IN AKI HAS ONLY MADE ITS MARK IN THE RECENT YEARS BUT HAS PROVIDED COMPELLING EVIDENCE THAT IMPLICATES THE INVOLVEMENT OF METHYLATION AND DEMETHYLATION CHANGES IN ITS PATHOPHYSIOLOGY. IN THIS REVIEW, WE EXPLORE THE ROLE OF METHYLATION AND DEMETHYLATION MACHINERY IN CELLULAR EPIGENETIC CONTROL AND FURTHER DISCUSS THE CONTRIBUTION OF METHYLOMIC CHANGES AND HISTONE MODIFICATIONS TO THE PATHOPHYSIOLOGY OF AKI. 2018 18 4668 25 NEW INSIGHTS INTO MOLECULAR MECHANISMS OF EPIGENETIC REGULATION IN KIDNEY DISEASE. THE NUMBER OF PATIENTS WITH KIDNEY FAILURE HAS INCREASED IN RECENT YEARS. DIFFERENT FACTORS CONTRIBUTE TO THE PROGRESSION OF CHRONIC KIDNEY DISEASE, INCLUDING GLOMERULAR SCLEROSIS, ATHEROSCLEROSIS OF THE RENAL ARTERIES AND TUBULOINTERSTITIAL FIBROSIS. TUBULOINTERSTITIAL INJURY IS INDUCED BY HYPOXIA AND OTHER INFLAMMATORY SIGNALS, LEADING TO FIBROBLAST ACTIVATION. TECHNOLOGICAL ADVANCES USING HIGH-THROUGHPUT SEQUENCING HAS ENABLED THE DETERMINATION OF THE EXPRESSION PROFILE OF ALMOST ALL GENES, REVEALING THAT GENE EXPRESSION IS INTRICATELY REGULATED BY DNA METHYLATION, HISTONE MODIFICATION, CHANGES IN CHROMOSOME CONFORMATION, LONG NON-CODING RNAS AND MICRORNAS. THESE EPIGENETIC MODIFICATIONS ARE STORED AS CELLULAR EPIGENETIC MEMORY. EPIGENETIC MEMORY LEADS TO ADULT-ONSET DISEASE OR AGEING IN THE LONG TERM AND MAY POSSIBLY PLAY AN IMPORTANT ROLE IN THE KIDNEY DISEASE PROCESS. HEREIN WE EMPHASIZE THE IMPORTANCE OF CLARIFYING THE MOLECULAR MECHANISMS UNDERLYING EPIGENETIC MODIFICATIONS BECAUSE THIS MAY LEAD TO THE DEVELOPMENT OF NEW THERAPEUTIC TARGETS IN KIDNEY DISEASE. 2016 19 3703 27 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 20 416 28 ANALYSIS OF THE DYNAMIC ABERRANT LANDSCAPE OF DNA METHYLATION AND GENE EXPRESSION DURING ARSENIC-INDUCED CELL TRANSFORMATION. INORGANIC ARSENIC IS A WELL-KNOWN CARCINOGEN ASSOCIATED WITH SEVERAL TYPES OF CANCER, BUT THE MECHANISMS INVOLVED IN ARSENIC-INDUCED CARCINOGENESIS ARE NOT FULLY UNDERSTOOD. RECENT EVIDENCE POINTS TO EPIGENETIC DYSREGULATION AS AN IMPORTANT MECHANISM IN THIS PROCESS; HOWEVER, THE EFFECTS OF EPIGENETIC ALTERATIONS IN GENE EXPRESSION HAVE NOT BEEN EXPLORED IN DEPTH. USING MICROARRAY DATA AND APPLYING A MULTIVARIATE CLUSTERING ANALYSIS IN A GAUSSIAN MIXTURE MODEL, WE DESCRIBE THE ALTERATIONS IN DNA METHYLATION AROUND THE PROMOTER REGION AND THE IMPACT ON GENE EXPRESSION IN HACAT CELLS DURING THE TRANSFORMATION PROCESS CAUSED BY CHRONIC EXPOSURE TO ARSENIC. USING THIS CLUSTERING APPROACH, THE GENES WERE GROUPED ACCORDING TO THEIR METHYLATION AND EXPRESSION STATUS IN THE EPIGENETIC LANDSCAPE, AND THE CHANGES THAT OCCURRED DURING THE CELLULAR TRANSFORMATION WERE IDENTIFIED ADEQUATELY. THUS, WE PRESENT A VALUABLE METHOD FOR IDENTIFYING EPIGENOMIC DYSREGULATION. 2019