1 1218 145 CRISPR INTERFERENCE OF A CLONALLY VARIANT GC-RICH NONCODING RNA FAMILY LEADS TO GENERAL REPRESSION OF VAR GENES IN PLASMODIUM FALCIPARUM. THE HUMAN MALARIA PARASITE PLASMODIUM FALCIPARUM USES MUTUALLY EXCLUSIVE EXPRESSION OF THE PFEMP1-ENCODING VAR GENE FAMILY TO EVADE THE HOST IMMUNE SYSTEM. DESPITE PROGRESS IN THE MOLECULAR UNDERSTANDING OF THE DEFAULT SILENCING MECHANISM, THE ACTIVATION MECHANISM OF THE UNIQUELY EXPRESSED VAR MEMBER REMAINS ELUSIVE. A GC-RICH NONCODING RNA (NCRNA) GENE FAMILY HAS COEVOLVED WITH PLASMODIUM SPECIES THAT EXPRESS VAR GENES. HERE, WE SHOW THAT THIS NCRNA FAMILY IS TRANSCRIBED IN A CLONALLY VARIANT MANNER, WITH PREDOMINANT TRANSCRIPTION OF A SINGLE MEMBER OCCURRING WHEN THE NCRNA IS LOCATED ADJACENT TO AND UPSTREAM OF AN ACTIVE VAR GENE. WE DEVELOPED A SPECIFIC CRISPR INTERFERENCE (CRISPRI) STRATEGY THAT ALLOWED FOR THE TRANSCRIPTIONAL REPRESSION OF ALL GC-RICH MEMBERS. A LACK OF GC-RICH NCRNA TRANSCRIPTION LED TO THE DOWNREGULATION OF THE ENTIRE VAR GENE FAMILY IN RING-STAGE PARASITES. STRIKINGLY, IN MATURE BLOOD-STAGE PARASITES, THE GC-RICH NCRNA CRISPRI AFFECTED THE TRANSCRIPTION PATTERNS OF OTHER CLONALLY VARIANT GENE FAMILIES, INCLUDING THE DOWNREGULATION OF ALL PFMC-2TM MEMBERS. WE PROVIDE EVIDENCE FOR THE KEY ROLE OF GC-RICH NCRNA TRANSCRIPTION IN VAR GENE ACTIVATION AND DISCOVERED A MOLECULAR LINK BETWEEN THE TRANSCRIPTIONAL CONTROL OF VARIOUS CLONALLY VARIANT MULTIGENE FAMILIES INVOLVED IN PARASITE VIRULENCE. THIS WORK OPENS NEW AVENUES FOR ELUCIDATING THE MOLECULAR PROCESSES THAT CONTROL IMMUNE EVASION AND PATHOGENESIS IN P. FALCIPARUMIMPORTANCEPLASMODIUM FALCIPARUM IS THE DEADLIEST MALARIA PARASITE SPECIES, ACCOUNTING FOR THE VAST MAJORITY OF DISEASE CASES AND DEATHS. THE VIRULENCE OF THIS PARASITE IS RELIANT UPON THE MUTUALLY EXCLUSIVE EXPRESSION OF CYTOADHERENCE PROTEINS ENCODED BY THE 60-MEMBER VAR GENE FAMILY. ANTIGENIC VARIATION OF THIS MULTIGENE FAMILY SERVES AS AN IMMUNE EVASION MECHANISM, ULTIMATELY LEADING TO CHRONIC INFECTION AND PATHOGENESIS. UNDERSTANDING THE REGULATION MECHANISM OF ANTIGENIC VARIATION IS KEY TO DEVELOPING NEW THERAPEUTIC AND CONTROL STRATEGIES. OUR STUDY UNCOVERS A NOVEL LAYER IN THE EPIGENETIC REGULATION OF TRANSCRIPTION OF THIS FAMILY OF VIRULENCE GENES BY MEANS OF A MULTIGENE-TARGETING CRISPR INTERFERENCE APPROACH. 2020 2 4423 26 MOLECULAR AND IMMUNOLOGIC MARKERS OF KIDNEY CANCER-POTENTIAL APPLICATIONS IN PREDICTIVE, PREVENTIVE AND PERSONALIZED MEDICINE. KIDNEY CANCER IS ONE OF THE DEADLIEST MALIGNANCIES DUE TO FREQUENT LATE DIAGNOSIS (33 % OR RENAL CELL CARCINOMA ARE METASTATIC AT DIAGNOSIS) AND POOR TREATMENT OPTIONS. THERE ARE TWO MAJOR SUBTYPES OF KIDNEY CANCER: RENAL CELL CARCINOMA (RCC) AND RENAL PELVIS CARCINOMA. THE RISK FACTORS FOR RCC, ACCOUNTING FOR MORE THAN 90 % OF ALL KIDNEY CANCERS, ARE SMOKING, OBESITY, HYPERTENSION, MISUSE OF PAIN MEDICATION, AND SOME GENETIC DISEASES. THE MOST COMMON MOLECULAR MARKERS OF KIDNEY CANCER INCLUDE MUTATIONS AND EPIGENETIC INACTIVATION OF VON HIPPEL-LINDAU (VHL) GENE, GENES OF VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) PATHWAY, AND CARBONIC ANHYDRASE IX (CIAX). THE ROLE OF EPIGENETIC PATHWAYS, INCLUDING DNA METHYLATION AND CHROMATIN STRUCTURE REMODELING, WAS ALSO DEMONSTRATED. IMMUNOLOGIC PROPERTIES OF RCC ENABLE THIS TYPE OF TUMOR TO ESCAPE IMMUNE RESPONSE EFFECTIVELY. AN IMPORTANT ROLE IN THIS PROCESS IS PLAYED BY TUMOR-ASSOCIATED MACROPHAGES THAT DEMONSTRATE MIXED M1/M2 PHENOTYPE. IN THIS REVIEW, WE DISCUSS MOLECULAR AND CELLULAR ASPECTS FOR RCC DEVELOPMENT AND CURRENT STATE OF KNOWLEDGE ALLOWING PERSONALIZED APPROACHES FOR DIAGNOSTICS AND PROGNOSTIC PREDICTION OF THIS DISEASE. A SET OF MACROPHAGE MARKERS IS SUGGESTED FOR THE ANALYSIS OF THE ASSOCIATION OF MACROPHAGE PHENOTYPE AND DISEASE PROGNOSIS. 2015 3 629 30 BIOLOGICAL AND GENETIC MECHANISMS OF COPD, ITS DIAGNOSIS, TREATMENT, AND RELATIONSHIP WITH LUNG CANCER. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS ONE OF THE MOST PREVALENT CHRONIC ADULT DISEASES, WITH SIGNIFICANT WORLDWIDE MORBIDITY AND MORTALITY. ALTHOUGH LONG-TERM TOBACCO SMOKING IS A CRITICAL RISK FACTOR FOR THIS GLOBAL HEALTH PROBLEM, ITS MOLECULAR MECHANISMS REMAIN UNCLEAR. SEVERAL PHENOMENA ARE THOUGHT TO BE INVOLVED IN THE EVOLUTION OF EMPHYSEMA, INCLUDING AIRWAY INFLAMMATION, PROTEINASE/ANTI-PROTEINASE IMBALANCE, OXIDATIVE STRESS, AND GENETIC/EPIGENETIC MODIFICATIONS. FURTHERMORE, COPD IS ONE MAIN RISK FOR LUNG CANCER (LC), THE DEADLIEST FORM OF HUMAN TUMOR; FORMATION AND CHRONIC INFLAMMATION ACCOMPANYING COPD CAN BE A POTENTIAL DRIVER OF MALIGNANCY MATURATION (0.8-1.7% OF COPD CASES DEVELOP CANCER/PER YEAR). RECENTLY, THE DEVELOPMENT OF MORE RESEARCH BASED ON COPD AND LUNG CANCER MOLECULAR ANALYSIS HAS PROVIDED NEW LIGHT FOR UNDERSTANDING THEIR PATHOGENESIS, IMPROVING THE DIAGNOSIS AND TREATMENTS, AND ELUCIDATING MANY CONNECTIONS BETWEEN THESE DISEASES. OUR REVIEW EMPHASIZES THE BIOLOGICAL FACTORS INVOLVED IN COPD AND LUNG CANCER, THE ADVANCES IN THEIR MOLECULAR MECHANISMS' RESEARCH, AND THE STATE OF THE ART OF DIAGNOSIS AND TREATMENTS. THIS WORK COMBINES MANY BIOLOGICAL AND GENETIC ELEMENTS INTO A SINGLE WHOLE AND STRONGLY LINKS COPD WITH LUNG TUMOR FEATURES. 2023 4 129 59 A UNIQUE VIRULENCE GENE OCCUPIES A PRINCIPAL POSITION IN IMMUNE EVASION BY THE MALARIA PARASITE PLASMODIUM FALCIPARUM. MUTUALLY EXCLUSIVE GENE EXPRESSION, WHEREBY ONLY ONE MEMBER OF A MULTI-GENE FAMILY IS SELECTED FOR ACTIVATION, IS USED BY THE MALARIA PARASITE PLASMODIUM FALCIPARUM TO ESCAPE THE HUMAN IMMUNE SYSTEM AND PERPETUATE LONG-TERM, CHRONIC INFECTIONS. A FAMILY OF GENES CALLED VAR ENCODES THE CHIEF ANTIGENIC AND VIRULENCE DETERMINANT OF P. FALCIPARUM MALARIA. VAR GENES ARE TRANSCRIBED IN A MUTUALLY EXCLUSIVE MANNER, WITH SWITCHING BETWEEN ACTIVE GENES RESULTING IN ANTIGENIC VARIATION. WHILE RECENT WORK HAS SHED CONSIDERABLE LIGHT ON THE EPIGENETIC BASIS FOR VAR GENE ACTIVATION AND SILENCING, HOW SWITCHING IS CONTROLLED REMAINS A MYSTERY. IN PARTICULAR, SWITCHING SEEMS NOT TO BE RANDOM, BUT INSTEAD APPEARS TO BE COORDINATED TO RESULT IN TIMELY ACTIVATION OF INDIVIDUAL GENES LEADING TO SEQUENTIAL WAVES OF ANTIGENICALLY DISTINCT PARASITE POPULATIONS. THE MOLECULAR BASIS FOR THIS APPARENT COORDINATION IS UNKNOWN. HERE WE SHOW THAT VAR2CSA, AN UNUSUAL AND HIGHLY CONSERVED VAR GENE, OCCUPIES A UNIQUE POSITION WITHIN THE VAR GENE SWITCHING HIERARCHY. INDUCTION OF SWITCHING THROUGH THE DESTABILIZATION OF VAR SPECIFIC CHROMATIN USING BOTH GENETIC AND CHEMICAL METHODS REPEATEDLY LED TO THE RAPID AND EXCLUSIVE ACTIVATION OF VAR2CSA. ADDITIONAL EXPERIMENTS DEMONSTRATED THAT THESE REPRESENT "TRUE" SWITCHING EVENTS AND NOT SIMPLY DE-SILENCING OF THE VAR2CSA PROMOTER, AND THAT ACTIVATION IS LIMITED TO THE UNIQUE LOCUS ON CHROMOSOME 12. COMBINED WITH TRANSLATIONAL REPRESSION OF VAR2CSA TRANSCRIPTS, FREQUENT "DEFAULT" SWITCHING TO THIS LOCUS AND DETECTION OF VAR2CSA UNTRANSLATED TRANSCRIPTS IN NON-PREGNANT INDIVIDUALS, THESE DATA SUGGEST THAT VAR2CSA COULD PLAY A CENTRAL ROLE IN COORDINATING SWITCHING, FULFILLING A PREDICTION MADE BY MATHEMATICAL MODELS DERIVED FROM POPULATION SWITCHING PATTERNS. THESE STUDIES PROVIDE THE FIRST INSIGHTS INTO THE MECHANISMS BY WHICH VAR GENE SWITCHING IS COORDINATED AS WELL AS AN EXAMPLE OF HOW A PHARMACOLOGICAL AGENT CAN DISRUPT ANTIGENIC VARIATION IN PLASMODIUM FALCIPARUM. 2015 5 1502 19 DNA METHYLATION AND EPIGENETIC EVENTS UNDERLYING RENAL CELL CARCINOMAS. RENAL CELL CARCINOMA (RCC) REFERS TO A GROUP OF TUMORS THAT DEVELOP FROM THE EPITHELIUM OF THE KIDNEY TUBES, INCLUDING CLEAR CELL RCC, PAPILLARY RCC, AND CHROMOPHOBE RCC. MOST CLEAR CELL RENAL CARCINOMAS HAVE A LARGE HISTOLOGIC SUBTYPE, GENETIC OR EPIGENETIC VON HIPPEL-LINDAU (VHL). A COMPREHENSIVE ANALYSIS OF THE GENETIC MODIFICATION GENOME SUGGESTED THAT CHROMOSOME 3P LOSS AND CHROMOSOME GAINS 5Q AND 7 MAY BE SIGNIFICANT COPY DEFECTS IN THE DEVELOPMENT OF CLEAR RCC. A MORE POTENT RCC MAY DEVELOP IF CHROMOSOME 1P, 4, 9, 13Q, OR 14Q IS ALSO LOST. RENAL CARCINOGENESIS IS NOT ASSOCIATED WITH CHRONIC INFLAMMATION OR HISTOLOGICAL CHANGES. HOWEVER, IF REGIONAL HYPERMETHYLATION OF DNA IN CPG C-TYPE ISLANDS HAS ALREADY ACCUMULATED IN CANCER-FREE KIDNEY TISSUE, IT IMPLIES THAT THE PRESENCE OF MALIGNANT KIDNEY LESIONS MAY ALSO BE DETECTED BY MODIFIED DNA METHYLATION. MODIFICATION OF DNA METHYLATION IN CANCEROUS KIDNEY TISSUE MAY ADVANCE KIDNEY TISSUE TO EPIGENETIC MUTATIONS AND GENES, LEADING TO MORE SERIOUS CANCERS AND EVEN DETERMINING A PATIENT'S OUTCOME. THE GENETIC AND EPIGENETIC PROFILE PROVIDES ACCURATE PREDICTORS FOR PATIENTS WITH KIDNEY CANCER. NEW GENETIC AND EPIGENETIC ANALYSIS TECHNOLOGIES WILL HELP TO SPEED UP THE IDENTIFICATION OF VITAL CELLS FOR KIDNEY CANCER PREVENTION, DIAGNOSIS, AND TREATMENT. 2022 6 2091 47 EPIGENETIC DYSREGULATION OF VIRULENCE GENE EXPRESSION IN SEVERE PLASMODIUM FALCIPARUM MALARIA. CHRONIC INFECTIONS WITH THE HUMAN MALARIA PARASITE PLASMODIUM FALCIPARUM DEPEND ON ANTIGENIC VARIATION. P. FALCIPARUM ERYTHROCYTE MEMBRANE PROTEIN 1 (PFEMP1), THE MAJOR ERYTHROCYTE SURFACE ANTIGEN MEDIATING PARASITE SEQUESTRATION IN THE MICROVASCULATURE, IS ENCODED IN PARASITES BY A HIGHLY DIVERSE FAMILY OF VAR GENES. ANTIGENIC SWITCHING IS MEDIATED BY CLONAL VARIATION IN VAR EXPRESSION, AND RECENT IN VITRO STUDIES HAVE DEMONSTRATED A ROLE FOR EPIGENETIC PROCESSES IN VAR REGULATION. EXPRESSION OF PARTICULAR PFEMP1 VARIANTS MAY RESULT IN PARASITE ENRICHMENT IN DIFFERENT TISSUES, A FACTOR IN THE DEVELOPMENT OF SEVERE DISEASE. HERE, WE STUDY IN VIVO HUMAN INFECTIONS AND PROVIDE EVIDENCE THAT INFECTION-INDUCED STRESS RESPONSES IN THE HOST CAN MODIFY PFEMP1 EXPRESSION VIA THE PERTURBATION OF EPIGENETIC MECHANISMS. OUR WORK SUGGESTS THAT SEVERE DISEASE MAY NOT BE THE DIRECT RESULT OF AN ADAPTIVE VIRULENCE STRATEGY TO MAXIMIZE PARASITE SURVIVAL BUT THAT IT MAY INDICATE A LOSS OF CONTROL OF THE CAREFULLY REGULATED PROCESS OF ANTIGENIC SWITCHING THAT MAINTAINS CHRONIC INFECTIONS. 2012 7 340 51 ALTERATIONS IN LOCAL CHROMATIN ENVIRONMENT ARE INVOLVED IN SILENCING AND ACTIVATION OF SUBTELOMERIC VAR GENES IN PLASMODIUM FALCIPARUM. PLASMODIUM FALCIPARUM ERYTHROCYTE MEMBRANE PROTEIN 1 (PFEMP1), ENCODED BY THE VAR GENE FAMILY, UNDERGOES ANTIGENIC VARIATION AND PLAYS AN IMPORTANT ROLE IN CHRONIC INFECTION AND SEVERE MALARIA. ONLY A SINGLE VAR GENE IS TRANSCRIBED PER PARASITE, AND EPIGENETIC CONTROL MECHANISMS ARE FUNDAMENTAL IN THIS STRATEGY OF MUTUALLY EXCLUSIVE TRANSCRIPTION. WE SHOW THAT SUBTELOMERIC UPSB VAR GENE PROMOTERS CARRIED ON EPISOMES ARE SILENCED BY DEFAULT, AND THAT PROMOTER ACTIVATION IS SUFFICIENT TO SILENCE ALL OTHER FAMILY MEMBERS. HOWEVER, THEY ARE ACTIVE BY DEFAULT WHEN PLACED DOWNSTREAM OF A SECOND ACTIVE VAR PROMOTER, UNDERSCORING THE SIGNIFICANCE OF LOCAL CHROMATIN ENVIRONMENT AND NUCLEAR COMPARTMENTALIZATION IN VAR PROMOTER REGULATION. NATIVE CHROMATIN COVERING THE SPE2-REPEAT ARRAY IN UPSB PROMOTERS IS RESISTANT TO NUCLEASE DIGESTION, AND INSERTION OF THESE REGULATORY ELEMENTS INTO A HETEROLOGOUS PROMOTER CAUSES LOCAL ALTERATIONS IN NUCLEOSOMAL ORGANIZATION AND PROMOTER REPRESSION. OUR FINDINGS SUGGEST A COMMON LOGIC UNDERLYING THE TRANSCRIPTIONAL CONTROL OF ALL VAR GENES, AND HAVE IMPORTANT IMPLICATIONS FOR OUR UNDERSTANDING OF THE EPIGENETIC PROCESSES INVOLVED IN THE REGULATION OF THIS MAJOR VIRULENCE GENE FAMILY. 2007 8 17 46 5' FLANKING REGION OF VAR GENES NUCLEATE HISTONE MODIFICATION PATTERNS LINKED TO PHENOTYPIC INHERITANCE OF VIRULENCE TRAITS IN MALARIA PARASITES. IN THE HUMAN MALARIA PARASITE PLASMODIUM FALCIPARUM ANTIGENIC VARIATION FACILITATES LONG-TERM CHRONIC INFECTION OF THE HOST. THIS IS ACHIEVED BY SEQUENTIAL EXPRESSION OF A SINGLE MEMBER OF THE 60-MEMBER VAR FAMILY. HERE WE SHOW THAT THE 5' FLANKING REGION NUCLEATES EPIGENETIC EVENTS STRONGLY LINKED TO THE MAINTENANCE OF MONO-ALLELIC VAR GENE EXPRESSION PATTERN DURING PARASITE PROLIFERATION. TRI- AND DIMETHYLATION OF HISTONE H3 LYSINE 4 PEAK IN THE 5' UPSTREAM REGION OF TRANSCRIBED VAR AND DURING THE POISED STATE (NON-TRANSCRIBED PHASE OF VAR GENES DURING THE 48 H ASEXUAL LIFE CYCLE), 'BOOKMARKING' THIS MEMBER FOR RE-ACTIVATION AT THE ONSET OF THE NEXT CYCLE. HISTONE H3 LYSINE 9 TRIMETHYLATION ACTS AS AN ANTAGONIST TO LYSINE 4 METHYLATION TO ESTABLISH STABLY SILENT VAR GENE STATES ALONG THE 5' FLANKING AND CODING REGION. FURTHERMORE, WE SHOW THAT COMPETITION EXISTS BETWEEN H3K9 METHYLATION AND H3K9 ACETYLATION IN THE 5' FLANKING REGION AND THAT THESE MARKS CONTRIBUTE EPIGENETICALLY TO REPRESSING OR ACTIVATING VAR GENE EXPRESSION. OUR WORK POINTS TO A PIVOTAL ROLE OF THE HISTONE METHYL MARK WRITING AND READING MACHINERY IN THE PHENOTYPIC INHERITANCE OF VIRULENCE TRAITS IN THE MALARIA PARASITE. 2007 9 6330 23 THE ROLE OF CIGARETTE SMOKE-INDUCED PULMONARY VASCULAR ENDOTHELIAL CELL APOPTOSIS IN COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS ONE OF THE MOST COMMON CHRONIC RESPIRATORY DISEASES WITH HIGH MORBIDITY AND MORTALITY. IT HAS BECOME THE FIFTH MOST BURDENED AND THE THIRD MOST DEADLY DISEASE IN THE GLOBAL ECONOMY AND INCREASES YEAR BY YEAR. THE PREVENTION AND TREATMENT OF COPD ARE URGENT. SMOKING IS THE MAIN AND MOST COMMON RISK FACTOR FOR COPD. CIGARETTE SMOKE (CS) CONTAINS A LARGE NUMBER OF TOXIC SUBSTANCES, CAN CAUSE A SERIES OF CHANGES IN THE TRACHEA, LUNG TISSUE, PULMONARY BLOOD VESSELS, AND PROMOTES THE OCCURRENCE AND DEVELOPMENT OF COPD. IN RECENT YEARS, THE DEVELOPMENT OF EPIGENETICS AND MOLECULAR BIOLOGY HAVE PROVIDED NEW GUIDANCE FOR REVEALING THE PATHOGENESIS, DIAGNOSIS, AND TREATMENT OF DISEASES. THE LATEST RESEARCH INDICATES THAT PULMONARY VASCULAR ENDOTHELIAL CELL APOPTOSIS INITIATES AND PARTICIPATES IN THE PATHOGENESIS OF COPD. IN THIS REVIEW, WE SUMMARIZE THE CURRENT RESEARCH ON THE EPIGENETIC MECHANISMS AND MOLECULAR BIOLOGY OF CS-INDUCED PULMONARY VASCULAR ENDOTHELIAL CELL APOPTOSIS IN COPD, PROVIDING A NEW RESEARCH DIRECTION FOR PATHOGENESIS OF COPD AND A NEW TARGET FOR THE DIAGNOSIS, TREATMENT, AND PREVENTION OF COPD. 2021 10 1219 53 CRISPR/CAS9 GENOME EDITING REVEALS THAT THE INTRON IS NOT ESSENTIAL FOR VAR2CSA GENE ACTIVATION OR SILENCING IN PLASMODIUM FALCIPARUM. PLASMODIUM FALCIPARUM RELIES ON MONOALLELIC EXPRESSION OF 1 OF 60 VAR VIRULENCE GENES FOR ANTIGENIC VARIATION AND HOST IMMUNE EVASION. EACH VAR GENE CONTAINS A CONSERVED INTRON WHICH HAS BEEN IMPLICATED IN PREVIOUS STUDIES IN BOTH ACTIVATION AND REPRESSION OF TRANSCRIPTION VIA SEVERAL EPIGENETIC MECHANISMS, INCLUDING INTERACTION WITH THE VAR PROMOTER, PRODUCTION OF LONG NONCODING RNAS (LNCRNAS), AND LOCALIZATION TO REPRESSIVE PERINUCLEAR SITES. HOWEVER, FUNCTIONAL STUDIES HAVE RELIED PRIMARILY ON ARTIFICIAL EXPRESSION CONSTRUCTS. USING THE RECENTLY DEVELOPED P. FALCIPARUM CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEATS (CRISPR)/CAS9 SYSTEM, WE DIRECTLY DELETED THE VAR2CSA P. FALCIPARUM 3D7_1200600 (PF3D7_1200600) ENDOGENOUS INTRON, RESULTING IN AN INTRONLESS VAR GENE IN A NATURAL, MARKER-FREE CHROMOSOMAL CONTEXT. DELETION OF THE VAR2CSA INTRON RESULTED IN AN UPREGULATION OF TRANSCRIPTION OF THE VAR2CSA GENE IN RING-STAGE PARASITES AND SUBSEQUENT EXPRESSION OF THE PFEMP1 PROTEIN IN LATE-STAGE PARASITES. INTRON DELETION DID NOT AFFECT THE NORMAL TEMPORAL REGULATION AND SUBSEQUENT TRANSCRIPTIONAL SILENCING OF THE VAR GENE IN TROPHOZOITES BUT DID RESULT IN INCREASED RATES OF VAR GENE SWITCHING IN SOME MUTANT CLONES. TRANSCRIPTIONAL REPRESSION OF THE INTRONLESS VAR2CSA GENE COULD BE ACHIEVED VIA LONG-TERM CULTURE OR PANNING WITH THE CD36 RECEPTOR, AFTER WHICH REACTIVATION WAS POSSIBLE WITH CHONDROITIN SULFATE A (CSA) PANNING. THESE DATA SUGGEST THAT THE VAR2CSA INTRON IS NOT REQUIRED FOR SILENCING OR ACTIVATION IN RING-STAGE PARASITES BUT POINT TO A SUBTLE ROLE IN REGULATION OF SWITCHING WITHIN THE VAR GENE FAMILY.IMPORTANCEPLASMODIUM FALCIPARUM IS THE MOST VIRULENT SPECIES OF MALARIA PARASITE, CAUSING HIGH RATES OF MORBIDITY AND MORTALITY IN THOSE INFECTED. CHRONIC INFECTION DEPENDS ON AN IMMUNE EVASION MECHANISM TERMED ANTIGENIC VARIATION, WHICH IN TURN RELIES ON MONOALLELIC EXPRESSION OF 1 OF ~60 VAR GENES. UNDERSTANDING ANTIGENIC VARIATION AND THE TRANSCRIPTIONAL REGULATION OF MONOALLELIC EXPRESSION IS IMPORTANT FOR DEVELOPING DRUGS AND/OR VACCINES. THE VAR GENE FAMILY ENCODES THE ANTIGENIC SURFACE PROTEINS THAT DECORATE INFECTED ERYTHROCYTES. UNTIL RECENTLY, STUDYING THE UNDERLYING GENETIC ELEMENTS THAT REGULATE MONOALLELIC EXPRESSION IN P. FALCIPARUM WAS DIFFICULT, AND MOST STUDIES RELIED ON ARTIFICIAL SYSTEMS SUCH AS EPISOMAL REPORTER GENES. OUR STUDY WAS THE FIRST TO USE CRISPR/CAS9 GENOME EDITING FOR THE FUNCTIONAL STUDY OF AN IMPORTANT, CONSERVED GENETIC ELEMENT OF VAR GENES-THE INTRON-IN AN ENDOGENOUS, EPISOME-FREE MANNER. OUR FINDINGS SHED LIGHT ON THE ROLE OF THE VAR GENE INTRON IN TRANSCRIPTIONAL REGULATION OF MONOALLELIC EXPRESSION. 2017 11 6695 38 VARIANT GENE EXPRESSION AND ANTIGENIC VARIATION BY MALARIA PARASITES. MALARIA IS A SIGNIFICANT THREAT THROUGHOUT THE DEVELOPING WORLD. AMONG THE MOST FASCINATING ASPECTS OF THE PROTOZOAN PARASITES RESPONSIBLE FOR THIS DISEASE ARE THE METHODS THEY EMPLOY TO AVOID THE IMMUNE SYSTEM AND PERPETUATE CHRONIC INFECTIONS. KEY AMONG THESE IS ANTIGENIC VARIATION: BY SYSTEMATICALLY ALTERING ANTIGENS THAT ARE DISPLAYED TO THE HOST'S IMMUNE SYSTEM, THE PARASITE RENDERS THE ADAPTIVE IMMUNE RESPONSE INEFFECTIVE. FOR PLASMODIUM FALCIPARUM, THE SPECIES RESPONSIBLE FOR THE MOST SEVERE FORM OF HUMAN MALARIA, THIS PROCESS INVOLVES A COMPLICATED MOLECULAR MECHANISM THAT RESULTS IN CONTINUOUSLY CHANGING PATTERNS OF VARIANT-ANTIGEN-ENCODING GENE EXPRESSION. ALTHOUGH MANY FEATURES OF THIS PROCESS REMAIN OBSCURE, SIGNIFICANT PROGRESS HAS BEEN MADE IN RECENT YEARS TO DECIPHER VARIOUS MOLECULAR ASPECTS OF THE REGULATORY CASCADE THAT CAUSES CHRONIC INFECTION. 2017 12 6179 43 THE HUMAN MALARIA PARASITE PLASMODIUM FALCIPARUM CAN SENSE ENVIRONMENTAL CHANGES AND RESPOND BY ANTIGENIC SWITCHING. THE PRIMARY ANTIGENIC AND VIRULENCE DETERMINANT OF THE HUMAN MALARIA PARASITE PLASMODIUM FALCIPARUM IS A VARIANT SURFACE PROTEIN CALLED PFEMP1. DIFFERENT FORMS OF PFEMP1 ARE ENCODED BY A MULTICOPY GENE FAMILY CALLED VAR, AND SWITCHING BETWEEN ACTIVE GENES ENABLES THE PARASITES TO EVADE THE ANTIBODY RESPONSE OF THEIR HUMAN HOSTS. VAR GENE SWITCHING IS KEY FOR THE MAINTENANCE OF CHRONIC INFECTIONS; HOWEVER, WHAT CONTROLS SWITCHING IS UNKNOWN, ALTHOUGH IT HAS BEEN SUGGESTED TO OCCUR AT A CONSTANT FREQUENCY WITH LITTLE OR NO ENVIRONMENTAL INFLUENCE. VAR GENE TRANSCRIPTION IS CONTROLLED EPIGENETICALLY THROUGH THE ACTIVITY OF HISTONE METHYLTRANSFERASES (HMTS). STUDIES IN MODEL SYSTEMS HAVE SHOWN THAT METABOLISM AND EPIGENETIC CONTROL OF GENE EXPRESSION ARE LINKED THROUGH THE AVAILABILITY OF INTRACELLULAR S-ADENOSYLMETHIONINE (SAM), THE PRINCIPAL METHYL DONOR IN BIOLOGICAL METHYLATION MODIFICATIONS, WHICH CAN FLUCTUATE BASED ON NUTRIENT AVAILABILITY. TO DETERMINE WHETHER ENVIRONMENTAL CONDITIONS AND CHANGES IN METABOLISM CAN INFLUENCE VAR GENE EXPRESSION, P. FALCIPARUM WAS CULTURED IN MEDIA WITH ALTERED CONCENTRATIONS OF NUTRIENTS INVOLVED IN SAM METABOLISM. WE FOUND THAT CONDITIONS THAT INFLUENCE LIPID METABOLISM INDUCE VAR GENE SWITCHING, INDICATING THAT PARASITES CAN RESPOND TO CHANGES IN THEIR ENVIRONMENT BY ALTERING VAR GENE EXPRESSION PATTERNS. GENETIC MODIFICATIONS THAT DIRECTLY MODIFIED EXPRESSION OF THE ENZYMES THAT CONTROL SAM LEVELS SIMILARLY LED TO PROFOUND CHANGES IN VAR GENE EXPRESSION, CONFIRMING THAT CHANGES IN SAM AVAILABILITY MODULATE VAR GENE SWITCHING. THESE OBSERVATIONS DIRECTLY CHALLENGE THE PARADIGM THAT ANTIGENIC VARIATION IN P. FALCIPARUM FOLLOWS AN INTRINSIC, PROGRAMED SWITCHING RATE, WHICH OPERATES INDEPENDENTLY OF ANY EXTERNAL STIMULI. 2023 13 2737 25 EXPOSING A DEADLY ALLIANCE: NOVEL INSIGHTS INTO THE BIOLOGICAL LINKS BETWEEN COPD AND LUNG CANCER. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AFFECTS MORE THAN 200 MILLION PEOPLE WORLDWIDE AND IS EXPECTED TO BECOME THE THIRD LEADING CAUSE OF DEATH IN 2020. COPD IS CHARACTERIZED BY PROGRESSIVE AIRFLOW LIMITATION, DUE TO A COMBINATION OF CHRONIC INFLAMMATION AND REMODELING OF THE SMALL AIRWAYS (BRONCHIOLITIS) AND LOSS OF ELASTIC RECOIL CAUSED BY DESTRUCTION OF THE ALVEOLAR WALLS (EMPHYSEMA). LUNG CANCER IS THE MOST IMPORTANT CAUSE OF CANCER-RELATED DEATH IN THE WORLD. (CIGARETTE) SMOKING IS THE PRINCIPAL CULPRIT CAUSING BOTH COPD AND LUNG CANCER; IN ADDITION, EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE, BIOMASS FUEL SMOKE, COAL SMOKE AND OUTDOOR AIR POLLUTION HAVE ALSO BEEN ASSOCIATED WITH AN INCREASED INCIDENCE OF BOTH DISEASES. IMPORTANTLY, SMOKERS WITH COPD--DEFINED AS EITHER NOT FULLY REVERSIBLE AIRFLOW LIMITATION OR EMPHYSEMA--HAVE A TWO- TO FOUR-FOLD INCREASED RISK TO DEVELOP LUNG CANCER. IN THIS REVIEW, WE HIGHLIGHT SEVERAL OF THE GENETIC, EPIGENETIC AND INFLAMMATORY MECHANISMS, WHICH LINK COPD AND CARCINOGENESIS IN THE LUNGS. ELUCIDATING THE BIOLOGICAL PATHWAYS AND NETWORKS, WHICH UNDERLIE THE INCREASED SUSCEPTIBILITY OF LUNG CANCER IN PATIENTS WITH COPD, HAS IMPORTANT IMPLICATIONS FOR SCREENING, PREVENTION, DIAGNOSIS AND TREATMENT OF THESE TWO DEVASTATING PULMONARY DISEASES. 2013 14 2937 27 GENETIC AND EPIGENETIC ALTERATIONS DURING RENAL CARCINOGENESIS. RENAL CELL CARCINOMA (RCC) IS NOT A SINGLE ENTITY, BUT COMPRISES A GROUP OF TUMORS INCLUDING CLEAR CELL RCC, PAPILLARY RCC AND CHROMOPHOBE RCC, WHICH ARISE FROM THE EPITHELIUM OF RENAL TUBULES. THE MAJORITY OF CLEAR CELL RCCS, THE MAJOR HISTOLOGICAL SUBTYPE, HAVE GENETIC OR EPIGENETIC INACTIVATION OF THE VON HIPPEL-LINDAU (VHL) GENE. GERMLINE MUTATIONS IN THE MET AND FUMARATE HYDRATASE (FH) GENES LEAD TO THE DEVELOPMENT OF TYPE 1 AND TYPE 2 PAPILLARY RCCS, RESPECTIVELY, AND SUCH MUTATIONS OF EITHER THE TSC1 OR TSC2 GENE INCREASE THE RISK OF RCC. GENOME-WIDE COPY NUMBER ALTERATION ANALYSIS HAS SUGGESTED THAT LOSS OF CHROMOSOME 3P AND GAIN OF CHROMOSOMES 5Q AND 7 MAY BE COPY NUMBER ABERRATIONS INDISPENSABLE FOR THE DEVELOPMENT OF CLEAR CELL RCC. WHEN CHROMOSOME 1P, 4, 9, 13Q OR 14Q IS ALSO LOST, MORE CLINICOPATHOLOGICALLY AGGRESSIVE CLEAR CELL RCC MAY DEVELOP. SINCE RENAL CARCINOGENESIS IS ASSOCIATED WITH NEITHER CHRONIC INFLAMMATION NOR PERSISTENT VIRAL INFECTION, AND HARDLY ANY HISTOLOGICAL CHANGE IS EVIDENT IN CORRESPONDING NON-TUMOROUS RENAL TISSUE FROM PATIENTS WITH RENAL TUMORS, PRECANCEROUS CONDITIONS IN THE KIDNEY HAVE BEEN RARELY DESCRIBED. HOWEVER, REGIONAL DNA HYPERMETHYLATION ON C-TYPE CPG ISLANDS HAS ALREADY ACCUMULATED IN SUCH NON-CANCEROUS RENAL TISSUES, SUGGESTING THAT, FROM THE VIEWPOINT OF ALTERED DNA METHYLATION, THE PRESENCE OF PRECANCEROUS CONDITIONS CAN BE RECOGNIZED EVEN IN THE KIDNEY. GENOME-WIDE DNA METHYLATION PROFILES IN PRECANCEROUS CONDITIONS ARE BASICALLY INHERITED BY THE CORRESPONDING CLEAR CELL RCCS DEVELOPING IN INDIVIDUAL PATIENTS: DNA METHYLATION ALTERATIONS AT THE PRECANCEROUS STAGE MAY FURTHER PREDISPOSE RENAL TISSUE TO EPIGENETIC AND GENETIC ALTERATIONS, GENERATE MORE MALIGNANT CANCERS, AND EVEN DETERMINE PATIENT OUTCOME. THE LIST OF TUMOR-RELATED GENES SILENCED BY DNA HYPERMETHYLATION HAS RECENTLY BEEN INCREASING. GENETIC AND EPIGENETIC PROFILING PROVIDES AN OPTIMAL MEANS OF PROGNOSTICATION FOR PATIENTS WITH RCCS. RECENTLY DEVELOPED HIGH-THROUGHPUT TECHNOLOGIES FOR GENETIC AND EPIGENETIC ANALYSES WILL FURTHER ACCELERATE THE IDENTIFICATION OF KEY MOLECULES FOR USE IN THE PREVENTION, DIAGNOSIS AND THERAPY OF RCCS. 2010 15 970 26 CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER: COMMON PATHWAYS FOR PATHOGENESIS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER COMPRISE THE LEADING CAUSES OF LUNG DISEASE-RELATED MORTALITY WORLDWIDE. EXPOSURE TO TOBACCO SMOKE IS A MUTUAL AETIOLOGY UNDERLYING THE TWO DISEASES, ACCOUNTING FOR ALMOST 90% OF CASES. THERE IS ACCUMULATING EVIDENCE SUPPORTING THE ROLE OF IMMUNE DYSFUNCTION, THE LUNG MICROBIOME, EXTRACELLULAR VESICLES AND UNDERLYING GENETIC SUSCEPTIBILITY IN THE DEVELOPMENT OF COPD AND LUNG CANCER. FURTHER, EPIGENETIC FACTORS, INVOLVING DNA METHYLATION AND MICRORNA EXPRESSION, HAVE BEEN IMPLICATED IN BOTH DISEASES. CHRONIC INFLAMMATION IS A KEY FEATURE OF COPD AND COULD BE A POTENTIAL DRIVER OF LUNG CANCER DEVELOPMENT. USING NEXT GENERATION TECHNOLOGIES, FURTHER STUDIES INVESTIGATING THE GENOMICS, EPIGENETICS AND GENE-ENVIRONMENT INTERACTION IN KEY MOLECULAR PATHWAYS WILL CONTINUE TO ELUCIDATE THE PATHOGENIC MECHANISMS UNDERLYING THE DEVELOPMENT OF COPD AND LUNG CANCER, AND CONTRIBUTE TO THE DEVELOPMENT OF NOVEL DIAGNOSTIC AND PROGNOSTIC TOOLS FOR EARLY INTERVENTION AND PERSONALISED THERAPEUTIC STRATEGIES. 2019 16 1245 33 CURRENT CONCEPTS ON THE ROLE OF INFLAMMATION IN COPD AND LUNG CANCER. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER ARE LEADING CAUSE OF DEATH, AND BOTH ARE ASSOCIATED WITH CIGARETTE SMOKE EXPOSURE. IT HAS BEEN SHOWN THAT 50-70% OF PATIENTS DIAGNOSED WITH LUNG CANCER SUFFER FROM COPD, AND REDUCED LUNG FUNCTION IS AN IMPORTANT EVENT IN LUNG CANCER SUGGESTING AN ASSOCIATION BETWEEN COPD AND LUNG CANCER. HOWEVER, A CAUSAL RELATIONSHIP BETWEEN COPD AND LUNG TUMORIGENESIS IS NOT YET FULLY UNDERSTOOD. RECENT STUDIES HAVE SUGGESTED A CENTRAL ROLE OF CHRONIC INFLAMMATION IN THE PATHOGENESIS OF BOTH THE DISEASES. FOR EXAMPLE, IMMUNE DYSFUNCTION, ABNORMAL ACTIVATION OF NF-KAPPAB, EPITHELIAL-TO-MESENCHYMAL TRANSITION, ALTERED ADHESION SIGNALING PATHWAYS, AND EXTRACELLULAR MATRIX DEGRADATION/ALTERED SIGNALING ARE THE KEY UNDERLYING MECHANISMS IN BOTH COPD AND LUNG CANCER. THESE PARAMETERS ALONG WITH OTHER PROCESSES, SUCH AS CHROMATIN MODIFICATIONS/EPIGENETIC CHANGES, ANGIOGENESIS, AND AUTOPHAGY/APOPTOSIS ARE ALTERED BY CIGARETTE SMOKE, ARE CRUCIAL IN THE DEVELOPMENT OF COPD AND LUNG CANCER. UNDERSTANDING THE CELLULAR AND MOLECULAR MECHANISMS UNDERLYING THESE PROCESSES WILL PROVIDE NOVEL AVENUES FOR HALTING THE CHRONIC INFLAMMATION IN COPD AND DEVISING THERAPEUTIC STRATEGIES AGAINST LUNG CANCER. 2009 17 1244 30 CURRENT CONCEPTS ON OXIDATIVE/CARBONYL STRESS, INFLAMMATION AND EPIGENETICS IN PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A GLOBAL HEALTH PROBLEM. THE CURRENT THERAPIES FOR COPD ARE POORLY EFFECTIVE AND THE MAINSTAYS OF PHARMACOTHERAPY ARE BRONCHODILATORS. A BETTER UNDERSTANDING OF THE PATHOBIOLOGY OF COPD IS CRITICAL FOR THE DEVELOPMENT OF NOVEL THERAPIES. IN THE PRESENT REVIEW, WE HAVE DISCUSSED THE ROLES OF OXIDATIVE/ALDEHYDE STRESS, INFLAMMATION/IMMUNITY, AND CHROMATIN REMODELING IN THE PATHOGENESIS OF COPD. AN IMBALANCE OF OXIDANTS/ANTIOXIDANTS CAUSED BY CIGARETTE SMOKE AND OTHER POLLUTANTS/BIOMASS FUELS PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF COPD BY REGULATING REDOX-SENSITIVE TRANSCRIPTION FACTORS (E.G., NF-KAPPAB), AUTOPHAGY AND UNFOLDED PROTEIN RESPONSE LEADING TO CHRONIC LUNG INFLAMMATORY RESPONSE. CIGARETTE SMOKE ALSO ACTIVATES CANONICAL/ALTERNATIVE NF-KAPPAB PATHWAYS AND THEIR UPSTREAM KINASES LEADING TO SUSTAINED INFLAMMATORY RESPONSE IN LUNGS. RECENTLY, EPIGENETIC REGULATION HAS BEEN SHOWN TO BE CRITICAL FOR THE DEVELOPMENT OF COPD BECAUSE THE EXPRESSION/ACTIVITY OF ENZYMES THAT REGULATE THESE EPIGENETIC MODIFICATIONS HAVE BEEN REPORTED TO BE ABNORMAL IN AIRWAYS OF COPD PATIENTS. HENCE, THE SIGNIFICANT ADVANCES MADE IN UNDERSTANDING THE PATHOPHYSIOLOGY OF COPD AS DESCRIBED HEREIN WILL IDENTIFY NOVEL THERAPEUTIC TARGETS FOR INTERVENTION IN COPD. 2011 18 927 22 CHRONIC INFLAMMATION, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND LUNG CANCER. PURPOSE OF REVIEW: SMOKING IS A MAJOR RISK FACTOR FOR LUNG CANCER, WHICH IS THE LEADING CAUSE OF CANCER-RELATED DEATHS BOTH IN THE USA AND WORLDWIDE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND EMPHYSEMA ARE COMORBID CONDITIONS OFTEN FOUND IN LUNG CANCER PATIENTS. THE INFLAMMATORY PATHWAYS THAT LINK CHRONIC OBSTRUCTIVE PULMONARY DISEASE, EMPHYSEMA, AND LUNG CANCER LIKELY INVOLVE GENETIC AND EPIGENETIC MODULATIONS DUE TO CHRONIC TISSUE INJURY AND ABNORMAL TUMOR IMMUNITY IN SUSCEPTIBLE HOSTS. RECENT FINDINGS: CHRONIC AIRWAY INFLAMMATION CONTRIBUTES TO ALTERATIONS IN THE BRONCHIAL EPITHELIUM AND LUNG MICROENVIRONMENT, PROVOKING A MILIEU CONDUCIVE TO PULMONARY CARCINOGENESIS. FOR EXAMPLE, INFLAMMATION-INDUCIBLE CYCLOOXYGENASE-2 IS UPREGULATED IN NONSMALL CELL LUNG CANCER AND ALSO PLAYS AN IMPORTANT ROLE IN PROMOTING EPITHELIAL-TO-MESENCHYMAL TRANSITION. GENETIC CHANGES IN THE AIRWAY EPITHELIUM OF SMOKERS MAY HELP PREDICT OR IDENTIFY INDIVIDUALS AT RISK FOR LUNG CANCER. FINALLY, RADIOGRAPHIC FINDINGS OF EMPHYSEMA HAVE BEEN ESTABLISHED AS INDEPENDENT RISK FACTORS FOR LUNG CANCER. SUMMARY: THE RELATIONSHIPS BETWEEN INFLAMMATION, AIRFLOW OBSTRUCTION, AND LUNG CANCER ARE COMPLEX. DEREGULATED INFLAMMATION IS COMPLICIT IN THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG CANCER, BUT THE OVERLAP OF SIGNALING EVENTS IS NOT YET FULLY UNDERSTOOD. TOBACCO EXPOSURE IS AN IMPORTANT RISK FACTOR THAT CONFERS LONG-TERM RISK OF LUNG DISEASE. DIAGNOSTIC SENSITIVITY OF DETECTING LUNG CANCER MAY IMPROVE WITH THE UTILIZATION OF GENETIC PROFILING IN COMBINATION WITH PATHOLOGIC EVALUATION OF AIRWAY EPITHELIUM. ADDITIONAL RESEARCH IS REQUIRED TO UNDERSTAND THE ROLE OF EPITHELIAL-TO-MESENCHYMAL TRANSITION IN CHRONIC INFLAMMATORY LUNG DISEASES AND LUNG CARCINOGENESIS. 2009 19 5096 45 PLASMODIUM FALCIPARUM SET2 DOMAIN IS ALLOSTERICALLY REGULATED BY ITS PHD-LIKE DOMAIN TO METHYLATE AT H3K36. THE ANTIGENIC VARIATION IS AN ESSENTIAL MECHANISM EMPLOYED BY THE MALARIA PARASITE TO ESTABLISH A CHRONIC INFECTION IN HUMANS. THREE MAJOR VIRULENT PROTEINS EMP1, RIFINS, AND STEVOR HAVE BEEN IMPLICATED IN CONTRIBUTING TO THE ANTIGENIC VARIATION PROCESS AND ARE ENCODED BY MULTIGENE FAMILIES IN PLASMODIUM SPP. THE KEY VIRULENCE FACTOR PFEMP1 IS ENCODED BY VAR GENES, AND IT EXHIBITS A MUTUALLY EXCLUSIVE TRANSCRIPTIONAL SWITCHING BETWEEN VAR GENES, ENSURING AN INDIVIDUAL PARASITE ONLY TRANSCRIBES A SINGLE VAR GENE AT A TIME. EXPRESSION OF VAR GENES IS TIGHTLY REGULATED BY TWO HISTONE EPIGENETIC METHYLATION MARKS H3K36ME3 AND H3K9ME3, OF WHICH THE H3K36ME3 MARK IS HIGHLY ENRICHED ON TRANSCRIPTION START SITES (TSSS) OF SUPPRESSED VAR GENES IN P. FALCIPARUM. HOWEVER, THE MECHANISMS OF H3K36ME3 MARK PROPAGATION ON ALL THE 59 VAR GENES OF P. FALCIPARUM ARE NOT KNOWN. HERE, WE HAVE IDENTIFIED A PHD (PLANT HOMEODOMAIN-LIKE DOMAIN) LIKE DOMAIN PRESENT WITHIN THE PFSET2 PROTEIN THAT SPECIFICALLY BINDS TO THE H3K36ME2 MARK, AN INTERMEDIATE PRODUCT OF THE H3K36ME3 MARK FORMATION ON THE NUCLEOSOME. SURPRISINGLY, WE HAVE FOUND THAT PHD - H3K36ME2 INTERACTION LEADS TO STIMULATION OF SET2 DOMAIN ACTIVITY ON THE NUCLEOSOME SUBSTRATES. THE ALLOSTERIC STIMULATION OF THE PFSET2 DOMAIN BY PHD-LIKE DOMAIN PRESENT WITHIN THE SAME PROTEIN SUGGESTS A NOVEL MECHANISM OF H3K36ME3 MARK PROPAGATION ON VAR GENES OF P. FALCIPARUM. THIS STUDY PROPOSES ALLOSTERIC REGULATION OF PFSET2 PROTEIN BY H3K36ME2 MARK AS AN ESSENTIAL MECHANISM OF VAR GENES SUPPRESSION TO ENSURE SUCCESSFUL ANTIGENIC VARIATION BY THE MALARIA PARASITE. 2021 20 6475 29 TOBACCO, INFLAMMATION, AND RESPIRATORY TRACT CANCER. CIGARETTE SMOKING IS THE MOST RECOGNIZED RISK FACTOR FOR MANY INFLAMMATORY DISEASES SUCH AS CARDIOVASCULAR DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND FOR A NUMBER OF MALIGNANCES SUCH AS LUNG CANCER. LUNG CANCER IS CURRENTLY CONSIDERED THE LEADING CAUSE OF CANCER-RELATED DEATHS BECAUSE ITS AGGRESSIVE NATURE AND THE LACK OF EFFECTIVE THERAPEUTIC OPTIONS. RECENT ADVANCES IN MOLECULAR BIOLOGY AND IMMUNOLOGY HAVE IMPROVED THE KNOWLEDGE ON DIFFERENT MECHANISMS IMPLICATED IN LUNG CELL MALIGNANT TRANSFORMATION, PROGRESSION AND METASTASIS, THUS PRESENTING AN EXCITING NEW ERA FOR LUNG ANTICANCER THERAPIES. THE WAY BY WHICH CIGARETTE SMOKE MAY INDUCE LUNG MALIGNANCY INCLUDES A LARGE NUMBER OF DIFFERENT MECHANISMS AND SUBSTANCES, MOST OF THEM CURRENTLY UNKNOWN. THUS, IDENTIFIED CARCINOGENIC COMPOUNDS OF CIGARETTE SMOKE MAY INDUCE THEMSELVES A DIRECT CYTOTOXICITY AND MUTAGENIC ACTION ON LUNG EPITHELIAL CELLS BY MEANS OF GENERATION OF SOMATIC MUTATIONS, EPIGENETIC EVENTS, EPITHELIAL CELL TO MESENCHYMAL CELL TRANSFORMATIONS, AS WELL AS BY CHRONIC CELL DAMAGE. HOWEVER, THE FACT THAT THERE IS A RELATIVE HIGH PREVALENCE OF EX-SMOKER WHO MAY DEVELOP LUNG CANCER AFTER YEARS OF SMOKING CESSATION SUGGEST THAT OTHER CAUSES ARE ALSO IMPLICATED. THUS CIGARETTE SMOKE-INDUCED CHRONIC LUNG INFLAMMATORY MICROENVIRONMENT, OXIDATIVE STRESS AND CELL STRUCTURAL ALTERATIONS SUCH AS THE INCREASE OF CELL PROLIFERATION, ANGIOGENESIS AND APOPTOSIS ARREST ARE IRREVERSIBLE PROCESSES THAT HAVE A HIGH INFLUENCE IN LUNG TUMOR GROWTH. IN THIS REVIEW WE FOCUSED IN CURRENT KNOWLEDGE ON THE MECHANISMS IMPLICATED IN CIGARETTE SMOKE-INDUCED LUNG CHRONIC INFLAMMATORY PROCESSES LEADING TO LUNG CARCINOGENESIS, AS WELL AS IN CURRENT THERAPIES BASED ON NOVEL MOLECULAR ADVANCES. 2012