1 1033 130 CITRULLINATION OF AUTOANTIGENS IMPLICATES NETOSIS IN THE INDUCTION OF AUTOIMMUNITY. TOLERANCE BLOCKS THE EXPRESSION OF AUTOANTIBODIES, WHEREAS AUTOIMMUNITY PROMOTES IT. HOW TOLERANCE BREAKS AND AUTOANTIBODY PRODUCTION BEGINS THUS ARE CRUCIAL QUESTIONS FOR UNDERSTANDING AND TREATMENT OF AUTOIMMUNE DISEASES. EVIDENCE IMPLICATES CELL DEATH AND AUTOANTIGEN MODIFICATIONS IN THE INITIATION OF AUTOIMMUNE REACTIONS. ONE FORM OF NEUTROPHIL CELL DEATH CALLED NETOSIS DESERVES ATTENTION BECAUSE IT REQUIRES THE POST-TRANSLATIONAL MODIFICATION OF HISTONES AND RESULTS IN THE EXTRACELLULAR RELEASE OF CHROMATIN. NETOSIS RECEIVED ITS NAME FROM NET, THE ACRONYM GIVEN TO NEUTROPHIL EXTRACELLULAR TRAP. THE EXTRACELLULAR CHROMATIN INCORPORATES HISTONES IN WHICH ARGININES HAVE BEEN CONVERTED TO CITRULLINES BY PEPTIDYLARGININE DEIMINASE IV (PAD4). THE DEIMINATED CHROMATIN MAY FUNCTION TO CAPTURE OR 'TRAP' BACTERIAL PATHOGENS, THUS GENERATING AN EXTRACELLULAR COMPLEX OF DEIMINATED HISTONES AND BACTERIAL CELL ADJUVANTS. THE COMPLEX OF BACTERIAL ANTIGENS AND DEIMINATED CHROMATIN MAY BE INTERNALISED BY HOST PHAGOCYTES DURING ACUTE INFLAMMATORY CONDITIONS, AS ARISE DURING BACTERIAL INFECTIONS OR CHRONIC AUTOINFLAMMATORY DISORDERS. THE UPTAKE AND PROCESSING OF DEIMINATED CHROMATIN TOGETHER WITH BACTERIAL ADJUVANTS BY PHAGOCYTES MAY INDUCE THE PRESENTATION OF MODIFIED HISTONE EPITOPES AND CO-STIMULATION, THUS YIELDING A POWERFUL STIMULUS TO BREAK TOLERANCE. AUTOANTIBODIES TO DEIMINATED HISTONES ARE PREVALENT IN FELTY'S SYNDROME PATIENTS AND ARE PRESENT IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AND PATIENTS WITH RHEUMATOID ARTHRITIS (RA). THESE OBSERVATIONS CLEARLY IMPLICATE HISTONE DEIMINATION AS AN EPIGENETIC MARK THAT CAN ACT AS AN AUTOANTIBODY STIMULANT. 2014 2 4775 33 NUCLEIC ACID-SENSING AND INTERFERON-INDUCIBLE PATHWAYS SHOW DIFFERENTIAL METHYLATION IN MZ TWINS DISCORDANT FOR LUPUS AND OVEREXPRESSION IN INDEPENDENT LUPUS SAMPLES: IMPLICATIONS FOR PATHOGENIC MECHANISM AND DRUG TARGETING. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, AUTOIMMUNE INFLAMMATORY DISEASE WITH GENOMIC AND NON-GENOMIC CONTRIBUTIONS TO RISK. WE HYPOTHESIZE THAT EPIGENETIC FACTORS ARE A SIGNIFICANT CONTRIBUTOR TO SLE RISK AND MAY BE INFORMATIVE FOR IDENTIFYING PATHOGENIC MECHANISMS AND THERAPEUTIC TARGETS. TO TEST THIS HYPOTHESIS WHILE CONTROLLING FOR GENETIC BACKGROUND, WE PERFORMED AN EPIGENOME-WIDE ANALYSIS OF DNA METHYLATION IN GENOMIC DNA FROM WHOLE BLOOD IN THREE PAIRS OF FEMALE MONOZYGOTIC (MZ) TWINS OF EUROPEAN ANCESTRY, DISCORDANT FOR SLE. RESULTS WERE REPLICATED ON THE SAME ARRAY IN FOUR CELL TYPES FROM A SET OF FOUR DANISH FEMALE MZ TWIN PAIRS DISCORDANT FOR SLE. GENES IMPLICATED BY THE EPIGENETIC ANALYSES WERE THEN EVALUATED IN 10 INDEPENDENT SLE GENE EXPRESSION DATASETS FROM THE GENE EXPRESSION OMNIBUS (GEO). THERE WERE 59 DIFFERENTIALLY METHYLATED LOCI BETWEEN UNAFFECTED AND AFFECTED MZ TWINS IN WHOLE BLOOD, INCLUDING 11 NOVEL LOCI. ALL BUT TWO OF THESE LOCI WERE HYPOMETHYLATED IN THE SLE TWINS RELATIVE TO THE UNAFFECTED TWINS. THE GENES HARBORING THESE HYPOMETHYLATED LOCI EXHIBITED INCREASED EXPRESSION IN MULTIPLE INDEPENDENT DATASETS OF SLE PATIENTS. THIS PATTERN WAS LARGELY CONSISTENT REGARDLESS OF DISEASE ACTIVITY, CELL TYPE, OR RENAL TISSUE TYPE. THE GENES PROXIMAL TO CPGS EXHIBITING DIFFERENTIAL METHYLATION (DM) IN THE SLE-DISCORDANT MZ TWINS AND EXHIBITING DIFFERENTIAL EXPRESSION (DE) IN INDEPENDENT SLE GEO COHORTS (DM-DE GENES) CLUSTERED INTO TWO PATHWAYS: THE NUCLEIC ACID-SENSING PATHWAY AND THE TYPE I INTERFERON PATHWAY. THE DM-DE GENES WERE ALSO INFORMATICALLY QUERIED FOR POTENTIAL GENE-DRUG INTERACTIONS, YIELDING A LIST OF 41 DRUGS INCLUDING A KNOWN SLE THERAPY. THE DM-DE GENES DELINEATE TWO IMPORTANT BIOLOGIC PATHWAYS THAT ARE NOT ONLY REFLECTIVE OF THE HETEROGENEITY OF SLE BUT MAY ALSO CORRELATE WITH DISTINCT IFN RESPONSES THAT DEPEND ON THE SOURCE, TYPE, AND LOCATION OF NUCLEIC ACID MOLECULES AND THE ACTIVATED RECEPTORS IN INDIVIDUAL PATIENTS. CELL- AND TISSUE-SPECIFIC ANALYSES WILL BE CRITICAL TO THE UNDERSTANDING OF GENETIC FACTORS DYSREGULATING THE NUCLEIC ACID-SENSING AND IFN PATHWAYS AND WHETHER THESE FACTORS COULD BE APPROPRIATE TARGETS FOR THERAPEUTIC INTERVENTION. 2021 3 3808 29 INTRANASAL ADMINISTRATION OF ACINETOBACTER LWOFFII IN A MURINE MODEL OF ASTHMA INDUCES IL-6-MEDIATED PROTECTION ASSOCIATED WITH CECAL MICROBIOTA CHANGES. BACKGROUND: EARLY-LIFE EXPOSURE TO CERTAIN ENVIRONMENTAL BACTERIA INCLUDING ACINETOBACTER LWOFFII (AL) HAS BEEN IMPLICATED IN PROTECTION FROM CHRONIC INFLAMMATORY DISEASES INCLUDING ASTHMA LATER IN LIFE. HOWEVER, THE UNDERLYING MECHANISMS AT THE IMMUNE-MICROBE INTERFACE REMAIN LARGELY UNKNOWN. METHODS: THE EFFECTS OF REPEATED INTRANASAL AL EXPOSURE ON LOCAL AND SYSTEMIC INNATE IMMUNE RESPONSES WERE INVESTIGATED IN WILD-TYPE AND IL6(-/-) , IL10(-/-) , AND IL17(-/-) MICE EXPOSED TO OVALBUMIN-INDUCED ALLERGIC AIRWAY INFLAMMATION. THOSE INVESTIGATIONS WERE EXPANDED BY MICROBIOME ANALYSES. TO ASSESS FOR AL-ASSOCIATED CHANGES IN GENE EXPRESSION, THE PICTURE ARISING FROM ANIMAL DATA WAS SUPPLEMENTED BY IN VITRO EXPERIMENTS OF MACROPHAGE AND T-CELL RESPONSES, YIELDING EXPRESSION AND EPIGENETIC DATA. RESULTS: THE ASTHMA PREVENTIVE EFFECT OF AL WAS CONFIRMED IN THE LUNG. REPEATED INTRANASAL AL ADMINISTRATION TRIGGERED A PROINFLAMMATORY IMMUNE RESPONSE PARTICULARLY CHARACTERIZED BY ELEVATED LEVELS OF IL-6, AND CONSEQUENTLY, IL-6 INDUCED IL-10 PRODUCTION IN CD4(+) T-CELLS. BOTH IL-6 AND IL-10, BUT NOT IL-17, WERE REQUIRED FOR ASTHMA PROTECTION. AL HAD A PROFOUND IMPACT ON THE GENE REGULATORY LANDSCAPE OF CD4(+) T-CELLS WHICH COULD BE LARGELY RECAPITULATED BY RECOMBINANT IL-6. AL ADMINISTRATION ALSO INDUCED MARKED CHANGES IN THE GASTROINTESTINAL MICROBIOME BUT NOT IN THE LUNG MICROBIOME. BY COMPARING THE EFFECTS ON THE MICROBIOTA ACCORDING TO MOUSE GENOTYPE AND AL-TREATMENT STATUS, WE HAVE IDENTIFIED MICROBIAL TAXA THAT WERE ASSOCIATED WITH EITHER DISEASE PROTECTION OR ACTIVITY. CONCLUSION: THESE EXPERIMENTS PROVIDE A NOVEL MECHANISM OF ACINETOBACTER LWOFFII-INDUCED ASTHMA PROTECTION OPERATING THROUGH IL-6-MEDIATED EPIGENETIC ACTIVATION OF IL-10 PRODUCTION AND WITH ASSOCIATED EFFECTS ON THE INTESTINAL MICROBIOME. 2023 4 5789 22 SRSF2(P95H/+) CO-OPERATES WITH LOSS OF TET2 TO PROMOTE MYELOID BIAS AND INITIATE A CHRONIC MYELOMONOCYTIC LEUKEMIA-LIKE DISEASE IN MICE. RECURRENT MUTATIONS IN RNA SPLICING PROTEINS AND EPIGENETIC REGULATORS CONTRIBUTE TO THE DEVELOPMENT OF MYELODYSPLASTIC SYNDROME (MDS) AND RELATED MYELOID NEOPLASMS. IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), SRSF2 MUTATIONS OCCUR IN ~50% OF PATIENTS AND TET2 MUTATIONS IN ~60%. CLONAL ANALYSIS INDICATES THAT EITHER MUTATION CAN ARISE AS THE FOUNDER LESION. BASED ON HUMAN CANCER GENETICS WE CROSSED AN INDUCIBLE SRSF2(P95H/+) MUTANT MODEL WITH TET2(FL/FL) MICE TO MUTATE BOTH CONCOMITANTLY IN HEMATOPOIETIC STEM CELLS. AT 20-24 WEEKS POST MUTATION INDUCTION, WE OBSERVED SUBTLE DIFFERENCES IN THE SRSF2/TET2 MUTANTS COMPARED TO EITHER SINGLE MUTANT. UNDER CONDITIONS OF NATIVE HEMATOPOIESIS WITH AGING, WE SEE A DISTINCT MYELOID BIAS AND MONOCYTOSIS IN THE SRSF2/TET2 MUTANTS. A SUBSET OF THE COMPOUND SRSF2/TET2 MUTANTS DISPLAY AN INCREASED GRANULOCYTIC AND DISTINCTIVE MONOCYTIC PROLIFERATION (MYELOMONOCYTIC HYPERPLASIA), WITH INCREASED IMMATURE PROMONOCYTES AND MONOBLASTS AND BINUCLEATE PROMONOCYTES. EXOME ANALYSIS OF PROGRESSED DISEASE DEMONSTRATED MUTATIONS IN GENES AND PATHWAYS SIMILAR TO THOSE REPORTED IN HUMAN CMML. UPON TRANSPLANTATION, RECIPIENTS DEVELOPED LEUKOCYTOSIS, MONOCYTOSIS, AND SPLENOMEGALY. WE REPRODUCE SRSF2/TET2 CO-OPERATIVITY IN VIVO, YIELDING A DISEASE WITH CORE CHARACTERISTICS OF CMML, UNLIKE SINGLE SRSF2 OR TET2 MUTATION. THIS MODEL REPRESENTS A SIGNIFICANT STEP TOWARD BUILDING HIGH FIDELITY AND GENETICALLY TRACTABLE MODELS OF CMML. 2022 5 4413 23 MOLECULAR AND CELLULAR INSIGHTS INTO THE DEVELOPMENT OF UTERINE FIBROIDS. UTERINE LEIOMYOMAS REPRESENT THE MOST COMMON BENIGN GYNECOLOGIC TUMOR. THESE HORMONE-DEPENDENT SMOOTH-MUSCLE FORMATIONS OCCUR WITH AN ESTIMATED PREVALENCE OF ~70% AMONG WOMEN OF REPRODUCTIVE AGE AND CAUSE SYMPTOMS INCLUDING PAIN, ABNORMAL UTERINE BLEEDING, INFERTILITY, AND RECURRENT ABORTION. DESPITE THE PREVALENCE AND PUBLIC HEALTH IMPACT OF UTERINE LEIOMYOMAS, AVAILABLE TREATMENTS REMAIN LIMITED. AMONG THE POTENTIAL CAUSES OF LEIOMYOMAS, EARLY HORMONAL EXPOSURE DURING PERIODS OF DEVELOPMENT MAY RESULT IN DEVELOPMENTAL REPROGRAMMING VIA EPIGENETIC CHANGES THAT PERSIST IN ADULTHOOD, LEADING TO DISEASE ONSET OR PROGRESSION. RECENT DEVELOPMENTS IN UNBIASED HIGH-THROUGHPUT SEQUENCING TECHNOLOGY ENABLE POWERFUL APPROACHES TO DETECT DRIVER MUTATIONS, YIELDING NEW INSIGHTS INTO THE GENOMIC INSTABILITY OF LEIOMYOMAS. CURRENT DATA ALSO SUGGEST THAT EACH LEIOMYOMA ORIGINATES FROM THE CLONAL EXPANSION OF A SINGLE TRANSFORMED SOMATIC STEM CELL OF THE MYOMETRIUM. IN THIS REVIEW, WE PROPOSE AN INTEGRATED CELLULAR AND MOLECULAR VIEW OF THE ORIGINS OF LEIOMYOMAS, AS WELL AS PARADIGM-SHIFTING STUDIES THAT WILL LEAD TO BETTER UNDERSTANDING AND THE FUTURE DEVELOPMENT OF NON-SURGICAL TREATMENTS FOR THESE HIGHLY FREQUENT TUMORS. 2021 6 5790 23 SRSF2-P95 HOTSPOT MUTATION IS HIGHLY ASSOCIATED WITH ADVANCED FORMS OF MASTOCYTOSIS AND MUTATIONS IN EPIGENETIC REGULATOR GENES. MASTOCYTOSIS IS A RARE AND CHRONIC DISEASE WITH PHENOTYPES RANGING FROM INDOLENT TO SEVERE. PROGNOSIS FOR THIS DISEASE IS VARIABLE AND VERY FEW BIOMARKERS TO PREDICT DISEASE EVOLUTION OR OUTCOME ARE CURRENTLY KNOWN. WE HAVE PERFORMED COMPREHENSIVE SCREENING IN OUR LARGE COHORT OF MASTOCYTOSIS PATIENTS FOR MUTATIONS PREVIOUSLY FOUND IN OTHER MYELOID DISEASES AND THAT COULD SERVE AS PROGNOSTIC INDICATORS. KIT, SRSF2-P95 AND TET2 MUTATIONS WERE BY FAR THE MOST FREQUENT, DETECTED IN 81%, 24% AND 21% OF PATIENTS, RESPECTIVELY. WHERE TET2 AND SRSF2-P95 MUTATION BOTH CORRELATED WITH ADVANCED DISEASE PHENOTYPES, SRSF2-P95 HOTSPOT MUTATION WAS FOUND ALMOST EXCLUSIVELY IN PATIENTS DIAGNOSED WITH ASSOCIATED CLONAL HEMATOLOGIC NON-MAST CELL DISEASE. STATISTICALLY, TET2 AND SRSF2-P95 MUTATIONS WERE HIGHLY ASSOCIATED, SUGGESTING A MECHANISTIC LINK BETWEEN THESE TWO FACTORS. FINALLY, ANALYSIS OF BOTH CLONAL AND SORTED CELL POPULATIONS FROM PATIENTS CONFIRMS THE PRESENCE OF THESE MUTATIONS IN THE MAST CELL COMPONENT OF THE DISEASE, SUGGESTS AN ONTOLOGICAL MUTATION HIERARCHY AND PROVIDES EVIDENCE FOR THE EXPANSION OF MULTIPLE CLONES. THIS HIGHLIGHTS THE PROGNOSTIC POTENTIAL OF SUCH APPROACHES, IF APPLIED SYSTEMATICALLY, FOR DELINEATING THE ROLES OF SPECIFIC MUTATIONS IN PREDISPOSING AND/OR DRIVING DISTINCT DISEASE PHENOTYPES. 2014 7 229 29 ADAPTATION OR PATHOLOGY? THE ROLE OF PRENATAL STRESSOR TYPE AND INTENSITY IN THE DEVELOPMENTAL PROGRAMING OF ADULT PHENOTYPE. THE MOTHER IS THE MAJOR INTERFACE BETWEEN THE OFFSPRING AND ITS PRENATAL ENVIRONMENT. PRENATAL TOXINS AND STRESS-INDUCING PHYSICAL AGENTS ARE IMPORTANT FACTORS PROGRAMMING THE DEVELOPMENTAL TRAJECTORY OF MAMMALS THAT LIKELY INVOLVE EPIGENETIC MODIFICATIONS. HOWEVER, PRENATAL STRESSORS COMMONLY-USED IN THE LABORATORY (E.G. PRENATAL RESTRAINT STRESS AND PRENATAL CHRONIC VARIABLE STRESS) ARE TYPICALLY ADMINISTERED AT HIGH INTENSITIES. THESE EXPOSURES TYPICALLY LEAD TO PATHOLOGICAL PHENOTYPES SUPPORTING THE DEVELOPMENT ORIGIN OF HEALTH AND DISEASE HYPOTHESIS. IN THIS REVIEW, WE COMPARE THE PHENOTYPIC OUTCOMES OF THESE COMMONLY-USED PRENATAL STRESSORS TO AN ECOLOGICALLY-RELEVANT, PSYCHOGENIC STRESSOR THAT HAS BEEN PRESENT OVER EVOLUTIONARY TIMES, PREDATOR OR PREDATOR CUES PRESENCE. PRENATAL STRESS BY PREDATOR THREAT RESULTS IN BEHAVIORAL, PHYSIOLOGICAL, ENDOCRINE, TRANSCRIPT ABUNDANCE AND EPIGENETIC (DNA METHYLATION) MODIFICATIONS. THESE PHENOTYPIC MODIFICATIONS ARE CONSISTENT WITH DEVELOPMENTAL FORECASTING ACCORDING TO THE PREDICTIVE ADAPTIVE RESPONSE HYPOTHESIS, YIELDING ADAPTIVE RESPONSES IN ENVIRONMENTS WHERE SUCH PREDATION STRESS IS PRESENT. THE EVIDENCE DESCRIBED IN THIS REVIEW SUGGESTS THAT THE TYPE OF PRENATAL STRESS AGENT AND ITS INTENSITY MODIFIES THE PHENOTYPE EXPRESSED, WHICH CAN RANGE FROM ADAPTIVE TO PATHOLOGICAL. PRENATAL BISPHENOL A EXPOSURE STUDIES ARE PRESENTED AS AN EXAMPLE WHERE GRADED INTENSITIES (CONCENTRATIONS) OF PRENATAL TOXIN EXPOSURE CAN BE COMPARED DIRECTLY. FINALLY, WE EMPHASIZE THE IMPORTANCE OF STUDYING BOTH SEXES IN THESE STUDIES, AS SEX DIFFERENCES APPEAR TO BE A COMMON FEATURE OF THE RESPONSE TO PRENATAL STRESS. 2018 8 851 20 CHIP-SEQ ANALYSIS OF HUMAN CHRONIC MYELOID LEUKEMIA CELLS. MANY TRANSCRIPTION FACTORS, CHROMATIN-ASSOCIATED PROTEINS AND REGULATORY DNA ELEMENTS ARE GENETICALLY AND/OR EPIGENETICALLY ALTERED IN CANCER, INCLUDING CHRONIC MYELOID LEUKEMIA (CML). THIS LEADS TO DEREGULATION OF TRANSCRIPTION THAT IS OFTEN CAUSALLY LINKED TO THE TUMORIGENIC STATE. CHROMATIN-IMMUNOPRECIPITATION COUPLED WITH MASSIVELY PARALLEL DNA SEQUENCING (CHIP-SEQ) IS THE KEY TECHNOLOGY TO STUDY TRANSCRIPTION AS IT ALLOWS IN VIVO WHOLE-GENOME MAPPING OF EPIGENETIC MODIFICATIONS AND INTERACTIONS OF PROTEINS WITH DNA OR CHROMATIN. HOWEVER, NUMEROUS DNA/CHROMATIN-BINDING PROTEINS, INCLUDING EZH2, REMAIN DIFFICULT TO "CHIP," THUS YIELDING GENOME-WIDE BINDING MAPS OF ONLY SUBOPTIMAL QUALITY. HERE, WE DESCRIBE A CHIP-SEQ PROTOCOL OPTIMIZED FOR HIGH-QUALITY PROTEIN-GENOME BINDING MAPS THAT HAVE PROVEN ESPECIALLY USEFUL FOR STUDYING DIFFICULT TO 'CHIP' TRANSCRIPTION REGULATORY FACTORS IN CHRONIC MYELOID LEUKEMIA (CML) AND RELATED MALIGNANCIES. 2016 9 269 33 AGE AND PERIODONTAL HEALTH - IMMUNOLOGICAL VIEW. PURPOSE OF THE REVIEW: AGING CLEARLY IMPACTS A WIDE ARRAY OF SYSTEMS, IN PARTICULAR THE BREADTH OF THE IMMUNE SYSTEM LEADING TO IMMUNOSENESCENCE, ALTERED IMMUNOACTIVATION, AND COINCIDENT INFLAMMAGING PROCESSES. THE NET RESULT OF THESE CHANGES LEADS TO INCREASED SUSCEPTIBILITY TO INFECTIONS, INCREASED NEOPLASTIC OCCURRENCES, AND ELEVATED FREQUENCY OF AUTOIMMUNE DISEASES WITH AGING. HOWEVER, AS THE BACTERIA IN THE ORAL MICROBIOME THAT CONTRIBUTE TO THE CHRONIC INFECTION OF PERIODONTITIS IS ACQUIRED EARLIER IN LIFE, THE CHARACTERISTICS OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMS TO REGULATE THESE MEMBERS OF THE AUTOCHTHONOUS MICROBIOTA ACROSS THE LIFESPAN REMAINS ILL DEFINED. RECENT FINDINGS: CLEAR DATA DEMONSTRATE THAT BOTH CELLS AND MOLECULES OF THE INNATE AND ADAPTIVE IMMUNE RESPONSE ARE ADVERSELY IMPACTED BY AGING, INCLUDING IN THE ORAL CAVITY, YIELDING A REASONABLE TENET THAT THE INCREASED PERIODONTITIS NOTED IN AGING POPULATIONS IS REFLECTIVE OF THE AGE-ASSOCIATED IMMUNE DYSREGULATION. ADDITIONALLY, THIS FACET OF HOST-MICROBE INTERACTIONS AND DISEASE NEEDS TO ACCOMMODATE THE POPULATION VARIATION IN DISEASE ONSET AND PROGRESSION, WHICH MAY ALSO REFLECT AN ACCUMULATION OF ENVIRONMENTAL STRESSORS AND/OR DECREASED PROTECTIVE NUTRIENTS THAT COULD FUNCTION AT THE GENE LEVEL (IE. EPIGENETIC) OR TRANSLATIONAL LEVEL FOR PRODUCTION AND SECRETION OF IMMUNE SYSTEM MOLECULES. SUMMARY: FINALLY, THE MAJORITY OF STUDIES OF AGING AND PERIODONTITIS HAVE EMPHASIZED THE INCREASED PREVALENCE/SEVERITY OF DISEASE WITH AGING, ALL BASED UPON CHRONOLOGICAL AGE. HOWEVER, EVOLVING AREAS OF STUDY FOCUSING ON "BIOLOGICAL AGING" TO HELP ACCOUNT FOR POPULATION VARIATION IN DISEASE EXPRESSION, MAY SUGGEST THAT CHRONIC PERIODONTITIS REPRESENTS A CO-MORBIDITY THAT CONTRIBUTES TO "GEROVULNERABILITY" WITHIN THE POPULATION. 2018 10 3209 26 HEALTH DISPARITIES IN SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC MULTISYSTEM AUTOIMMUNE DISEASE CHARACTERIZED BY AUTOANTIBODY PRODUCTION AND DIVERSE CLINICAL MANIFESTATIONS. THE MANY COMPLEX, OVERLAPPING, AND CLOSELY ASSOCIATED FACTORS THAT INFLUENCE SLE SUSCEPTIBILITY AND OUTCOMES INCLUDE ETHNIC DISPARITIES, LOW ADHERENCE TO MEDICATIONS, AND POVERTY, AND GEOGRAPHY. EPIGENETIC MECHANISMS MAY PROVIDE THE LINK BETWEEN THESE ENVIRONMENTAL EXPOSURES AND BEHAVIORS AND THE DISPROPORTIONATE BURDEN OF SLE SEEN IN ETHNIC MINORITIES. ATTENTION TO THESE MODIFIABLE SOCIAL DETERMINANTS OF HEALTH WOULD NOT ONLY IMPROVE OUTCOMES FOR VULNERABLE PATIENTS WITH SLE BUT LIKELY REDUCE SUSCEPTIBILITY TO SLE AS WELL THROUGH EPIGENETIC CHANGES. 2020 11 3858 21 ISCHEMIA-INDUCED DNA HYPERMETHYLATION DURING KIDNEY TRANSPLANT PREDICTS CHRONIC ALLOGRAFT INJURY. BACKGROUND ISCHEMIA DURING KIDNEY TRANSPLANT CAUSES CHRONIC ALLOGRAFT INJURY AND ADVERSELY AFFECTS OUTCOME, BUT THE UNDERLYING MECHANISMS ARE INCOMPLETELY UNDERSTOOD. IN TUMORS, OXYGEN SHORTAGE REDUCES THE DNA DEMETHYLATING ACTIVITY OF THE TEN-11 TRANSLOCATION (TET) ENZYMES, YIELDING HYPERMETHYLATED GENOMES THAT PROMOTE TUMOR PROGRESSION. WE INVESTIGATED WHETHER ISCHEMIA SIMILARLY INDUCES DNA HYPERMETHYLATION IN KIDNEY TRANSPLANTS AND CONTRIBUTES TO CHRONIC INJURY.METHODS WE PROFILED GENOME-WIDE DNA METHYLATION IN THREE COHORTS OF BRAIN-DEAD DONOR KIDNEY ALLOGRAFT BIOPSY SPECIMENS: A LONGITUDINAL COHORT WITH PAIRED BIOPSY SPECIMENS OBTAINED AT ALLOGRAFT PROCUREMENT (PREISCHEMIA; N=13), AFTER IMPLANTATION AND REPERFUSION (POSTISCHEMIA; N=13), AND AT 3 OR 12 MONTHS AFTER TRANSPLANT (N=5 EACH); A CROSS-SECTIONAL COHORT WITH PREIMPLANTATION BIOPSY SPECIMENS (N=82); AND A CROSS-SECTIONAL COHORT WITH POSTREPERFUSION BIOPSY SPECIMENS (N=46).RESULTS ANALYSIS OF THE PAIRED PREISCHEMIA AND POSTISCHEMIA SPECIMENS REVEALED THAT METHYLATION INCREASED DRASTICALLY IN ALL ALLOGRAFTS ON ISCHEMIA. HYPERMETHYLATION WAS CAUSED BY LOSS OF 5-HYDROXYMETHYLCYTOSINE, THE PRODUCT OF TET ACTIVITY, AND IT WAS STABLE 1 YEAR AFTER TRANSPLANT. IN THE PREIMPLANTATION COHORT, CPG HYPERMETHYLATION DIRECTLY CORRELATED WITH ISCHEMIA TIME AND FOR SOME CPGS, INCREASED 2.6% PER ADDITIONAL HOUR OF ISCHEMIA. HYPERMETHYLATION PREFERENTIALLY AFFECTED AND REDUCED THE EXPRESSION OF GENES INVOLVED IN SUPPRESSING KIDNEY INJURY AND FIBROSIS. MOREOVER, CPG HYPERMETHYLATION IN PREIMPLANTATION SPECIMENS PREDICTED CHRONIC INJURY, PARTICULARLY FIBROSIS AND GLOMERULOSCLEROSIS, 1 YEAR AFTER TRANSPLANT. THIS FINDING WAS VALIDATED IN THE INDEPENDENT POSTREPERFUSION COHORT, IN WHICH HYPERMETHYLATION ALSO PREDICTED REDUCED ALLOGRAFT FUNCTION 1 YEAR AFTER TRANSPLANT, OUTPERFORMING ESTABLISHED CLINICAL VARIABLES.CONCLUSIONS WE HIGHLIGHT A NOVEL EPIGENETIC BASIS FOR ISCHEMIA-INDUCED CHRONIC ALLOGRAFT INJURY WITH BIOMARKER POTENTIAL. 2018 12 4551 29 MUTATIONAL HIERARCHIES IN MYELODYSPLASTIC SYNDROMES DYNAMICALLY ADAPT AND EVOLVE UPON THERAPY RESPONSE AND FAILURE. CLONAL EVOLUTION IS BELIEVED TO BE A MAIN DRIVER FOR PROGRESSION OF VARIOUS TYPES OF CANCER AND IMPLICATED IN FACILITATING RESISTANCE TO DRUGS. HOWEVER, THE HIERARCHICAL ORGANIZATION OF MALIGNANT CLONES IN THE HEMATOPOIESIS OF MYELODYSPLASTIC SYNDROMES (MDS) AND ITS IMPACT ON RESPONSE TO DRUG THERAPY REMAIN POORLY UNDERSTOOD. USING HIGH-THROUGHPUT SEQUENCING OF PATIENT AND XENOGRAFTED CELLS, WE EVALUATED THE INTRATUMORAL HETEROGENEITY (N= 54) AND RECONSTRUCTED MUTATIONAL TRAJECTORIES (N = 39) IN PATIENTS SUFFERING FROM MDS (N = 52) AND CHRONIC MYELOMONOCYTIC LEUKEMIA-1 (N = 2). WE IDENTIFIED LINEAR AND ALSO BRANCHING EVOLUTION PATHS AND CONFIRMED ON A PATIENT-SPECIFIC LEVEL THAT SOMATIC MUTATIONS IN EPIGENETIC REGULATORS AND RNA SPLICING GENES FREQUENTLY CONSTITUTE ISOLATED DISEASE-INITIATING EVENTS. USING HIGH-THROUGHPUT EXOME- AND/OR DEEP-SEQUENCING, WE ANALYZED 103 CHRONOLOGICALLY ACQUIRED SAMPLES FROM 22 PATIENTS COVERING A CUMULATIVE OBSERVATION TIME OF 75 YEARS MDS DISEASE PROGRESSION. OUR DATA REVEALED HIGHLY DYNAMIC SHAPING OF COMPLEX OLIGOCLONAL ARCHITECTURES, SPECIFICALLY UPON TREATMENT WITH LENALIDOMIDE AND OTHER DRUGS. DESPITE INITIAL CLINICAL RESPONSE TO TREATMENT, PATIENTS' MARROW PERSISTENTLY REMAINED CLONAL WITH RAPID OUTGROWTH OF FOUNDER-, SUB-, OR EVEN FULLY INDEPENDENT CLONES, INDICATING AN INCREASED DYNAMIC RATE OF CLONAL TURNOVER. THE EMERGENCE AND DISAPPEARANCE OF SPECIFIC CLONES FREQUENTLY CORRELATED WITH CHANGES OF CLINICAL PARAMETERS, HIGHLIGHTING THEIR DISTINCT AND FAR-REACHING FUNCTIONAL PROPERTIES. INTRIGUINGLY, INCREASINGLY COMPLEX MUTATIONAL TRAJECTORIES ARE FREQUENTLY ACCOMPANIED BY CLINICAL PROGRESSION DURING THE COURSE OF DISEASE. THESE DATA SUBSTANTIATE A NEED FOR REGULAR BROAD MOLECULAR MONITORING TO GUIDE CLINICAL TREATMENT DECISIONS IN MDS. 2016 13 2990 25 GENETIC FACTORS PREDISPOSING TO SYSTEMIC LUPUS ERYTHEMATOSUS AND LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY A LOSS OF TOLERANCE TO SELF-ANTIGENS AND THE PRODUCTION OF HIGH TITERS OF SERUM AUTOANTIBODIES. LUPUS NEPHRITIS CAN AFFECT UP TO 74% OF SLE PATIENTS, PARTICULARLY THOSE OF HISPANIC AND AFRICAN ANCESTRIES, AND REMAINS A MAJOR CAUSE OF MORBIDITY AND MORTALITY. A GENETIC ETIOLOGY IN SLE IS NOW WELL SUBSTANTIATED. THANKS TO EXTENSIVE COLLABORATIONS, EXTRAORDINARY PROGRESS HAS BEEN MADE IN THE PAST FEW YEARS AND THE NUMBER OF CONFIRMED GENES PREDISPOSING TO SLE HAS CATAPULTED TO APPROXIMATELY 30. STUDIES OF OTHER FORMS OF GENETIC VARIATION, SUCH AS COPY NUMBER VARIANTS AND EPIGENETIC ALTERATIONS, ARE EMERGING AND PROMISE TO REVOLUTIONIZE OUR KNOWLEDGE ABOUT DISEASE MECHANISMS. HOWEVER, TO DATE LITTLE PROGRESS HAS BEEN MADE ON THE IDENTIFICATION OF GENETIC FACTORS SPECIFIC TO LUPUS NEPHRITIS. ON THE NEAR HORIZON, TWO LARGE-SCALE EFFORTS, A COLLABORATIVE META-ANALYSIS OF LUPUS NEPHRITIS BASED ON ALL GENOME-WIDE ASSOCIATION DATA IN CAUCASIANS AND PARALLEL SCANS IN FOUR OTHER ETHNICITIES, ARE POISED TO MAKE FUNDAMENTAL DISCOVERIES IN THE GENETICS OF LUPUS NEPHRITIS. COLLECTIVELY, THESE FINDINGS WILL SHOW THAT A BROAD ARRAY OF PATHWAYS UNDERLINES THE GENETIC HETEROGENEITY OF SLE AND LUPUS NEPHRITIS, AND PROVIDE POTENTIAL AVENUES FOR THE DEVELOPMENT OF NOVEL THERAPIES. 2010 14 4530 21 MULTILAYER INTRACLONAL HETEROGENEITY IN CHRONIC MYELOMONOCYTIC LEUKEMIA. THE FUNCTIONAL DIVERSITY OF CELLS THAT COMPOSE MYELOID MALIGNANCIES, I.E., THE RESPECTIVE ROLES OF GENETIC AND EPIGENETIC HETEROGENEITY IN THIS DIVERSITY, REMAINS POORLY UNDERSTOOD. THIS QUESTION IS ADDRESSED IN CHRONIC MYELOMONOCYTIC LEUKEMIA, A MYELOID NEOPLASM IN WHICH CLINICAL DIVERSITY CONTRASTS WITH LIMITED GENETIC HETEROGENEITY. TO GENERATE INDUCED PLURIPOTENT STEM CELL CLONES, WE REPROGRAMMED CD34(+) CELLS COLLECTED FROM A PATIENT WITH A CHRONIC MYELOMONOCYTIC LEUKEMIA IN WHICH WHOLE EXOME SEQUENCING OF PERIPHERAL BLOOD MONOCYTE DNA HAD IDENTIFIED 12 GENE MUTATIONS, INCLUDING A MUTATION IN KDM6A AND TWO HETEROZYGOUS MUTATIONS IN TET2 IN THE FOUNDING CLONE AND A SECONDARY KRAS(G12D) MUTATION. CD34(+) CELLS FROM AN AGE-MATCHED HEALTHY DONOR WERE ALSO REPROGRAMMED. WE CAPTURED A PART OF THE GENETIC HETEROGENEITY OBSERVED IN THE PATIENT, I.E. WE ANALYZED FIVE CLONES WITH TWO GENETIC BACKGROUNDS, WITHOUT AND WITH THE KRAS(G12D) MUTATION. HEMATOPOIETIC DIFFERENTIATION OF THESE CLONES RECAPITULATED THE MAIN FEATURES OF THE PATIENT'S DISEASE, INCLUDING OVERPRODUCTION OF GRANULOMONOCYTES AND DYSMEGAKARYOPOIESIS. THESE ANALYSES ALSO DISCLOSED SIGNIFICANT DISCREPANCIES IN THE BEHAVIOR OF HEMATOPOIETIC CELLS DERIVED FROM INDUCED PLURIPOTENT STEM CELL CLONES WITH SIMILAR GENETIC BACKGROUND, CORRELATING WITH LIMITED EPIGENETIC CHANGES. THESE ANALYSES SUGGEST THAT, BEYOND THE CODING MUTATIONS, SEVERAL LEVELS OF INTRACLONAL HETEROGENEITY MAY PARTICIPATE IN THE YET UNEXPLAINED CLINICAL HETEROGENEITY OF THE DISEASE. 2020 15 2106 25 EPIGENETIC EVOLUTION AND LINEAGE HISTORIES OF CHRONIC LYMPHOCYTIC LEUKAEMIA. GENETIC AND EPIGENETIC INTRA-TUMORAL HETEROGENEITY COOPERATE TO SHAPE THE EVOLUTIONARY COURSE OF CANCER(1). CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IS A HIGHLY INFORMATIVE MODEL FOR CANCER EVOLUTION AS IT UNDERGOES SUBSTANTIAL GENETIC DIVERSIFICATION AND EVOLUTION AFTER THERAPY(2,3). THE CLL EPIGENOME IS ALSO AN IMPORTANT DISEASE-DEFINING FEATURE(4,5), AND GROWING POPULATIONS OF CELLS IN CLL DIVERSIFY BY STOCHASTIC CHANGES IN DNA METHYLATION KNOWN AS EPIMUTATIONS(6). HOWEVER, PREVIOUS STUDIES USING BULK SEQUENCING METHODS TO ANALYSE THE PATTERNS OF DNA METHYLATION WERE UNABLE TO DETERMINE WHETHER EPIMUTATIONS AFFECT CLL POPULATIONS HOMOGENEOUSLY. HERE, TO MEASURE THE EPIMUTATION RATE AT SINGLE-CELL RESOLUTION, WE APPLIED MULTIPLEXED SINGLE-CELL REDUCED-REPRESENTATION BISULFITE SEQUENCING TO B CELLS FROM HEALTHY DONORS AND PATIENTS WITH CLL. WE OBSERVED THAT THE COMMON CLONAL ORIGIN OF CLL RESULTS IN A CONSISTENTLY INCREASED EPIMUTATION RATE, WITH LOW VARIABILITY IN THE CELL-TO-CELL EPIMUTATION RATE. BY CONTRAST, VARIABLE EPIMUTATION RATES ACROSS HEALTHY B CELLS REFLECT DIVERSE EVOLUTIONARY AGES ACROSS THE TRAJECTORY OF B CELL DIFFERENTIATION, CONSISTENT WITH EPIMUTATIONS SERVING AS A MOLECULAR CLOCK. HERITABLE EPIMUTATION INFORMATION ALLOWED US TO RECONSTRUCT LINEAGES AT HIGH-RESOLUTION WITH SINGLE-CELL DATA, AND TO APPLY THIS DIRECTLY TO PATIENT SAMPLES. THE CLL LINEAGE TREE SHAPE REVEALED EARLIER BRANCHING AND LONGER BRANCH LENGTHS THAN IN NORMAL B CELLS, REFLECTING RAPID DRIFT AFTER THE INITIAL MALIGNANT TRANSFORMATION AND A GREATER PROLIFERATIVE HISTORY. INTEGRATION OF SINGLE-CELL BISULFITE SEQUENCING ANALYSIS WITH SINGLE-CELL TRANSCRIPTOMES AND GENOTYPING CONFIRMED THAT GENETIC SUBCLONES MAPPED TO DISTINCT CLADES, AS INFERRED SOLELY ON THE BASIS OF EPIMUTATION INFORMATION. FINALLY, TO EXAMINE POTENTIAL LINEAGE BIASES DURING THERAPY, WE PROFILED SERIAL SAMPLES DURING IBRUTINIB-ASSOCIATED LYMPHOCYTOSIS, AND IDENTIFIED CLADES OF CELLS THAT WERE PREFERENTIALLY EXPELLED FROM THE LYMPH NODE AFTER TREATMENT, MARKED BY DISTINCT TRANSCRIPTIONAL PROFILES. THE SINGLE-CELL INTEGRATION OF GENETIC, EPIGENETIC AND TRANSCRIPTIONAL INFORMATION THUS CHARTS THE LINEAGE HISTORY OF CLL AND ITS EVOLUTION WITH THERAPY. 2019 16 1202 27 COULD DNA HYDROXYMETHYLATION BE CRUCIAL IN INFLUENCING STEROID HORMONE SIGNALING IN ENDOMETRIAL BIOLOGY AND ENDOMETRIOSIS? ENDOMETRIOSIS AFFECTS 10% OF REPRODUCTIVE-AGED WOMEN. IT IS CHARACTERIZED BY THE GROWTH OF THE ENDOMETRIUM, OUTSIDE THE UTERUS AND IS ASSOCIATED WITH INFERTILITY AND CHRONIC ABDOMINAL PAIN. LACK OF NONINVASIVE DIAGNOSTIC TOOLS AND EARLY SCREENING TESTS RESULTS IN DELAYED TREATMENT AND SUBSEQUENTLY INCREASED DISEASE SEVERITY. ENDOMETRIOSIS IS A DISEASE ASSOCIATED WITH A DEREGULATED HORMONAL RESPONSE, THEREFORE, UNDERSTANDING THE MOLECULAR MECHANISMS THAT GOVERN THIS HORMONAL INTERPLAY IS OF PARAMOUNT IMPORTANCE. DNA METHYLATION IS AN EPIGENETIC MARK THAT REGULATES GENE EXPRESSION AND IS OFTEN ASSOCIATED WITH GENES THAT CODE FOR STEROID RECEPTORS AND ENZYMES ASSOCIATED WITH ESTROGEN SYNTHESIS AND METABOLISM IN ENDOMETRIOSIS. DNA HYDROXYMETHYLATION, WHICH IS STRUCTURALLY SIMILAR TO METHYLATION BUT FUNCTIONALLY DIFFERENT, IS A BIOLOGICALLY CRITICAL MECHANISM THAT IS ALSO KNOWN TO REGULATE GENE EXPRESSION. TEN ELEVEN TRANSLOCATION (TET) PROTEINS MEDIATE HYDROXYMETHYLATION. HOWEVER, THE ROLE OF DNA HYDROXYMETHYLATION OR TETS IN THE ENDOMETRIUM REMAINS RELATIVELY UNEXPLORED. CURRENTLY, THE "GOLD STANDARD" TECHNIQUE USED TO STUDY METHYLATION PATTERNS IS BISULFITE GENOMIC SEQUENCING. THIS TECHNIQUE ALSO DETECTS HYDROXYMETHYLATION BUT FAILS TO DISTINGUISH BETWEEN THE TWO, THEREBY LIMITING OUR UNDERSTANDING OF THESE TWO PROCESSES. THE PRESENCE OF TETS IN THE MALE AND FEMALE REPRODUCTIVE TRACT AND ITS CONTRIBUTION TO ENDOMETRIAL CANCER MAKES IT AN IMPORTANT FACTOR TO STUDY IN ENDOMETRIOSIS. THIS REVIEW SUMMARIZES THE ROLE OF DNA METHYLATION IN ABERRANT STEROID HORMONE SIGNALING AND HYPOTHESIZES THAT HYDROXYMETHYLATION COULD BE A FACTOR INFLUENCING HORMONAL INSTABILITY SEEN IN ENDOMETRIOSIS. 2020 17 1195 19 CORRUPTED COORDINATION OF EPIGENETIC MODIFICATIONS LEADS TO DIVERGING CHROMATIN STATES AND TRANSCRIPTIONAL HETEROGENEITY IN CLL. CANCER EVOLUTION IS FUELED BY EPIGENETIC AS WELL AS GENETIC DIVERSITY. IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), INTRA-TUMORAL DNA METHYLATION (DNAME) HETEROGENEITY EMPOWERS EVOLUTION. HERE, TO COMPREHENSIVELY STUDY THE EPIGENETIC DIMENSION OF CANCER EVOLUTION, WE INTEGRATE DNAME ANALYSIS WITH HISTONE MODIFICATION MAPPING AND SINGLE CELL ANALYSES OF RNA EXPRESSION AND DNAME IN 22 PRIMARY CLL AND 13 HEALTHY DONOR B LYMPHOCYTE SAMPLES. OUR DATA REVEAL CORRUPTED COHERENCE ACROSS DIFFERENT LAYERS OF THE CLL EPIGENOME. THIS MANIFESTS IN DECREASED MUTUAL INFORMATION ACROSS EPIGENETIC MODIFICATIONS AND GENE EXPRESSION ATTRIBUTED TO CELL-TO-CELL HETEROGENEITY. DISRUPTED EPIGENETIC-TRANSCRIPTIONAL COORDINATION IN CLL IS ALSO REFLECTED IN THE DYSREGULATION OF THE TRANSCRIPTIONAL OUTPUT AS A FUNCTION OF THE COMBINATORIAL CHROMATIN STATES, INCLUDING INCOMPLETE POLYCOMB-MEDIATED GENE SILENCING. NOTABLY, WE OBSERVE UNEXPECTED CO-MAPPING OF TYPICALLY MUTUALLY EXCLUSIVE ACTIVATING AND REPRESSING HISTONE MODIFICATIONS, SUGGESTIVE OF INTRA-TUMORAL EPIGENETIC DIVERSITY. THUS, CLL EPIGENETIC DIVERSIFICATION LEADS TO DECREASED COORDINATION ACROSS LAYERS OF EPIGENETIC INFORMATION, LIKELY REFLECTING AN ADMIXTURE OF CELLS WITH DIVERGING CELLULAR IDENTITIES. 2019 18 3056 29 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY. 2023 19 5885 28 SYSTEMIC LUPUS ERYTHEMATOSUS FOLLOWING HUMAN PAPILLOMAVIRUS VACCINATION: A CASE-BASED REVIEW. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A HETEROGENEOUS SYSTEMIC AUTOIMMUNE DISEASES (AIDS) WITH MANY PATHOGENIC FACTORS, RANGING FROM GENETIC TO EPIGENETIC TO ENVIRONMENTAL. THE HUMAN PAPILLOMAVIRUS (HPV), A VIRAL INFECTIOUS AGENT, IS A COMMON CONTRIBUTOR TO THE ONSET AND EXACERBATION OF SLE. HPV INFECTIONS ARE MORE PREVALENT AMONG SLE PATIENTS THAN HEALTHY INDIVIDUALS, BRINGING ABOUT A SUBSTANTIAL NEED FOR TREATMENT. WHILE HPV RECOMBINANT GENE VACCINES ARE ACCEPTED AS A UNIVERSAL METHOD FOR INFECTION PREVENTION, THEY POSE A RISK FOR ADVERSE EVENTS SUCH AS FEVER, JOINT PAIN, AND RASHES. IN RARE CASES, THEY MIGHT EVEN TRIGGER AIDS SUCH AS SLE, ESPECIALLY IN PATIENTS WITH A PERSONAL OR FAMILY HISTORY OF SUCH DISEASES. IN THIS ARTICLE, WE PROVIDE A REPORT OF A CASE OF SLE ONSET FOLLOWING HPV VACCINATION AND A REVIEW OF 11 SIMILAR CASES. AN ANALYSIS OF 12 PATIENTS REVEALED THAT 7 CASES OF SLE DEVELOPED BETWEEN 3 WEEKS AND 2 MONTHS POST-VACCINATION. SYMPTOMS OF SLE GENERALLY MANIFEST AS FATIGUE, FEVER, JOINT PAIN, AND MYALGIA. TWO PATIENTS HAD LUPUS NEPHRITIS, 2 SHOWED CENTRAL NERVOUS SYSTEM INVOLVEMENT, INCLUDING ABNORMAL BEHAVIOR AND EPILEPTIC SEIZURES, AND 1 HAD INTESTINAL PSEUDO-OBSTRUCTION. ALL PATIENTS SHOWED RAPID REMISSION WITH GLUCOCORTICOID AND IMMUNOSUPPRESSIVE THERAPY AND REMAINED STABLE DURING SEVERAL MONTHS OF FOLLOW-UP. 2022 20 1463 37 DISSECTING COMPLEX EPIGENETIC ALTERATIONS IN HUMAN LUPUS. SYSTEMIC LUPUS ERYTHEMATOSUS IS A CHRONIC RELAPSING AUTOIMMUNE DISEASE THAT PRIMARILY AFFLICTS WOMEN, AND BOTH A GENETIC PREDISPOSITION AND APPROPRIATE ENVIRONMENTAL EXPOSURES ARE REQUIRED FOR LUPUS TO DEVELOP AND FLARE. THE GENETIC REQUIREMENT IS EVIDENCED BY AN INCREASED CONCORDANCE IN IDENTICAL TWINS AND BY THE VALIDATION OF AT LEAST 35 SINGLE-NUCLEOTIDE POLYMORPHISMS PREDISPOSING PATIENTS TO LUPUS. GENES ALONE, THOUGH, ARE NOT ENOUGH. THE CONCORDANCE OF LUPUS IN IDENTICAL TWINS IS OFTEN INCOMPLETE, AND WHEN CONCORDANT, THE AGE OF ONSET IS USUALLY DIFFERENT. LUPUS IS ALSO NOT PRESENT AT BIRTH, BUT ONCE THE DISEASE DEVELOPS, IT TYPICALLY FOLLOWS A CHRONIC RELAPSING COURSE. THUS, GENES ALONE ARE INSUFFICIENT TO CAUSE HUMAN LUPUS, AND ADDITIONAL FACTORS ENCOUNTERED IN THE ENVIRONMENT AND OVER TIME ARE REQUIRED TO INITIATE THE DISEASE AND SUBSEQUENT FLARES. THE NATURE OF THE ENVIRONMENTAL CONTRIBUTION, THOUGH, AND THE MECHANISMS BY WHICH ENVIRONMENTAL AGENTS MODIFY THE IMMUNE RESPONSE TO CAUSE LUPUS ONSET AND FLARES IN GENETICALLY PREDISPOSED PEOPLE HAVE BEEN CONTROVERSIAL. REPORTS THAT THE LUPUS-INDUCING DRUGS PROCAINAMIDE AND HYDRALAZINE ARE EPIGENETIC MODIFIERS, THAT EPIGENETICALLY MODIFIED T CELLS ARE SUFFICIENT TO CAUSE LUPUS-LIKE AUTOIMMUNITY IN ANIMAL MODELS, AND THAT PATIENTS WITH ACTIVE LUPUS HAVE EPIGENETIC CHANGES SIMILAR TO THOSE CAUSED BY PROCAINAMIDE AND HYDRALAZINE HAVE PROMPTED A GROWING INTEREST IN HOW EPIGENETIC ALTERATIONS CONTRIBUTE TO THIS DISEASE. UNDERSTANDING HOW EPIGENETIC MECHANISMS MODIFY T CELLS TO CONTRIBUTE TO LUPUS REQUIRES AN UNDERSTANDING OF HOW EPIGENETIC MECHANISMS REGULATE GENE EXPRESSION. THE ROLES OF DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS IN LUPUS PATHOGENESIS WILL BE REVIEWED HERE. 2013