1  3364 101 HISTONE METHYLATION BY THE KLEEFSTRA SYNDROME PROTEIN EHMT1 MEDIATES HOMEOSTATIC SYNAPTIC SCALING. HOMEOSTATIC PLASTICITY, A FORM OF SYNAPTIC PLASTICITY, MAINTAINS THE FINE BALANCE BETWEEN OVERALL EXCITATION AND INHIBITION IN DEVELOPING AND MATURE NEURONAL NETWORKS. ALTHOUGH THE SYNAPTIC MECHANISMS OF HOMEOSTATIC PLASTICITY ARE WELL CHARACTERIZED, THE ASSOCIATED TRANSCRIPTIONAL PROGRAM REMAINS POORLY UNDERSTOOD. WE SHOW THAT THE KLEEFSTRA-SYNDROME-ASSOCIATED PROTEIN EHMT1 PLAYS A CRITICAL AND CELL-AUTONOMOUS ROLE IN SYNAPTIC SCALING BY RESPONDING TO ATTENUATED NEURONAL FIRING OR SENSORY DRIVE. CHRONIC ACTIVITY DEPRIVATION INCREASED THE AMOUNT OF NEURONAL DIMETHYLATED H3 AT LYSINE 9 (H3K9ME2), THE CATALYTIC PRODUCT OF EHMT1 AND AN EPIGENETIC MARKER FOR GENE REPRESSION. GENETIC KNOCKDOWN AND PHARMACOLOGICAL BLOCKADE OF EHMT1 OR EHMT2 PREVENTED THE INCREASE OF H3K9ME2 AND SYNAPTIC SCALING UP. FURTHERMORE, BDNF REPRESSION WAS PRECEDED BY EHMT1/2-MEDIATED H3K9ME2 DEPOSITION AT THE BDNF PROMOTER DURING SYNAPTIC SCALING UP, BOTH IN VITRO AND IN VIVO. OUR FINDINGS SUGGEST THAT H3K9ME2-MEDIATED CHANGES IN CHROMATIN STRUCTURE GOVERN A REPRESSIVE PROGRAM THAT CONTROLS SYNAPTIC SCALING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  1697  32 DYNAMIC DNA METHYLATION CONTROLS GLUTAMATE RECEPTOR TRAFFICKING AND SYNAPTIC SCALING. HEBBIAN PLASTICITY, INCLUDING LONG-TERM POTENTIATION AND LONG-TERM DEPRESSION, HAS LONG BEEN REGARDED AS IMPORTANT FOR LOCAL CIRCUIT REFINEMENT IN THE CONTEXT OF MEMORY FORMATION AND STABILIZATION. HOWEVER, CIRCUIT DEVELOPMENT AND STABILIZATION ADDITIONALLY RELIES ON NON-HEBBIAN, HOMEOSTATIC, FORMS OF PLASTICITY SUCH AS SYNAPTIC SCALING. SYNAPTIC SCALING IS INDUCED BY CHRONIC INCREASES OR DECREASES IN NEURONAL ACTIVITY. SYNAPTIC SCALING IS ASSOCIATED WITH CELL-WIDE ADJUSTMENTS IN POSTSYNAPTIC RECEPTOR DENSITY, AND CAN OCCUR IN A MULTIPLICATIVE MANNER RESULTING IN PRESERVATION OF RELATIVE SYNAPTIC STRENGTHS ACROSS THE ENTIRE NEURON'S POPULATION OF SYNAPSES. BOTH ACTIVE DNA METHYLATION AND DEMETHYLATION HAVE BEEN VALIDATED AS CRUCIAL REGULATORS OF GENE TRANSCRIPTION DURING LEARNING, AND SYNAPTIC SCALING IS KNOWN TO BE TRANSCRIPTIONALLY DEPENDENT. HOWEVER, IT HAS BEEN UNCLEAR WHETHER HOMEOSTATIC FORMS OF PLASTICITY SUCH AS SYNAPTIC SCALING ARE REGULATED VIA EPIGENETIC MECHANISMS. THIS REVIEW DESCRIBES EXCITING RECENT WORK THAT HAS DEMONSTRATED A ROLE FOR ACTIVE CHANGES IN NEURONAL DNA METHYLATION AND DEMETHYLATION AS A CONTROLLER OF SYNAPTIC SCALING AND GLUTAMATE RECEPTOR TRAFFICKING. THESE FINDINGS BRING TOGETHER THREE MAJOR CATEGORIES OF MEMORY-ASSOCIATED MECHANISMS THAT WERE PREVIOUSLY LARGELY CONSIDERED SEPARATELY: DNA METHYLATION, HOMEOSTATIC PLASTICITY, AND GLUTAMATE RECEPTOR TRAFFICKING. THIS REVIEW DESCRIBES EXCITING RECENT WORK THAT HAS DEMONSTRATED A ROLE FOR ACTIVE CHANGES IN NEURONAL DNA METHYLATION AND DEMETHYLATION AS A CONTROLLER OF SYNAPTIC SCALING AND GLUTAMATE RECEPTOR TRAFFICKING. THESE FINDINGS BRING TOGETHER THREE MAJOR CATEGORIES OF MEMORY-ASSOCIATED MECHANISMS THAT WERE PREVIOUSLY CONSIDERED SEPARATELY: GLUTAMATE RECEPTOR TRAFFICKING, DNA METHYLATION, AND HOMEOSTATIC PLASTICITY.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3  3645  22 INCREASED PRESENCE AND DIFFERENTIAL MOLECULAR IMPRINTING OF TRANSIT AMPLIFYING CELLS IN PSORIASIS. PSORIASIS IS A VERY COMMON CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EPIDERMAL THICKENING AND SCALING RESULTING FROM KERATINOCYTE HYPERPROLIFERATION AND IMPAIRED DIFFERENTIATION. PATHOMECHANISTIC STUDIES IN PSORIASIS ARE OFTEN LIMITED BY USING WHOLE SKIN TISSUE BIOPSIES, NEGLECTING THEIR STRATIFICATION AND CELLULAR DIVERSITY. THIS STUDY AIMED AT CHARACTERIZING EPIDERMAL ALTERATIONS IN PSORIASIS AT THE LEVEL OF KERATINOCYTE POPULATIONS. EPIDERMAL CELL POPULATIONS WERE PURIFIED FROM SKIN BIOPSIES OF PSORIASIS PATIENTS AND HEALTHY DONORS USING A NOVEL CELL TYPE-SPECIFIC APPROACH. MOLECULAR CHARACTERIZATION OF THE TRANSIT-AMPLIFYING CELLS (TAC), THE KEY PLAYERS OF EPIDERMAL RENEWAL, WAS PERFORMED USING IMMUNOCYTOFLUORESCENCE-TECHNIQUE AND INTEGRATED MULTISCALE-OMICS ANALYSES. ALREADY TAC FROM NON-LESIONAL PSORIATIC SKIN SHOWED ALTERED METHYLATION AND DIFFERENTIAL EXPRESSION IN 1.7% AND 1.0% OF ALL PROTEIN-CODING GENES, RESPECTIVELY. IN PSORIATIC LESIONS, TAC WERE STRONGLY EXPANDED SHOWING FURTHER INCREASED DIFFERENTIALLY METHYLATED (10-FOLD) AND EXPRESSED (22-FOLD) GENES NUMBERS. IMPORTANTLY, 17.2% OF DIFFERENTIALLY EXPRESSED GENES WERE ASSOCIATED WITH RESPECTIVE GENE METHYLATIONS. COMPARED WITH NON-LESIONAL TAC, PATHWAY ANALYSES REVEALED METABOLIC ALTERATIONS AS ONE FEATURE PREDOMINANTLY CHANGED IN TAC DERIVED FROM ACTIVE PSORIATIC LESIONS. OVERALL, OUR STUDY SHOWED STAGE-SPECIFIC MOLECULAR ALTERATIONS, ALLOWS NEW INSIGHTS INTO THE PATHOGENESIS, AND IMPLIES THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LESION DEVELOPMENT IN PSORIASIS. KEY MESSAGES: TRANSIT AMPLIFYING CELL (TAC) NUMBERS ARE HIGHLY INCREASED IN PSORIATIC LESIONS PSORIATIC TAC SHOW PROFOUND MOLECULAR ALTERATIONS & STAGE-SPECIFIC IDENTITY TAC FROM UNAFFECTED AREAS ALREADY SHOW FIRST SIGNS OF MOLECULAR ALTERATIONS LESIONAL TAC SHOW A PREFERENCE IN METABOLIC-RELATED ALTERATIONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4  5619  23 SCALING UP PRENATAL NUTRITION COULD REDUCE THE GLOBAL BURDEN OF NONCOMMUNICABLE DISEASES IN THE NEXT GENERATION: A MODELING ANALYSIS. BACKGROUND: NUTRITIONAL CONDITIONS DURING PREGNANCY MAY INFLUENCE THE EPIGENETIC DEVELOPMENT OF AN INDIVIDUAL AND CONSEQUENTLY THEIR LATER-LIFE RISK OF NONCOMMUNICABLE DISEASE (NCD). IMPROVING NUTRITION FOR PREGNANT FEMALES MAY THEREFORE SERVE THE DUAL PURPOSE OF DIRECTLY IMPROVING PREGNANCY OUTCOMES AND PREVENTING NCDS IN THE NEXT GENERATION. OBJECTIVES: WE ESTIMATED THE IMPACT OF PRENATAL SUPPLEMENTATION WITH IRON AND FOLIC ACID (IFA), MULTIPLE MICRONUTRIENTS (MMS), OR CALCIUM AT 50%, 75%, OR 90% COVERAGE ON FUTURE NCDS BY AGE AND SEX IN 2015. METHODS: WE USED SECONDARY DATA SOURCES FROM 132 COUNTRIES TO QUANTIFY THE CASES OF DIABETES AND HYPERTENSION AND THE DEATHS FROM SELECTED NCDS THAT COULD BE AVERTED OR DELAYED BY SCALING UP PRENATAL MICRONUTRIENT SUPPLEMENTATION. RESULTS: GLOBALLY, >51,000 NCD DEATHS, 6 MILLION CASES OF HYPERTENSION, AND 3 MILLION CASES OF DIABETES COULD BE PREVENTED PER OFFSPRING BIRTH COHORT IF MOTHERS WERE PRENATALLY SUPPLEMENTED WITH MMS AT 90% COVERAGE. FOR IFA THESE NUMBERS WOULD BE ROUGHLY HALF. CALCIUM SUPPLEMENTATION AT 90% COULD DELAY 51,000 DEATHS PER BIRTH COHORT. OUR MODEL SUGGESTS THAT SUBSTANTIAL NUMBERS OF NCD DEATHS AND CASES OF HYPERTENSION AND DIABETES COULD BE PREVENTED IN FUTURE GENERATIONS BY SCALING UP MICRONUTRIENT SUPPLEMENTATION FOR MOTHERS DURING PREGNANCY. CONCLUSIONS: HIGHLIGHTING THE ADDITIONAL BENEFITS OF PROVEN NUTRITION INTERVENTIONS IS CRITICAL IN ENSURING ADEQUATE AND SUSTAINED INVESTMENTS, AND PROGRAMMATIC INTEGRATION. AS THE DOUBLE BURDEN OF DISEASE CONTINUES TO GROW, POPULATION-WIDE EFFORTS TO SCALE UP MICRONUTRIENT SUPPLEMENTATION TO PREGNANT FEMALES COULD HELP PREVENT BOTH UNDERNUTRITION AND CHRONIC DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
5  2271  30 EPIGENETIC READER SP140 LOSS OF FUNCTION DRIVES CROHN'S DISEASE DUE TO UNCONTROLLED MACROPHAGE TOPOISOMERASES. HOW MIS-REGULATED CHROMATIN DIRECTLY IMPACTS HUMAN IMMUNE DISORDERS IS POORLY UNDERSTOOD. SPECKLED PROTEIN 140 (SP140) IS AN IMMUNE-RESTRICTED PHD AND BROMODOMAIN-CONTAINING EPIGENETIC "READER," AND SP140 LOSS-OF-FUNCTION MUTATIONS ASSOCIATE WITH CROHN'S DISEASE (CD), MULTIPLE SCLEROSIS (MS), AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). HOWEVER, THE RELEVANCE OF THESE MUTATIONS AND MECHANISMS UNDERLYING SP140-DRIVEN PATHOGENICITY REMAINS UNEXPLORED. USING A GLOBAL PROTEOMIC STRATEGY, WE IDENTIFIED SP140 AS A REPRESSOR OF TOPOISOMERASES (TOPS) THAT MAINTAINS HETEROCHROMATIN AND MACROPHAGE FATE. IN HUMANS AND MICE, SP140 LOSS RESULTED IN UNLEASHED TOP ACTIVITY, DE-REPRESSION OF DEVELOPMENTALLY SILENCED GENES, AND ULTIMATELY DEFECTIVE MICROBE-INDUCIBLE MACROPHAGE TRANSCRIPTIONAL PROGRAMS AND BACTERIAL KILLING THAT DRIVE INTESTINAL PATHOLOGY. PHARMACOLOGICAL INHIBITION OF TOP1/2 RESCUED THESE DEFECTS. FURTHERMORE, EXACERBATED COLITIS WAS RESTORED WITH TOP1/2 INHIBITORS IN SP140(-/-) MICE, BUT NOT WILD-TYPE MICE, IN VIVO. COLLECTIVELY, WE IDENTIFY SP140 AS A TOP REPRESSOR AND REVEAL REPURPOSING OF TOP INHIBITION TO REVERSE IMMUNE DISEASES DRIVEN BY SP140 LOSS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
6  5973  29 TET-CATALYZED 5-HYDROXYMETHYLATION PRECEDES HNF4A PROMOTER CHOICE DURING DIFFERENTIATION OF BIPOTENT LIVER PROGENITORS. UNDERSTANDING THE PROCESSES THAT GOVERN LIVER PROGENITOR CELL DIFFERENTIATION HAS IMPORTANT IMPLICATIONS FOR THE DESIGN OF STRATEGIES TARGETING CHRONIC LIVER DISEASES, WHEREBY REGENERATION OF LIVER TISSUE IS CRITICAL. ALTHOUGH DNA METHYLATION (5MC) AND HYDROXYMETHYLATION (5HMC) ARE HIGHLY DYNAMIC DURING EARLY EMBRYONIC DEVELOPMENT, LESS IS KNOWN ABOUT THEIR ROLES AT LATER STAGES OF DIFFERENTIATION. USING AN IN VITRO MODEL OF HEPATOCYTE DIFFERENTIATION, WE SHOW HERE THAT 5HMC PRECEDES THE EXPRESSION OF PROMOTER 1 (P1)-DEPENDENT ISOFORMS OF HNF4A, A MASTER TRANSCRIPTION FACTOR OF HEPATOCYTE IDENTITY. 5HMC AND HNF4A EXPRESSION FROM P1 ARE DEPENDENT ON TEN-ELEVEN TRANSLOCATION (TET) DIOXYGENASES. IN TURN, THE LIVER PIONEER FACTOR FOXA2 IS NECESSARY FOR TET1 BINDING TO THE P1 LOCUS. BOTH FOXA2 AND TETS ARE REQUIRED FOR THE 5HMC-RELATED SWITCH IN HNF4A EXPRESSION. THE EPIGENETIC EVENT IDENTIFIED HERE MAY BE A KEY STEP FOR THE ESTABLISHMENT OF THE HEPATOCYTE PROGRAM BY HNF4A.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7   647  15 BIRTH ORDER PATTERN IN THE INHERITANCE OF CHRONIC LYMPHOCYTIC LEUKAEMIA AND RELATED LYMPHOPROLIFERATIVE DISEASE. RANK ORDER OF AFFECTED OFFSPRING IN A SIBSHIP CAN INFORM ON EPIGENETIC FACTORS IN DISEASE SUSCEPTIBILITY. HERE WE REPORT AN ANALYSIS OF BIRTH ORDER IN 32 FAMILIES SEGREGATING CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) AND OTHER B-CELL LYMPHOPROLIFERATIVE DISORDERS. A PATERNAL-OFFSPRING, BUT NOT A MATERNAL-OFFSPRING BIRTH RANK ORDER WAS OBSERVED. COX REGRESSION ANALYSIS PROVIDED RELATIVE RISKS (RR) FOR PATERNAL AND MATERNAL TRANSMISSION OF 3.60 (CI 95%: 1.54 - 8.42; P = 0.0005) AND 1.64 (CI 95%: 0.90 - 3.01; P = 0.096), RESPECTIVELY. THE SIGNIFICANCE OF PATERNAL AND MATERNAL TRANSMISSION OF CLL-CLL PAIRS EMPLOYING HALDANE AND SMITH'S TEST WERE 0.006 AND 0.63, RESPECTIVELY. THERE WAS NO EVIDENCE OF A RELATIONSHIP BETWEEN PARENTAL AGE AND BIRTH ORDER. THE GENETIC MECHANISM BEHIND THE BIRTH ORDER EFFECT OBSERVED IS DISCUSSED IN THE LIGHT OF NON-MENDELIAN IMPRINTING AND PREGNANCY RELATED MICROCHIMERISM.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
8  1499  19 DNA METHYLATION ANALYSIS IN NONALCOHOLIC FATTY LIVER DISEASE SUGGESTS DISTINCT DISEASE-SPECIFIC AND REMODELING SIGNATURES AFTER BARIATRIC SURGERY. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CHRONIC LIVER DISORDER IN INDUSTRIALIZED COUNTRIES. LIVER SAMPLES FROM MORBIDLY OBESE PATIENTS (N = 45) WITH ALL STAGES OF NAFLD AND CONTROLS (N = 18) WERE ANALYZED BY ARRAY-BASED DNA METHYLATION AND MRNA EXPRESSION PROFILING. NAFLD-SPECIFIC EXPRESSION AND METHYLATION DIFFERENCES WERE SEEN FOR NINE GENES CODING FOR KEY ENZYMES IN INTERMEDIATE METABOLISM (INCLUDING PC, ACLY, AND PLCG1) AND INSULIN/INSULIN-LIKE SIGNALING (INCLUDING IGF1, IGFBP2, AND PRKCE) AND REPLICATED BY BISULFITE PYROSEQUENING (INDEPENDENT N = 39). TRANSCRIPTION FACTOR BINDING SITES AT NAFLD-SPECIFIC CPG SITES WERE >1,000-FOLD ENRICHED FOR ZNF274, PGC1A, AND SREBP2. INTRAINDIVIDUAL COMPARISON OF LIVER BIOPSIES BEFORE AND AFTER BARIATRIC SURGERY SHOWED NAFLD-ASSOCIATED METHYLATION CHANGES TO BE PARTIALLY REVERSIBLE. POSTBARIATRIC AND NAFLD-SPECIFIC METHYLATION SIGNATURES WERE CLEARLY DISTINCT BOTH IN GENE ONTOLOGY AND TRANSCRIPTION FACTOR BINDING SITE ANALYSES, WITH >400-FOLD ENRICHMENT OF NRF1, HSF1, AND ESRRA SITES. OUR FINDINGS PROVIDE AN EXAMPLE OF TREATMENT-INDUCED EPIGENETIC ORGAN REMODELING IN HUMANS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9  3740  25 INSIGHT INTO GENETIC PREDISPOSITION TO CHRONIC LYMPHOCYTIC LEUKEMIA FROM INTEGRATIVE EPIGENOMICS. GENOME-WIDE ASSOCIATION STUDIES HAVE PROVIDED EVIDENCE FOR INHERITED GENETIC PREDISPOSITION TO CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). TO GAIN INSIGHT INTO THE MECHANISMS UNDERLYING CLL RISK WE ANALYZE CHROMATIN ACCESSIBILITY, ACTIVE REGULATORY ELEMENTS MARKED BY H3K27AC, AND DNA METHYLATION AT 42 RISK LOCI IN UP TO 486 PRIMARY CLLS. WE IDENTIFY THAT RISK LOCI ARE SIGNIFICANTLY ENRICHED FOR ACTIVE CHROMATIN IN CLL WITH EVIDENCE OF BEING CLL-SPECIFIC OR DIFFERENTIALLY REGULATED IN NORMAL B-CELL DEVELOPMENT. WE THEN USE IN SITU PROMOTER CAPTURE HI-C, IN CONJUNCTION WITH GENE EXPRESSION DATA TO REVEAL LIKELY TARGET GENES OF THE RISK LOCI. CANDIDATE TARGET GENES ARE ENRICHED FOR PATHWAYS RELATED TO B-CELL DEVELOPMENT SUCH AS MYC AND BCL2 SIGNALLING. AT 14 LOCI THE ANALYSIS HIGHLIGHTS 63 VARIANTS AS THE PROBABLE FUNCTIONAL BASIS OF CLL RISK. BY INTEGRATING GENETIC AND EPIGENETIC INFORMATION OUR ANALYSIS REVEALS NOVEL INSIGHTS INTO THE RELATIONSHIP BETWEEN INHERITED PREDISPOSITION AND THE REGULATORY CHROMATIN LANDSCAPE OF CLL.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10   374  30 AN ENDOSIRNA-BASED REPRESSION MECHANISM COUNTERACTS TRANSPOSON ACTIVATION DURING GLOBAL DNA DEMETHYLATION IN EMBRYONIC STEM CELLS. ERASURE OF DNA METHYLATION AND REPRESSIVE CHROMATIN MARKS IN THE MAMMALIAN GERMLINE LEADS TO RISK OF TRANSCRIPTIONAL ACTIVATION OF TRANSPOSABLE ELEMENTS (TES). HERE, WE USED MOUSE EMBRYONIC STEM CELLS (ESCS) TO IDENTIFY AN ENDOSIRNA-BASED MECHANISM INVOLVED IN SUPPRESSION OF TE TRANSCRIPTION. IN ESCS WITH DNA DEMETHYLATION INDUCED BY ACUTE DELETION OF DNMT1, WE SAW AN INCREASE IN SENSE TRANSCRIPTION AT TES, RESULTING IN AN ABUNDANCE OF SENSE/ANTISENSE TRANSCRIPTS LEADING TO HIGH LEVELS OF ARGONAUTE2 (AGO2)-BOUND SMALL RNAS. INHIBITION OF DICER OR AGO2 EXPRESSION REVEALED THAT SMALL RNAS ARE INVOLVED IN AN IMMEDIATE RESPONSE TO DEMETHYLATION-INDUCED TRANSPOSON ACTIVATION, WHILE THE DEPOSITION OF REPRESSIVE HISTONE MARKS FOLLOWS AS A CHRONIC RESPONSE. IN VIVO, WE ALSO FOUND TE-SPECIFIC ENDOSIRNAS PRESENT DURING PRIMORDIAL GERM CELL DEVELOPMENT. OUR RESULTS SUGGEST THAT ANTISENSE TE TRANSCRIPTION IS A "TRAP" THAT ELICITS AN ENDOSIRNA RESPONSE TO RESTRAIN ACUTE TRANSPOSON ACTIVITY DURING EPIGENETIC REPROGRAMMING IN THE MAMMALIAN GERMLINE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
11  2173  18 EPIGENETIC MECHANISMS INVOLVED IN INTRAUTERINE GROWTH RESTRICTION AND ABERRANT KIDNEY DEVELOPMENT AND FUNCTION. INTRAUTERINE GROWTH RESTRICTION (IUGR) DUE TO UTEROPLACENTAL INSUFFICIENCY RESULTS IN A PLACENTA THAT IS UNABLE TO PROVIDE ADEQUATE NUTRIENTS AND OXYGEN TO THE FETUS. THESE GROWTH-RESTRICTED BABIES HAVE AN INCREASED RISK OF HYPERTENSION AND CHRONIC KIDNEY DISEASE LATER IN LIFE. IN RATS, BOTH MALE AND FEMALE GROWTH-RESTRICTED OFFSPRING HAVE NEPHRON DEFICITS BUT ONLY MALES DEVELOP KIDNEY DYSFUNCTION AND HIGH BLOOD PRESSURE. IN ADDITION, THERE IS TRANSGENERATIONAL TRANSMISSION OF NEPHRON DEFICITS AND HYPERTENSION RISK. THEREFORE, EPIGENETIC MECHANISMS MAY EXPLAIN THE SEX-SPECIFIC PROGRAMMING AND MULTIGENERATIONAL TRANSMISSION OF IUGR-RELATED PHENOTYPES. EXPRESSION OF DNA METHYLTRANSFERASES (DNMT1AND DNMT3A) AND IMPRINTED GENES (PEG3, SNRPN, KCNQ1, AND CDKN1C) WERE INVESTIGATED IN KIDNEY TISSUES OF SHAM AND IUGR RATS IN F1 (EMBRYONIC DAY 20 (E20) AND POSTNATAL DAY 1 (PN1)) AND F2 (6 AND 12 MONTHS OF AGE, PATERNAL AND MATERNAL LINES) GENERATIONS (N = 6-13/GROUP). IN COMPARISON TO SHAM OFFSPRING, F1 IUGR RATS HAD A 19% DECREASE IN DNMT3A EXPRESSION AT E20 (P < 0.05), WITH DECREASED CDKN1C (19%, P < 0.05) AND INCREASED KCNQ1 (1.6-FOLD, P < 0.01) AT PN1. THERE WAS A SEX-SPECIFIC DIFFERENCE IN CDKN1C AND SNRPN EXPRESSION AT E20, WITH 29% AND 34% HIGHER EXPRESSION IN IUGR MALES COMPARED TO FEMALES, RESPECTIVELY (P < 0.05). PEG3 SEX-SPECIFIC EXPRESSION WAS LOST IN THE F2 IUGR OFFSPRING, ONLY IN THE MATERNAL LINE. THESE FINDINGS SUGGEST THAT EPIGENETIC MECHANISMS MAY BE ALTERED IN RENAL EMBRYONIC AND/OR FETAL DEVELOPMENT IN GROWTH-RESTRICTED OFFSPRING, WHICH COULD ALTER KIDNEY FUNCTION, PREDISPOSING THESE OFFSPRING TO KIDNEY DISEASE LATER IN LIFE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12   118  21 A SUBSET OF METHYLATED CPG SITES DIFFERENTIATE PSORIATIC FROM NORMAL SKIN. PSORIASIS IS A CHRONIC INFLAMMATORY IMMUNE-MEDIATED DISORDER AFFECTING THE SKIN AND OTHER ORGANS INCLUDING JOINTS. OVER 1,300 TRANSCRIPTS ARE ALTERED IN PSORIATIC INVOLVED SKIN COMPARED WITH NORMAL SKIN. HOWEVER, TO OUR KNOWLEDGE, GLOBAL EPIGENETIC PROFILING OF PSORIATIC SKIN IS PREVIOUSLY UNREPORTED. HERE, WE DESCRIBE A GENOME-WIDE STUDY OF ALTERED CPG METHYLATION IN PSORIATIC SKIN. WE DETERMINED THE METHYLATION LEVELS AT 27,578 CPG SITES IN SKIN SAMPLES FROM INDIVIDUALS WITH PSORIASIS (12 INVOLVED, 8 UNINVOLVED) AND 10 UNAFFECTED INDIVIDUALS. CPG METHYLATION OF INVOLVED SKIN DIFFERED FROM NORMAL SKIN AT 1,108 SITES. TWELVE MAPPED TO THE EPIDERMAL DIFFERENTIATION COMPLEX, UPSTREAM OR WITHIN GENES THAT ARE HIGHLY UPREGULATED IN PSORIASIS. HIERARCHICAL CLUSTERING OF 50 OF THE TOP DIFFERENTIALLY METHYLATED (DM) SITES SEPARATED PSORIATIC FROM NORMAL SKIN SAMPLES WITH UNINVOLVED SKIN EXHIBITING INTERMEDIATE METHYLATION. CPG SITES WHERE METHYLATION WAS CORRELATED WITH GENE EXPRESSION ARE REPORTED. SITES WITH INVERSE CORRELATIONS BETWEEN METHYLATION AND NEARBY GENE EXPRESSION INCLUDE THOSE OF KYNU, OAS2, S100A12, AND SERPINB3, WHOSE STRONG TRANSCRIPTIONAL UPREGULATION IS AN IMPORTANT DISCRIMINATOR OF PSORIASIS. PYROSEQUENCING OF BISULFITE-TREATED DNA FROM SKIN BIOPSIES AT THREE DM LOCI CONFIRMED EARLIER FINDINGS AND REVEALED REVERSION OF METHYLATION LEVELS TOWARD THE NON-PSORIATIC STATE AFTER 1 MONTH OF ANTI-TNF-ALPHA THERAPY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13  5092  19 PLACENTAL EPIGENETIC MARKS RELATED TO GESTATIONAL WEIGHT GAIN REVEAL POTENTIAL GENES ASSOCIATED WITH OFFSPRING OBESITY PARAMETERS. OBJECTIVE: OFFSPRING EXPOSED TO GESTATIONAL OBESITY HAVE AN INCREASED RISK FOR CHRONIC DISEASES. INCREASING EVIDENCE SUGGESTS THAT EPIGENETICS MAY PLAY A MECHANISTIC ROLE IN METABOLIC PROGRAMMING. THIS STUDY AIMED TO IDENTIFY PLACENTAL DNA METHYLATION MARKS ASSOCIATED WITH GESTATIONAL WEIGHT GAIN (GWG) AND TO STUDY THEIR ASSOCIATION WITH OFFSPRING OBESITY PARAMETERS AT SCHOOL AGE. METHODS: A GLOBAL METHYLATION ARRAY WAS PERFORMED IN 24 PLACENTAS FROM MOTHERS WITH DIFFERENT DEGREES OF GWG (SCREENING SAMPLE). THE METHYLATION PERCENTAGE OF FOUR CYTOSINE-GUANINE (CPG) SITES AND THE RELATIVE EXPRESSION OF THE RESPECTIVE ANNOTATED GENES WERE STUDIED IN 90 ADDITIONAL PLACENTAS (VALIDATION SAMPLE). ASSOCIATIONS OF THESE EPIGENETIC MARKS WITH CLINICAL PARAMETERS IN THE OFFSPRING AT 6 YEARS OF AGE WERE EXAMINED. RESULTS: THE SCREENING ANALYSIS IDENTIFIED 104 CPG SITES (97 GENES) ASSOCIATED WITH GWG. THE VALIDATION ANALYSIS OF FOUR SELECTED CPG SITES (ANNOTATING FOR FRAT1, SNX5, AND KCNK3 GENES) SHOWED THAT THE UPREGULATION OF SNX5 METHYLATION, THE DOWNREGULATION OF FRAT1 METHYLATION, AND KCNK3 UNDEREXPRESSION ASSOCIATED WITH AN ADVERSE METABOLIC PHENOTYPE IN CHILDREN OF WOMEN WITH INCREASED GWG. CONCLUSIONS: THESE RESULTS SUGGEST THAT PLACENTAL REGULATION OF FRAT1, SNX5, AND KCNK3 RELATES TO OBESITY PARAMETERS IN OFFSPRING EXPOSED TO EXCESSIVE GWG AND THEREBY COULD CONDITION THE RISK FOR FUTURE METABOLIC DISORDERS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14    99  27 A PUTATIVE "HEPITYPE" IN THE ATM GENE ASSOCIATED WITH CHRONIC LYMPHOCYTIC LEUKEMIA RISK. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CELLS ARE CHARACTERIZED BY SEVERAL CHROMOSOMAL LESIONS. SOME OF THESE ABERRATIONS IMPLY CHROMOSOME BREAKS AS A RESULT OF UNREPAIRED DOUBLE STRAND BREAKS (DSBS) IN THE DNA. THE ATM (ATAXIA TELANGIECTASIA-MUTATED) PROTEIN IS THE PRINCIPAL INTEGRATOR OF CELLULAR RESPONSES TO DSBS. ATM DELETION IS ALSO AN ADVERSE PROGNOSTIC FACTOR IN CLL. TAKING THIS INTO ACCOUNT, WE EVALUATED IF GENETIC AND/OR EPIGENETIC VARIATION IN THE ATM GENE MAY MODULATE THE INDIVIDUAL SUSCEPTIBILITY TO DEVELOP CLL. OUR CASE-CONTROL ASSOCIATION STUDY WAS PERFORMED IN A LARGE SPANISH POPULATION OF 1,503 INDIVIDUALS, INCLUDING 742 PATIENTS WITH CLL AND 761 CONTROLS. WE IDENTIFIED ONE HAPLOTYPE WITHIN THE ATM GENE THAT CONFERS AN INCREASED RISK OF CLL DEVELOPMENT (OR = 1.33; 95% CI: 1.10-1.60). TWO POLYMORPHISMS OF THIS ATM HAPLOTYPE ELIMINATED ONE CPG SITE EACH IN INTRONS 15 AND 61, CAUSING CHANGES IN DNA METHYLATION PATTERN. THESE DATA PROVIDE THE FIRST EVIDENCE FOR THE EXISTENCE OF A PUTATIVE "HEPITYPE" IN THE ATM GENE ASSOCIATED WITH CLL RISK.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15   612  29 BINDING OF TFIIIC TO SINE ELEMENTS CONTROLS THE RELOCATION OF ACTIVITY-DEPENDENT NEURONAL GENES TO TRANSCRIPTION FACTORIES. IN NEURONS, THE TIMELY AND ACCURATE EXPRESSION OF GENES IN RESPONSE TO SYNAPTIC ACTIVITY RELIES ON THE INTERPLAY BETWEEN EPIGENETIC MODIFICATIONS OF HISTONES, RECRUITMENT OF REGULATORY PROTEINS TO CHROMATIN AND CHANGES TO NUCLEAR STRUCTURE. TO IDENTIFY GENES AND REGULATORY ELEMENTS RESPONSIVE TO SYNAPTIC ACTIVATION IN VIVO, WE PERFORMED A GENOME-WIDE CHIPSEQ ANALYSIS OF ACETYLATED HISTONE H3 USING SOMATOSENSORY CORTEX OF MICE EXPOSED TO NOVEL ENRICHED ENVIRONMENTAL (NEE) CONDITIONS. WE DISCOVERED THAT SHORT INTERSPERSED ELEMENTS (SINES) LOCATED DISTAL TO PROMOTERS OF ACTIVITY-DEPENDENT GENES BECAME ACETYLATED FOLLOWING EXPOSURE TO NEE AND WERE BOUND BY THE GENERAL TRANSCRIPTION FACTOR TFIIIC. IMPORTANTLY, UNDER DEPOLARIZING CONDITIONS, INDUCIBLE GENES RELOCATED TO TRANSCRIPTION FACTORIES (TFS), AND THIS EVENT WAS CONTROLLED BY TFIIIC. SILENCING OF THE TFIIIC SUBUNIT GTF3C5 IN NON-STIMULATED NEURONS INDUCED UNCONTROLLED RELOCATION TO TFS AND TRANSCRIPTION OF ACTIVITY-DEPENDENT GENES. REMARKABLY, IN CORTICAL NEURONS, SILENCING OF GTF3C5 MIMICKED THE EFFECTS OF CHRONIC DEPOLARIZATION, INDUCING A DRAMATIC INCREASE OF BOTH DENDRITIC LENGTH AND BRANCHING. THESE FINDINGS REVEAL A NOVEL AND ESSENTIAL REGULATORY FUNCTION OF BOTH SINES AND TFIIIC IN MEDIATING GENE RELOCATION AND TRANSCRIPTION. THEY ALSO SUGGEST THAT TFIIIC MAY REGULATE THE REARRANGEMENT OF NUCLEAR ARCHITECTURE, ALLOWING THE COORDINATED EXPRESSION OF ACTIVITY-DEPENDENT NEURONAL GENES.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16  3813  27 INTRAUTERINE GROWTH RESTRICTION INHIBITS EXPRESSION OF EUKARYOTIC ELONGATION FACTOR 2 KINASE, A REGULATOR OF PROTEIN TRANSLATION. NUTRIENT DEPRIVATION SUPPRESSES PROTEIN SYNTHESIS BY BLOCKING PEPTIDE ELONGATION. TRANSCRIPTIONAL UPREGULATION AND ACTIVATION OF EUKARYOTIC ELONGATION FACTOR 2 KINASE (EEF2K) BLOCKS PEPTIDE ELONGATION BY PHOSPHORYLATING EUKARYOTIC ELONGATION FACTOR 2. PREVIOUS STUDIES EXAMINING PLACENTAS FROM INTRAUTERINE GROWTH RESTRICTED (IUGR) NEWBORN INFANTS SHOW DECREASED EEF2K EXPRESSION AND ACTIVITY DESPITE CHRONIC NUTRIENT DEPRIVATION. HOWEVER, THE EFFECT OF IUGR ON HEPATIC EEF2K EXPRESSION IN THE FETUS IS UNKNOWN. WE, THEREFORE, EXAMINED THE TRANSCRIPTIONAL REGULATION OF HEPATIC EEF2K GENE EXPRESSION IN A SPRAGUE-DAWLEY RAT MODEL OF IUGR. WE FOUND DECREASED HEPATIC EEF2K MRNA AND PROTEIN LEVELS IN IUGR OFFSPRING AT BIRTH COMPARED WITH CONTROL, CONSISTENT WITH PREVIOUS PLACENTAL OBSERVATIONS. FURTHERMORE, THE CPG ISLAND WITHIN THE EEF2K PROMOTER DEMONSTRATED INCREASED METHYLATION AT A CRITICAL USF 1/2 TRANSCRIPTION FACTOR BINDING SITE. IN VITRO METHYLATION OF THIS BINDING SITE CAUSED NEAR COMPLETE LOSS OF EEF2K PROMOTER ACTIVITY, DESIGNATING THIS PROMOTER AS METHYLATION SENSITIVE. THE EEF2K PROMOTOR IN IUGR OFFSPRING ALSO LOST THE PROTECTIVE HISTONE COVALENT MODIFICATIONS ASSOCIATED WITH UNMETHYLATED CGIS. IN ADDITION, THE +1 NUCLEOSOME WAS DISPLACED 3' AND RNA POLYMERASE LOADING WAS REDUCED AT THE IUGR EEF2K PROMOTER. OUR FINDINGS PROVIDE EVIDENCE TO EXPLAIN WHY IUGR-INDUCED CHRONIC NUTRIENT DEPRIVATION DOES NOT RESULT IN THE UPREGULATION OF EEF2K GENE TRANSCRIPTION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
17  1995  24 EPIGENETIC AND GENETIC ALTERATIONS AND THEIR INFLUENCE ON GENE REGULATION IN CHRONIC LYMPHOCYTIC LEUKEMIA. BACKGROUND: TO UNDERSTAND THE CHANGES OF GENE REGULATION IN CARCINOGENESIS, WE EXPLORED SIGNALS OF DNA METHYLATION - A STABLE EPIGENETIC MARK OF GENE REGULATORY ELEMENTS - AND DESIGNED A COMPUTATIONAL MODEL TO PROFILE LOSS AND GAIN OF REGULATORY ELEMENTS (RES) DURING CARCINOGENESIS. WE ALSO UTILIZED SEQUENCING DATA TO ANALYZE THE ALLELE FREQUENCY OF SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AND DETECTED THE CANCER-ASSOCIATED SNPS, I.E., THE SNPS DISPLAYING THE SIGNIFICANT ALLELE FREQUENCY DIFFERENCE BETWEEN CANCER AND NORMAL SAMPLES. RESULTS: AFTER APPLYING THIS MODEL TO CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) DATA, WE IDENTIFIED RES DIFFERENTIALLY ACTIVATED (DRES) BETWEEN NORMAL AND CLL CELLS, CONSISTING OF 6,802 DRES GAINED AND 4,606 DRES LOST IN CLL. THE IDENTIFIED REGULATORY PERTURBATIONS COINCIDE WITH CHANGES IN THE EXPRESSION OF TARGET GENES. IN PARTICULAR, THE GENES ENCODING DNA METHYLTRANSFERASES HARBOR MULTIPLE LOST-IN-CANCER DRES AND ZERO GAINED-IN-CANCER DRES, INDICATING THAT THE DAMAGED REGULATION OF THESE GENES MIGHT BE ONE OF THE KEY CAUSES OF TUMOR FORMATION. DRES DISPLAY A SIGNIFICANTLY ELEVATED DENSITY OF THE GENOME-WIDE ASSOCIATION STUDY (GWAS) SNPS ASSOCIATED WITH CLL AND CLL-RELATED TRAITS. WE OBSERVED THAT MOST OF DRE GWAS SNPS ASSOCIATED WITH CLL AND CLL-RELATED TRAITS (83%) DISPLAY A SIGNIFICANT HAPLOTYPE ASSOCIATION AMONG THE IDENTIFIED CANCER-ASSOCIATED ALLELES AND THE RISK ALLELES THAT HAVE BEEN REPORTED IN GWAS. ALSO DRES ARE ENRICHED FOR THE BINDING SITES OF THE WELL-ESTABLISHED B-CELL AND CLL TRANSCRIPTION FACTORS (TFS) NF-KB, AP2, P53, E2F1, PAX5, AND SP1. WE ALSO IDENTIFIED CLL-ASSOCIATED SNPS AND DEMONSTRATED THAT THE MUTATIONS AT THESE SNPS CHANGE THE BINDING SITES OF KEY TFS MUCH MORE FREQUENTLY THAN EXPECTED. CONCLUSIONS: THROUGH EXPLORING SEQUENCING DATA MEASURING DNA METHYLATION, WE IDENTIFIED THE EPIGENETIC ALTERATIONS (MORE SPECIFICALLY, DNA METHYLATION) AND GENETIC MUTATIONS ALONG NON-CODING GENOMIC REGIONS CLL, AND DEMONSTRATED THAT THESE CHANGES PLAY A CRITICAL ROLE IN CARCINOGENESIS THROUGH DAMAGING THE REGULATION OF KEY GENES AND ALTERNATING THE BINDING OF KEY TFS IN B AND CLL CELLS.	2017	
                                                                                                                                                                                                                                                                           
18  3858  23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                          
19  4090  27 MATERNAL PRE-PREGNANCY BMI, OFFSPRING EPIGENOME-WIDE DNA METHYLATION, AND CHILDHOOD OBESITY: FINDINGS FROM THE BOSTON BIRTH COHORT. BACKGROUND: MATERNAL PRE-PREGNANCY OBESITY IS AN ESTABLISHED RISK FACTOR FOR CHILDHOOD OBESITY. INVESTIGATING EPIGENETIC ALTERATIONS INDUCED BY MATERNAL OBESITY DURING FETAL DEVELOPMENT COULD GAIN MECHANISTIC INSIGHT INTO THE DEVELOPMENTAL ORIGINS OF CHILDHOOD OBESITY. WHILE OBESITY DISPROPORTIONATELY AFFECTS UNDERREPRESENTED RACIAL AND ETHNIC MOTHERS AND CHILDREN IN THE USA, FEW STUDIES INVESTIGATED THE ROLE OF PRENATAL EPIGENETIC PROGRAMMING IN INTERGENERATIONAL OBESITY OF THESE HIGH-RISK POPULATIONS. METHODS: THIS STUDY INCLUDED 903 MOTHER-CHILD PAIRS FROM THE BOSTON BIRTH COHORT, A PREDOMINANTLY URBAN, LOW-INCOME MINORITY BIRTH COHORT. MOTHER-INFANT DYADS WERE ENROLLED AT BIRTH AND THE CHILDREN WERE FOLLOWED PROSPECTIVELY TO AGE 18 YEARS. INFINIUM METHYLATION EPIC BEADCHIP WAS USED TO MEASURE EPIGENOME-WIDE METHYLATION LEVEL OF CORD BLOOD. WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY OF MATERNAL PRE-PREGNANCY BODY MASS INDEX (BMI) AND CORD BLOOD DNA METHYLATION (DNAM). TO QUANTIFY THE DEGREE TO WHICH CORD BLOOD DNAM MEDIATES THE MATERNAL BMI-CHILDHOOD OBESITY, WE FURTHER INVESTIGATED WHETHER MATERNAL BMI-ASSOCIATED DNAM SITES IMPACT BIRTHWEIGHT OR CHILDHOOD OVERWEIGHT OR OBESITY (OWO) FROM AGE 1 TO AGE 18 AND PERFORMED CORRESPONDING MEDIATION ANALYSES. RESULTS: THE STUDY SAMPLE CONTAINED 52.8% MATERNAL PRE-PREGNANCY OWO AND 63.2% OFFSPRING OWO AT AGE 1-18 YEARS. MATERNAL BMI WAS ASSOCIATED WITH CORD BLOOD DNAM AT 8 CPG SITES (GENOME-WIDE FALSE DISCOVERY RATE [FDR] < 0.05). AFTER ACCOUNTING FOR THE POSSIBLE INTERPLAY OF MATERNAL BMI AND SMOKING, 481 CPG SITES WERE DISCOVERED FOR ASSOCIATION WITH MATERNAL BMI. AMONG THEM 123 CPGS WERE ASSOCIATED WITH CHILDHOOD OWO, RANGING FROM 42% DECREASE TO 87% INCREASE IN OWO RISK FOR EACH SD INCREASE IN DNAM. A TOTAL OF 14 IDENTIFIED CPG SITES SHOWED A SIGNIFICANT MEDIATION EFFECT ON THE MATERNAL BMI-CHILD OWO ASSOCIATION (FDR < 0.05), WITH MEDIATING PROPORTION RANGING FROM 3.99% TO 25.21%. SEVERAL OF THESE 14 CPGS WERE MAPPED TO GENES IN ASSOCIATION WITH ENERGY BALANCE AND METABOLISM (AKAP7) AND ADULTHOOD METABOLIC SYNDROME (CAMK2B). CONCLUSIONS: THIS PROSPECTIVE BIRTH COHORT STUDY IN A HIGH-RISK YET UNDERSTUDIED US POPULATION FOUND THAT MATERNAL PRE-PREGNANCY OWO SIGNIFICANTLY ALTERED DNAM IN NEWBORN CORD BLOOD AND PROVIDED SUGGESTIVE EVIDENCE OF EPIGENETIC INVOLVEMENT IN THE INTERGENERATIONAL RISK OF OBESITY.	2023	

20  4432  19 MOLECULAR CHARACTERIZATION OF RICHTER SYNDROME IDENTIFIES DE NOVO DIFFUSE LARGE B-CELL LYMPHOMAS WITH POOR PROGNOSIS. RICHTER SYNDROME (RS) IS THE TRANSFORMATION OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) INTO AGGRESSIVE LYMPHOMA, MOST COMMONLY DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL). WE CHARACTERIZE 58 PRIMARY HUMAN RS SAMPLES BY GENOME-WIDE DNA METHYLATION AND WHOLE-TRANSCRIPTOME PROFILING. OUR COMPREHENSIVE APPROACH DETERMINES RS DNA METHYLATION PROFILE AND UNRAVELS A CLL EPIGENETIC IMPRINT, ALLOWING CLL-RS CLONAL RELATIONSHIP ASSESSMENT WITHOUT THE NEED OF THE INITIAL CLL TUMOR DNA. DNA METHYLATION- AND TRANSCRIPTOMIC-BASED CLASSIFIERS WERE DEVELOPED, AND TESTING ON LANDMARK DLBCL DATASETS IDENTIFIES A POOR-PROGNOSIS, ACTIVATED B-CELL-LIKE DLBCL SUBSET IN 111/1772 SAMPLES. THE CLASSIFICATION ROBUSTLY IDENTIFIES PHENOTYPES VERY SIMILAR TO RS WITH A SPECIFIC GENOMIC PROFILE, ACCOUNTING FOR 4.3-8.3% OF DE NOVO DLBCLS. IN THIS WORK, RS MULTI-OMICS CHARACTERIZATION DETERMINES ONCOGENIC MECHANISMS, ESTABLISHES A SURROGATE MARKER FOR CLL-RS CLONAL RELATIONSHIP, AND PROVIDES A CLINICALLY RELEVANT CLASSIFIER FOR A SUBSET OF PRIMARY "RS-TYPE DLBCL" WITH UNFAVORABLE PROGNOSIS.	2023