geneimprint : Hot off the Press

'; ?> geneimprint : Hot off the Press http://www.geneimprint.com/site/hot-off-the-press Daily listing of the most recent articles in epigenetics and imprinting, collected from the PubMed database. en-us Tue, 09 Aug 2022 21:25:17 EDT Tue, 09 Aug 2022 21:25:17 EDT jirtle@radonc.duke.edu james001@jirtle.com Chromatin dynamics controls epigenetic domain formation. Katava M, Shi G, Thirumalai D
Biophys J (Aug 2022)

In multicellular organisms, nucleosomes carry epigenetic information that defines distinct patterns of gene expression, which are inherited over multiple generations. The enhanced capacity for information storage arises by nucleosome modifications, which are triggered by enzymes. Modified nucleosomes can transfer the mark to others that are in proximity by a positive-feedback (modification begets modification) mechanism. We created a generic polymer model, referred to as 3DSpreader, in which each bead, representing a nucleosome, stochastically switches between unmodified (U) and modified (M) states depending on the states of the neighbors. Modification begins at a specific nucleation site (NS) that is permanently in the M state, and could spread to other loci that is dictated by chromatin dynamics. Transfer of marks among the non-nucleation loci occurs stochastically as chromatin evolves in time. If the spreading rate is slower than the chromatin relaxation rate, which is biologically pertinent, then finite-sized domains form, driven by contacts between nucleosomes through a three-dimensional looping mechanism. Surprisingly, simulations based on the 3DSpreader model result in finite bounded domains that arise without the need for any boundary elements. Maintenance of spatially and temporally stable domains requires the presence of the NS, whose removal eliminates finite-sized modified domains. The theoretical predictions are in excellent agreement with experimental data for H3K9me3 spreading in mouse embryonic stem cells.]]> Wed, 31 Dec 1969 19:00:00 EST Cogito: automated and generic comparison of annotated genomic intervals. BÃ¼rger A, Dugas M
BMC Bioinformatics (Aug 2022)

Genetic and epigenetic biological studies often combine different types of experiments and multiple conditions. While the corresponding raw and processed data are made available through specialized public databases, the processed files are usually limited to a specific research question. Hence, they are unsuitable for an unbiased, systematic overview of a complex dataset. However, possible combinations of different sample types and conditions grow exponentially with the amount of sample types and conditions. Therefore the risk to miss a correlation or to overrate an identified correlation should be mitigated in a complex dataset. Since reanalysis of a full study is rarely a viable option, new methods are needed to address these issues systematically, reliably, reproducibly and efficiently.]]> Wed, 31 Dec 1969 19:00:00 EST Deciphering Epigenetic Backgrounds in a Korean Cohort with Beckwith-Wiedemann Syndrome. Kim HY, Shin CH, Lee YA, Shin CH, Kim GH, Ko JM
Ann Lab Med (Nov 2022)

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth disorder caused by genetic or epigenetic alterations at two imprinting centers (ICs) in the 11p15.5 region. Delineation of the molecular defects is important for prognosis and predicting familial recurrence. We evaluated epigenetic alterations and potential epigenotype-phenotype correlations in Korean children with BWS.]]> Wed, 31 Dec 1969 19:00:00 EST Epigenetic modifications in metabolic memory: What are the memories, and can we erase them? Chen Z, Natarajan R
Am J Physiol Cell Physiol (Aug 2022)

Inherent and acquired abnormalities in gene regulation due to the influence of genetics and epigenetics (traits related to environment rather than genetic factors) underlie many diseases including diabetes. Diabetes could lead to multiple complications including retinopathy, nephropathy, and cardiovascular disease that greatly increase morbidity and mortality. Epigenetic changes have also been linked to diabetes-related complications. Genes associated with many pathophysiological features of these vascular complications (e.g., inflammation, fibrosis, and oxidative stress) can be regulated by epigenetic mechanisms involving histone posttranslational modifications, DNA methylation, changes in chromatin structure/remodeling, and noncoding RNAs. Intriguingly, these epigenetic changes triggered during early periods of hyperglycemic exposure and uncontrolled diabetes are not immediately corrected even after restoration of normoglycemia and metabolic balance. This latency in effect across time and conditions is associated with persistent development of complications in diabetes with prior history of poor glycemic control, termed as metabolic memory or legacy effect. Epigenetic modifications are generally reversible and provide a window of therapeutic opportunity to ameliorate cellular dysfunction and mitigate or "erase" metabolic memory. Notably, trained immunity and related epigenetic changes transmitted from hematopoietic stem cells to innate immune cells have also been implicated in metabolic memory. Hence, identification of epigenetic variations at candidate genes, or epigenetic signatures genome-wide by epigenome-wide association studies can aid in prompt diagnosis to prevent progression of complications and identification of much-needed new therapeutic targets. Herein, we provide a review of epigenetics and epigenomics in metabolic memory of diabetic complications covering the current basic research, clinical data, and translational implications.]]> Wed, 31 Dec 1969 19:00:00 EST EWSR1::YY1 fusion positive peritoneal epithelioid mesothelioma harbors mesothelioma epigenetic signature: Report of 3 cases in support of an emerging entity. Dermawan JK, Torrence D, Lee CH, Villafania L, Mullaney KA, DiNapoli S, Sukhadia P, Benayed R, Borsu L, Agaram NP, Nash GM, Dickson BC, Benhamida J, Antonescu CR
Genes Chromosomes Cancer (Oct 2022)

Mesothelioma is a rare, aggressive malignant neoplasm of mesothelial origin. A small subset of peritoneal mesothelioma is driven by recurrent gene fusions, mostly EWSR1/FUS::ATF1 fusions, with predilection for young adults. To date, only two cases of mesothelioma harboring EWSR1::YY1 fusions have been described. We present three additional cases of EWSR1::YY1-fused peritoneal mesotheliomas, two localized and one diffuse, all occurring in the peritoneum of middle-aged adults (2 females and 1 male), and discovered incidentally by imaging or during surgery performed for unrelated reasons. None presented with symptoms or had a known history of asbestos exposure. All three cases were cellular epithelioid neoplasms with heterogeneous architectural patterns comprising mostly solid nests and sheets with variably papillary and trabecular areas against collagenous stroma. Cytologically, the cells were monomorphic, polygonal, epithelioid cells with dense eosinophilic cytoplasm and centrally located nuclei. Overt mitotic activity or tumor necrosis was absent. All cases showed strong diffuse immunoreactivity for pancytokeratin, CK7, and nuclear WT1, patchy to negative calretinin, retained BAP1 expression, and were negative for Ber-EP4 and MOC31. RNA-sequencing confirmed in-frame gene fusion transcripts involving EWSR1 exon 7/8 and YY1 exon 2/3. By unsupervised clustering analysis, the methylation profiles of EWSR1::YY1-fused mesotheliomas clustered similarly with EWSR1/FUS::ATF1-fused mesotheliomas and conventional mesotheliomas, suggesting a mesothelioma epigenetic signature. All three patients underwent surgical resection or cytoreductive surgery of the masses. On follow-up imaging, no recurrence or progression of disease was identified. Our findings suggest that EWSR1::YY1-fusion defines a small subset of peritoneal epithelioid mesothelioma in middle-aged adults without history of asbestos exposure.]]> Wed, 31 Dec 1969 19:00:00 EST Social Epigenomics: Conceptualizations and Considerations for Oral Health. Gomaa N
J Dent Res (Aug 2022)

Advances in high-throughput technologies and the generation of multiomics, such as genomic, epigenomic, transcriptomic, and metabolomic data, are paving the way for the biological risk stratification and prediction of oral diseases. When integrated with electronic health records, survey, census, and/or epidemiologic data, multiomics are anticipated to facilitate data-driven precision oral health, or the delivery of the right oral health intervention to the right individuals/populations at the right time. Meanwhile, multiomics may be modified by a multitude of social exposures, cumulatively along the life course and at various time points from conception onward, also referred to as the . For example, adverse exposures, such as precarious social and living conditions and related psychosocial stress among others, have been linked to specific genes being switched "on and off" through epigenetic mechanisms. These in turn are associated with various health conditions in different age groups and populations. This article argues that considering the impact of the socio-exposome in the biological profiling for precision oral health applications is necessary to ensure that definitions of biological risk do not override social ones. To facilitate the uptake of the socio-exposome in multiomics oral health studies and subsequent interventions, 3 pertinent facets are discussed. First, a summary of the epigenetic landscape of oral health is presented. Next, findings from the nondental literature are drawn on to elaborate the pathways and mechanisms that link the socio-exposome with gene expression-or the biological embedding of social experiences through epigenetics. Then, methodological considerations for implementing social epigenomics into oral health research are highlighted, with emphasis on the implications for study design and interpretation. The article concludes by shedding light on some of the current and prospective opportunities for social epigenomics research applied to the study of life course oral epidemiology.]]> Wed, 31 Dec 1969 19:00:00 EST Umbilical cord blood DNA methylation in children who later develop type 1 diabetes. Laajala E, Kalim UU, GrÃ¶nroos T, Rasool O, Halla-Aho V, Konki M, Kattelus R, MykkÃ¤nen J, Nurmio M, VÃ¤hÃ¤-MÃ¤kilÃ¤ M, KallionpÃ¤Ã¤ H, LietzÃ©n N, Ghimire BR, Laiho A, HyÃ¶ty H, Elo LL, Ilonen J, Knip M, Lund RJ, OreÅ¡iÄ M, Veijola R, LÃ¤hdesmÃ¤ki H, Toppari J, Lahesmaa R
Diabetologia (Sep 2022)

Distinct DNA methylation patterns have recently been observed to precede type 1 diabetes in whole blood collected from young children. Our aim was to determine whether perinatal DNA methylation is associated with later progression to type 1 diabetes.]]> Wed, 31 Dec 1969 19:00:00 EST Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity. MÃ¶hrmann L, Werner M, OleÅ M, Mock A, Uhrig S, Jahn A, Kreutzfeldt S, FrÃ¶hlich M, Hutter B, Paramasivam N, Richter D, Beck K, Winter U, PfÃ¼tze K, Heilig CE, Teleanu V, Lipka DB, Zapatka M, Hanf D, List C, AllgÃ¤uer M, Penzel R, RÃ¼ter G, Jelas I, Hamacher R, Falkenhorst J, Wagner S, Brandts CH, Boerries M, Illert AL, Metzeler KH, Westphalen CB, Desuki A, Kindler T, Folprecht G, Weichert W, Brors B, Stenzinger A, SchrÃ¶ck E, HÃ¼bschmann D, Horak P, Heining C, FrÃ¶hling S, Glimm H
Nat Commun (Aug 2022)

The benefit of molecularly-informed therapies in cancer of unknown primary (CUP) is unclear. Here, we use comprehensive molecular characterization by whole genome/exome, transcriptome and methylome analysis in 70 CUP patients to reveal substantial mutational heterogeneity with TP53, MUC16, KRAS, LRP1B and CSMD3 being the most frequently mutated known cancer-related genes. The most common fusion partner is FGFR2, the most common focal homozygous deletion affects CDKN2A. 56/70 (80%) patients receive genomics-based treatment recommendations which are applied in 20/56 (36%) cases. Transcriptome and methylome data provide evidence for the underlying entity in 62/70 (89%) cases. Germline analysis reveals five (likely) pathogenic mutations in five patients. Recommended off-label therapies translate into a mean PFS ratio of 3.6 with a median PFS1 of 2.9 months (17 patients) and a median PFS2 of 7.8 months (20 patients). Our data emphasize the clinical value of molecular analysis and underline the need for innovative, mechanism-based clinical trials.]]> Wed, 31 Dec 1969 19:00:00 EST Maternal-fetal genetic interactions, imprinting, and risk of placental abruption. Workalemahu T, Enquobahrie DA, Gelaye B, Tadesse MG, Sanchez SE, Tekola-Ayele F, Hajat A, Thornton TA, Ananth CV, Williams MA
J Matern Fetal Neonatal Med (Sep 2022)

Abruption cases were more likely to experience preeclampsia, have shorter gestational age, and deliver infants with lower birthweight compared with controls. Models with MFGI effects provided improved fit than models with only maternal and fetal genotype main effects for SNP rs12530904 (-value = 1.2e-04) in calcium/calmodulin-dependent protein kinase [CaM kinase] II beta (), and, SNP rs73136795 (-value = 1.9e-04) in peroxisome proliferator-activated receptor-gamma (), both MB genes. We identified 320 SNPs in 45 maternally-imprinted genes (including potassium voltage-gated channel subfamily Q member 1 [], neurotrimin [], and, ATPase phospholipid transporting 10âA []) associated with abruption. Top hits included rs2012323 (-value = 1.6E-16) and rs12221520 (-value1.3e-13) in , rs8036892 (-value = 9.3E-17) and rs188497582 in , rs12589854 (-value = 2.9E-11) and rs80203467 (-value = 4.6e-11) in maternally expressed 8, small nucleolar RNA host (), and rs138281088 in solute carrier family 22 member 2 () (-value = 6.8e-9).]]> Wed, 31 Dec 1969 19:00:00 EST Metabolic reprogramming and epigenetic modifications on the path to cancer. Sun L, Zhang H, Gao P
Protein Cell (12 2022)

Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes as a consequence of the translocation or spatial regionalization of enzymes or metabolites. Various metabolic alterations and epigenetic modifications also reportedly drive immune escape or impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how metabolic reprogramming of tumor cells and immune cells reshapes epigenetic alterations, in particular the acetylation and methylation of histone proteins and DNA. We also discuss other eminent metabolic modifications such as, succinylation, hydroxybutyrylation, and lactylation, and update the current advances in metabolism- and epigenetic modification-based therapeutic prospects in cancer.]]> Wed, 31 Dec 1969 19:00:00 EST Epigenomic technologies for precision oncology. Weichenhan D, Lipka DB, Lutsik P, Goyal A, Plass C
Semin Cancer Biol (Sep 2022)

Epigenetic patterns in a cell control the expression of genes and consequently determine the phenotype of a cell. Cancer cells possess altered epigenomes which include aberrant patterns of DNA methylation, histone tail modifications, nucleosome positioning and of the three-dimensional chromatin organization within a nucleus. These altered epigenetic patterns are potential useful biomarkers to detect cancer cells and to classify tumor types. In addition, the cancer epigenome dictates the response of a cancer cell to therapeutic intervention and, therefore its knowledge, will allow to predict response to different therapeutic approaches. Here we review the current state-of-the-art technologies that have been developed to decipher epigenetic patterns on the genomic level and discuss how these methods are potentially useful for precision oncology.]]> Wed, 31 Dec 1969 19:00:00 EST The Diagnostic Impact of Epigenomics in Pituicyte-derived Tumors: Report of an Unusual Sellar Lesion with Extensive Hemorrhage and Necrotic Debris. Dottermusch M, Rotermund R, Ricklefs FL, Wefers AK, Saeger W, Flitsch J, Glatzel M, Matschke J
Endocr Pathol (Aug 2022)

]]> Wed, 31 Dec 1969 19:00:00 EST Male-specific coordinated changes in expression of miRNA genes, but not other genes within the DLK1-DIO3 locus in multiple sclerosis. Baulina N, Kiselev I, Kozin M, Kabaeva A, Boyko A, Favorova O
Gene (Aug 2022)

The role of miRNAs, small non-coding regulatory RNAs, in the molecular mechanisms of multiple sclerosis (MS) development has been intensively studied. MiRNAs tend to be clustered within imprinted regions, and the largest number of miRNA genes is observed in the DLK1-DIO3 locus. Earlier using RNA-seq we identified sex-specific upregulation of the set of miRNA genes from this locus in peripheral blood mononuclear cells (PBMC) of treatment-naive relapsing-remitting MS (RRMS) patients. In the present study we set up to independently investigate the expression of a vast array of genes present in the DLK1-DIO3 imprinted locus. First, we analyzed the expression of miRNA genes, which levels in RRMS were mostly inconsistent based on RNA-seq data and not previously explored using qPCR. We identified that all selected miRNAs - miR-337-3p and -665 from 14q32.2 cluster and miR-370c, -380, -494, -654-3p, -300, -539, -668, and -323b-5p - were upregulated in MS men, but not women when compared to controls, regardless of conflicting RNA-seq data. The expression of miRNAs from the DLK1-DIO3 locus was highly correlated, indicating the existence of a common regulatory mechanism(s) that controls miRNA expression, regardless of the position of their genes within this region. Second, we performed the expression analysis of non-miRNA genes within the locus. The genes encoding proteins (DLK1, DIO3, RTL1), long non-coding RNAs (MEG3, MEG8, and MEG9) and small nucleolar RNAs (SNORD112, SNORD113-5, SNORD113-7, SNORD114-3, SNORD114-8, SNORD114-19) were not dysregulated in RRMS both in men and women. DNA methylation analysis of selected CpG sites within the differentially methylated regions IG-DMR, MEG3-DMR, and MEG8-DMR of the DLK1-DIO3 imprinted locus pointed out that they were not involved in the regulation of miRNA gene expression in RRMS, at least in PBMC population. The question of whether the observed changes in expression of miRNA genes (given that there is a constant expression of other non-miRNA genes of the DLK1-DIO3 locus) are involved in the development of RRMS or are they a consequence of the disease progress, remains open and needs further investigation.]]> Wed, 31 Dec 1969 19:00:00 EST Aberrant OCIAD2 demethylation in lung adenocarcinoma is associated with outcome. Maki M, JeongMin H, Nakagawa T, Kawai H, Sakamoto N, Sato Y, Noguchi M
Pathol Int (Aug 2022)

Overexpression of OCIAD2 in lung adenocarcinoma has already been reported in several research articles, but the molecular mechanism involved remains unknown. Promoter CpG methylation is a representative form of epigenetic gene regulation, and a considerable number of tumor suppressor genes show hypermethylation in many cancers. In contrast, promoter CpG hypomethylation causes oncogene overexpression, resulting in carcinogenesis and malignant progression. In the present study, we investigated the CpG methylation and expression status of OCIAD2 using tumor tissues and adjacent normal tissues from seven cases of lung adenocarcinoma. We also examined the relationship between CpG methylation status and outcome in 58 patients with adenocarcinoma. Pyrosequencing showed that CpG sites in OCIAD2 promoter regions were more frequently demethylated in tumor tissues than in adjacent normal tissues, and reverse transcription-quantitative polymerase chain reaction revealed overexpression of OCIAD2 in lung adenocarcinoma. There was a correlation between OCIAD2 CpG demethylation and the level of mRNA expression, and statistical analysis showed that CpG hypomethylation of OCIAD2 was associated with poor outcomes. Our results suggest that overexpression of OCIAD2 might be caused mainly by CpG hypomethylation and that OCIAD2 methylation status might be a useful prognostic indicator in lung adenocarcinoma.]]> Wed, 31 Dec 1969 19:00:00 EST In-utero exposure to indoor air pollution or tobacco smoke and cognitive development in a South African birth cohort study. Christensen GM, Rowcliffe C, Chen J, Vanker A, Koen N, Jones MJ, Gladish N, Hoffman N, Donald KA, Wedderburn CJ, Kobor MS, Zar HJ, Stein DJ, HÃ¼ls A
Sci Total Environ (Aug 2022)

There is increasing evidence indicating that air pollution exposure is associated with neuronal damage. Since pregnancy is a critical window of vulnerability, air pollution exposure during this period could have adverse effects on neurodevelopment. This study aims 1) to analyze associations of prenatal exposure to indoor air pollution (particulate matter with diameters â¤10 Î¼m, PM) and tobacco smoke with neurodevelopment and 2) to determine whether these associations are mediated by deviations of epigenetic gestational age from chronological gestational age (ÎGA).]]> Wed, 31 Dec 1969 19:00:00 EST The mismatch-repair proteins MSH2 and MSH6 interact with the imprinting control regions through the ZFP57-KAP1 complex. Acurzio B, Cecere F, Giaccari C, Verma A, Russo R, Valletta M, Hay Mele B, Angelini C, Chambery A, Riccio A
Epigenetics Chromatin (Aug 2022)

Imprinting Control Regions (ICRs) are CpG-rich sequences acquiring differential methylation in the female and male germline and maintaining it in a parental origin-specific manner in somatic cells. Despite their expected high mutation rate due to spontaneous deamination of methylated cytosines, ICRs show conservation of CpG-richness and CpG-containing transcription factor binding sites in mammalian species. However, little is known about the mechanisms contributing to the maintenance of a high density of methyl CpGs at these loci.]]> Wed, 31 Dec 1969 19:00:00 EST Chromatin Remodeling Factors Drive Epigenetic Changes Crucial for T-cell Exhaustion.
Cancer Discov (Aug 2022)

Depleting components of the cBAF chromatin remodeling complex improves antitumor T-cell function.]]> Wed, 31 Dec 1969 19:00:00 EST A 79-kb paternally inherited 7q32.2 microdeletion involving MEST in a patient with a Silver-Russell syndrome-like phenotype. Vincent KM, Stavropoulos DJ, Beaulieu-Bergeron M, Yang C, Jiang M, Zuijdwijk C, Dyment DA, Graham GE
Am J Med Genet A (Aug 2022)

Maternal uniparental disomy of human chromosome 7 [upd(7)mat] is well-characterized as a cause of the growth disorder Silver-Russell syndrome (SRS). However, the causative gene is not currently known. There is growing evidence that molecular changes at the imprinted MEST region in 7q32.2 are associated with a phenotype evocative of SRS. This report details a patient with a SRS-like phenotype and a paternally inherited microdeletion of 79 kilobases (35-fold smaller than the previously reported smallest deletion) in the 7q32.2 region. This microdeletion encompasses only five genes, including MEST, which corroborates the hypothesis that MEST plays a central role in the 7q32.2 microdeletion growth disorder, as well as further implicating MEST in upd(7)mat SRS itself.]]> Wed, 31 Dec 1969 19:00:00 EST Sample-multiplexing approaches for single-cell sequencing. Zhang Y, Xu S, Wen Z, Gao J, Li S, Weissman SM, Pan X
Cell Mol Life Sci (Aug 2022)

Single-cell sequencing is widely used in biological and medical studies. However, its application with multiple samples is hindered by inefficient sample processing, high experimental costs, ambiguous identification of true single cells, and technical batch effects. Here, we introduce sample-multiplexing approaches for single-cell sequencing in transcriptomics, epigenomics, genomics, and multiomics. In single-cell transcriptomics, sample multiplexing uses variants of native or artificial features as sample markers, enabling sample pooling and decoding. Such features include: (1) natural genetic variation, (2) nucleotide-barcode anchoring on cellular or nuclear membranes, (3) nucleotide-barcode internalization to the cytoplasm or nucleus, (4) vector-based barcode expression in cells, and (5) nucleotide-barcode incorporation during library construction. Other single-cell omics methods are based on similar concepts, particularly single-cell combinatorial indexing. These methods overcome current challenges, while enabling super-loading of single cells. Finally, selection guidelines are presented that can accelerate technological application.]]> Wed, 31 Dec 1969 19:00:00 EST Pulmonary Function and Blood DNA Methylation: A Multiancestry Epigenome-Wide Association Meta-analysis. Lee M, Huan T, McCartney DL, Chittoor G, de Vries M, Lahousse L, Nguyen JN, Brody JA, Castillo-Fernandez J, Terzikhan N, Qi C, Joehanes R, Min JL, Smilnak GJ, Shaw JR, Yang CX, Colicino E, Hoang TT, Bermingham ML, Xu H, Justice AE, Xu CJ, Rich SS, Cox SR, Vonk JM, ProkiÄ I, Sotoodehnia N, Tsai PC, Schwartz JD, Leung JM, Sikdar S, Walker RM, Harris SE, van der Plaat DA, Van Den Berg DJ, Bartz TM, Spector TD, Vokonas PS, Marioni RE, Taylor AM, Liu Y, Barr RG, Lange LA, Baccarelli AA, Obeidat M, Fornage M, Wang T, Ward JM, Motsinger-Reif AA, Hemani G, Koppelman GH, Bell JT, Gharib SA, Brusselle G, Boezen HM, North KE, Levy D, Evans KL, Dupuis J, Breeze CE, Manichaikul A, London SJ
Am J Respir Crit Care Med (08 2022)

Methylation integrates factors present at birth and modifiable across the lifespan that can influence pulmonary function. Studies are limited in scope and replication. To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function. Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina 450K or EPIC/850K arrays, with FEV, FVC, and FEV/FVC. We performed multiancestry epigenome-wide meta-analyses (total of 17,503 individuals; 14,761 European, 2,549 African, and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics. We identified 1,267 CpGs (1,042 genes) differentially methylated (false discovery rate, <0.025) in relation to FEV, FVC, or FEV/FVC, including 1,240 novel and 73 also related to chronic obstructive pulmonary disease (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is Mendelian randomization and colocalization analyses suggest that epigenome-wide association study signals capture causal regulatory genomic loci. We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies, providing insights into lung pathogenesis.]]> Wed, 31 Dec 1969 19:00:00 EST