Search

Identification of the cis-regulatory elements controlling oncogenic transcriptional programs is critical to understanding tumor biology. To find cis-regulatory elements (i.e. gene enhancers) of oncogenic dependencies in Triple-Negative Breast Cancers (TNBC) of the Basal-like gene expression subtype, we generated matched single-cell transcriptome (scRNA-seq) and chromatin accessibility (scATAC-seq) profiles for two human Basal-like tumors and four normal mammary reduction samples. This unique dataset enabled us to correlate variations in chromatin structure with variations in gene expression revealing putative enhancers that are specifically active within cancer cells, but not within normal mammary ductal epithelial cells. We then leveraged the Cancer Dependency Map (DepMap) portal at the BROAD Institute to infer gene expression dependencies in breast cancer cell lines of the Basal-like molecular subtype. Putative cancer-specific enhancers were prioritized based on the transcriptional dependency of their target gene(s) in Basal-like cell lines as reported by the DepMap portal. Based on our preliminary analyses, we report several cancer-specific enhancers that drive the expression of important transcription factors such as EN1 and SOX4. These transcription factors are known to have profound effects on tumor biology, especially considering that high expression of EN1 is associated with brain metastasis and SOX4 is known to regulate immune evasion and PI3K/Akt signaling. Moreover, both of these transcription factors portend a worse outcome in TNBC patients. Thus, our analysis suggests that high levels of expression of these transcription factors is sustained specifically within the malignant cell types of these tumors, by the activity of these cancer-specific enhancers that are not typically active in normal epithelial cells. We are now performing CRISPR dCas9-KRAB experiments to epigenetically silence these cancer-specific enhancers and measure the consequences on expression of their predicted target genes. Additionally, we are investigating the trans-acting transcription factors that may physically bind to these enhancers to further regulate oncogenic transcription. By defining the regulatory logic of cancer cells at single-cell resolution, our work highlights the importance of cancer-specific and clinically relevant oncogenic regulatory elements in TNBC of the Basal-like subtype. Citation Format: Matthew J. Regner, Aatish Thennavan, Kamila Wisniewska, Susana Garcia-Recio, Raul Mendez-Giraldez, Philip Spanheimer, Charles M. Perou, Hector L. Franco. Identifying oncogenic enhancer elements in TNBC of the Basal-like subtype using single-cell ATAC-seq and RNA-seq [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-14-02.

ER-positive breast cancers compose most breast cancers at the time of diagnosis and are primarily driven by mitogenic estrogen signaling. In ER-positive breast cancers, the pioneer transcription factor FOXA1 plays a critical role in the estrogen receptor (ER) function. It binds to condensed chromatin and promotes chromatin accessibility for subsequent ER binding upon estrogen stimulation. We have reported that TNFa-stimulated proinflammatory signaling relocates FOXA1 to a new set of latent enhancers, which initiates the binding of estrogen liganded ER and subsequent expression of a unique transcriptome with clinical significance. The redistribution of FOXA1 occurs within 40 mins of the TNFa treatment, which implies a rapid signaling cascade that arises from changes to either FOXA1’s post-translational modifications (PTMs) or its binding partners. To understand this genomic redistribution of FOXA1, we compared the post-translational modifications (PTMs) of FOXA1 from Vehicle, E2, TNFa, and E2+TNFa treated MCF-7 breast cancer cells. More than five acetylation and phosphorylation events have been identified around the DNA binding domain of FOXA1 by semi-quantitative and quantitative mass spectrometry approaches, and their abundance varies across treatments. To study these PTMs of FOXA1, we used CRISPR/Cas9 to create specific knock-in mutations to mimic or prevent acetylation events in MCF-7 cells. Specifically, we engineered MCF-7 cell lines where K270 was mutated to glutamine (K270Q) to mimic acetylation. And for comparison, we also created cell lines where K270 was mutated to arginine (K270R) to prevent acetylation of FOXA1. Our data, including FOXA1 ChIP-seq and RNA-seq, revealed the genomic redistribution of FOXA1 with these PTMs, which subsequently alters gene expression programs and promotes cell growth, migration, or chemoresistance. These results were confirmed in other ER+ cell lines (such as T47D cells) providing evidence for the generalizability of our findings. Taken together, our data suggest that inflammatory signaling signaling can reshape the enhancer landscape of FOXA1 through post-translational modifications, resulting in changes to estrogen signaling that have profound effects on breast cancer biology. Citation Format: Shen Li, Hector L. Franco, Hyunsoo Kim, Rosemary N. Plagens, Raul Mendez-Giraldez, Colby Tubbs, Venkat Malladi, Joseph Garay. Proinflammatory and estrogen signaling modulates the chemoresistance and metastasis of breast cancer cells through post-translational modifications of pioneering factor FOXA1 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-12-03.

The objective of this research is to show the production management in the construction of a multifamily building in Lima - Peru, it is worth mentioning that the main problem is that the companies do not adequately plan the optimal use of resources, the plan of attack of work, the sequence of activities through a correct design of production batch and sizing of crews, which are decisive during the execution of the work. The methodology used in this context is load and crew balancing. This allows us to manage resources and work scheduling, resulting in 100% efficiency. In conclusion, we can say that companies must maintain a correct control of their resources in order to achieve their schedules.

This research work has a great influence on the physical security of the urban infrastructure and the citizens of our capital city, that is why it is necessary to apply prevention strategies since our city is located in a very vulnerable area to seismic events, mainly huaycos, floods and landslides, settlements, landslides and other superficial mass movements, so it is necessary to have knowledge of the causes and effects of these phenomena, the different types and carrying capacity of soils in the districts of Metropolitan Lima, in order to contribute to the knowledge of the degree of vulnerability in which urban areas, marginal urban areas, human settlements are exposed. In conclusion, surveys of public servants allowed us to determine that only 55% of them know the meaning of risk and vulnerability, so 45% are totally unaware of these terms. Likewise, surveys of the general public on the lack of a prevention culture, 83% indicated that they did, hence the need to apply a course or training on disaster risk management issues at all educational levels.

Eukaryotic genome replication depends on thousands of DNA replication origins (ORIs). A major challenge is to learn ORI biology in multicellular organisms in the context of growing organs to understand their developmental plasticity. We have identified a set of ORIs of Arabidopsis thaliana and their chromatin landscape at two stages of post-embryonic development. ORIs associate with multiple chromatin signatures including transcription start sites (TSS) but also proximal and distal regulatory regions and heterochromatin, where ORIs colocalize with retrotransposons. In addition, quantitative analysis of ORI activity led us to conclude that strong ORIs have high GC content and clusters of GGN trinucleotides. Development primarily influences ORI firing strength rather than ORI location. ORIs that preferentially fire at early developmental stages colocalize with GC-rich heterochromatin, but at later stages with transcribed genes, perhaps as a consequence of changes in chromatin features associated with developmental processes. Our study provides the set of ORIs active in an organism at the post-embryo stage that should allow us to study ORI biology in response to development, environment, and mutations with a quantitative approach. In a wider scope, the computational strategies developed here can be transferred to other eukaryotic systems., This research was supported by Secretaría de Estado de Investigación, Desarrollo e Innovación, grants BFU2012-34821, BFU2013-50098-EXP, and BFU2015-68396-R to C.G., BIO2016-79043-P to U.B. and AGL2013-43244-R to J.M.C., as well as by institutional grants from Fundacion Ramon Areces and Banco de Santander to the CBMSO.

This research aims to develop a didactic proposal for the use of Geographic Information Technologies (TIG), which will allow authorities to access more resources to make better decisions in tasks of monitoring, controlling and responding to the COVID -19 (disease associated with SARS-CoV-2 infection) pandemic. The entire universe of the population in the Peruvian territory was analyzed. Through specialized Geographic Information Systems (GIS) programs designed to show multiple visualizations on a single screen, a complete and attractive view of the data is offered. Results obtained show tables and projections of COVID-19, concluding that it affects more men than women, its mortality rate is 3.82% and the largest number of deaths are older adults, claimed the lives of 193 people and infected 7519 until April 11, 2020. It is planned that the next 12th may, COVID-19 reaches the maximum number of infected La investigación tiene como objetivo elaborar una propuesta didáctica para el uso de Tecnologías de la Información Geográfica (TIG), que permitirá a las autoridades acceder a más recursos para tomar mejores decisiones en las tareas de seguimiento, control y respuesta a la pandemia del COVID-19 (enfermedad asociada con la infección por SARS-CoV-2). Se analizó todo el universo de la población del territorio peruano. Mediante programas especializados en Sistemas de Información Geográfica (SIG) diseñados para mostrar múltiples visualizaciones en una sola pantalla, se ofrece una vista completa y atractiva de los datos. Los resultados obtenidos muestran cuadros y proyecciones del COVID-19, concluyendo que afecta a más hombres que mujeres. Además, tiene una tasa de letalidad del 3,82% y la mayor cantidad de fallecidos son adultos mayores, cobrando la vida de 193 personas e infectado a 7519, hasta la fecha de 11 de abril del 2020. Se tiene previsto que el próximo 12 de mayo, el COVID-19 llegue al número máximo de contagiados.Palabras clave: Tecnologías de información geográfica, Sistemas de Información Geográfica, COVID-19, Perú. ABSTRACTThis research aims to develop a didactic proposal for the use of Geographic Information Technologies (TIG), which will allow authorities to access more resources to make better decisions in tasks of monitoring, controlling and responding to the COVID -19 (disease associated with SARS-CoV-2 infection) pandemic. The entire universe of the population in the Peruvian territory was analyzed. Through specialized Geographic Information Systems (GIS) programs designed to show multiple visualizations on a single screen, a complete and attractive view of the data is offered. Results obtained show tables and projections of COVID-19, concluding that it affects more men than women, its mortality rate is 3.82% and the largest number of deaths are older adults, claimed the lives of 193 people and infected 7519 until April 11, 2020. It is planned that the next 12th may, COVID-19 reaches the maximum number of infected.Key words: Geographic information technologies, Geographic Information Systems, COVID-19, Perú.

The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10−8) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10−8) and multi-trait analysis (P = 2.9 × 10−9) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.

Deconvolution of regulatory mechanisms that drive transcriptional programs in cancer cells is key to understanding tumor biology. Herein, we present matched transcriptome (scRNA-seq) and chromatin accessibility (scATAC-seq) profiles at single-cell resolution from human ovarian and endometrial tumors processed immediately following surgical resection. This dataset reveals the complex cellular heterogeneity of these tumors and enabled us to quantitatively link variation in chromatin accessibility to gene expression. We show that malignant cells acquire previously unannotated regulatory elements to drive hallmark cancer pathways. Moreover, malignant cells from within the same patients show substantial variation in chromatin accessibility linked to transcriptional output, highlighting the importance of intratumoral heterogeneity. Finally, we infer the malignant cell type-specific activity of transcription factors. By defining the regulatory logic of cancer cells, this work reveals an important reliance on oncogenic regulatory elements and highlights the ability of matched scRNA-seq/scATAC-seq to uncover clinically relevant mechanisms of tumorigenesis in gynecologic cancers.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P

Background Although time–domain measures of heart rate variability (HRV) are used to estimate cardiac autonomic tone and disease risk in multiethnic populations, the genetic epidemiology of HRV in Hispanics/Latinos has not been characterized. Objective The purpose of this study was to conduct a genome-wide association study of heart rate (HR) and its variability in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Women's Health Initiative Hispanic SNP-Health Association Resource project (n = 13,767). Methods We estimated HR (bpm), standard deviation of normal-to-normal interbeat intervals (SDNN, ms), and root mean squared difference in successive, normal-to-normal interbeat intervals (RMSSD, ms) from resting, standard 12-lead ECGs. We estimated associations between each phenotype and 17 million genotyped or imputed single nucleotide polymorphisms (SNPs), accounting for relatedness and adjusting for age, sex, study site, and ancestry. Cohort-specific estimates were combined using fixed-effects, inverse-variance meta-analysis. We investigated replication for select SNPs exceeding genome-wide (P Results Two genome-wide significant SNPs replicated in a European ancestry cohort, 1 one for RMSSD (rs4963772; chromosome 12) and another for SDNN (rs12982903; chromosome 19). A suggestive SNP for HR (rs236352; chromosome 6) replicated in an African-American cohort. Functional annotation of replicated SNPs in cardiac and neuronal tissues identified potentially causal variants and mechanisms. Conclusion This first genome-wide association study of HRV and HR in Hispanics/Latinos underscores the potential for even modestly sized samples of non-European ancestry to inform the genetic epidemiology of complex traits.

Temporal lobe epilepsy is the most common and refractory form of epilepsy in adults. Gene expression within affected structures such as the hippocampus displays extensive dysregulation and is implicated as a central pathomechanism. Post-transcriptional mechanisms are increasingly recognized as determinants of the gene expression landscape, but key mechanisms remain unexplored. Here we show, for first time, that cytoplasmic mRNA polyadenylation, one of the post-transcriptional mechanisms regulating gene expression, undergoes widespread reorganization in temporal lobe epilepsy. In the hippocampus of mice subjected to status epilepticus and epilepsy, we report 425% of the transcriptome displays changes in their poly(A) tail length, with deadenylation disproportionately affecting genes previously associated with epilepsy. Suggesting cytoplasmic polyadenylation element binding proteins (CPEBs) being one of the main contributors to mRNA polyadenylation changes, transcripts targeted by CPEBs were particularly enriched among the gene pool undergoing poly(A) tail alterations during epilepsy. Transcripts bound by CPEB4 were over-represented among transcripts with poly(A) tail alterations and epilepsy-related genes and CPEB4 expression was found to be increased in mouse models of seizures and resected hippocampi from patients with drug-refractory temporal lobe epilepsy. Finally, supporting an adaptive function for CPEB4, deletion of Cpeb4 exacerbated seizure severity and neurodegeneration during status epilepticus and the development of epilepsy in mice. Together, these findings reveal an additional layer of gene expression regulation during epilepsy and point to novel targets for seizure control and disease-modification in epilepsy.

Background: DNA methylation (DNAm) may contribute to processes that underlie associations between air pollution and poor health. Therefore, our objective was to evaluate associations between DNAm and ambient concentrations of particulate matter (PM) ≤2.5, ≤10, and 2.5–10 μm in diameter (PM2.5; PM10; PM2.5–10). Methods: We conducted a methylome-wide association study among twelve cohort- and race/ethnicity-stratified subpopulations from the Women's Health Initiative and the Atherosclerosis Risk in Communities study (n = 8397; mean age: 61.5 years; 83% female; 45% African American; 9% Hispanic/Latino American). We averaged geocoded address-specific estimates of daily and monthly mean PM concentrations over 2, 7, 28, and 365 days and 1 and 12 months before exams at which we measured leukocyte DNAm in whole blood. We estimated subpopulation-specific, DNAm-PM associations at approximately 485,000 Cytosine-phosphate-Guanine (CpG) sites in multi-level, linear, mixed-effects models. We combined subpopulation- and site-specific estimates in fixed-effects, inverse variance-weighted meta-analyses, then for associations that exceeded methylome-wide significance and were not heterogeneous across subpopulations (P 0.10), we characterized associations using publicly accessible genomic databases and attempted replication in the Cooperative Health Research in the Region of Augsburg (KORA) study. Results: Analyses identified significant DNAm-PM associations at three CpG sites. Twenty-eight-day mean PM10 was positively associated with DNAm at cg19004594 (chromosome 20; MATN4; P = 3.33 × 10−8). One-month mean PM10 and PM2.5–10 were positively associated with DNAm at cg24102420 (chromosome 10; ARPP21; P = 5.84 × 10−8) and inversely associated with DNAm at cg12124767 (chromosome 7; CFTR; P = 9.86 × 10−8). The PM-sensitive CpG sites mapped to neurological, pulmonary, endocrine, and cardiovascular disease-related genes, but DNAm at those sites was not associated with gene expression in blood cells and did not replicate in KORA. Conclusions: Ambient PM concentrations were associated with DNAm at genomic regions potentially related to poor health among racially, ethnically and environmentally diverse populations of U.S. women and men. Further investigation is warranted to uncover mechanisms through which PM-induced epigenomic changes may cause disease. Keywords: Particulate matter, DNA methylation, Epigenetics, Air pollution, Epigenome-wide association study

BackgroundThe electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.MethodsWe performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n=15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.ResultsWe identified six loci associated with QRS (P−8), including two novel loci:MYOCD, a nuclear protein expressed in the heart, andSYT1, an integral membrane protein. The top association in theMYOCDlocus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was for intronic SNP rs3922344 (P= 8.56×10−26) inSCN5A/SCN10A. Three additional previously identified loci,CDKN1A,VTI1A, andHAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos.ConclusionsOur QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.

Background: Epigenetic mechanisms underlying associations between coronary artery disease (CAD) and ambient exposures to carbon monoxide (CO), nitrogen oxides (NO 2 /NOx), ozone (O 3 ), and sulfur dioxide (SO 2 ) are incompletely understood. We therefore examined associations between these gaseous air pollutants and DNA methylation (DNAm)—a process that controls gene expression. Methods: We conducted a race/ethnicity- and study-stratified, methylome-wide association study of 12 Women’s Health Initiative and Atherosclerosis Risk in Communities subpopulations (N=8567, mean age 61.3 years, 83% female, 46% African American, 8% Hispanic/Latino American). In each subpopulation, we estimated daily mean ambient pollutant concentrations at geocoded participant addresses using national-scale, lognormal ordinary kriging. We averaged the concentrations over the 2, 28, and 365 days before phlebotomy, the source of leukocyte DNA used in estimating DNAm at 485,000 Cytosine-phosphate-Guanine (CpG) sites on the Illumina Infinium HumanMethylation450 BeadChip. We estimated pollutant-DNAm associations using multi-level, linear mixed-effects models adjusted for socio-demographic, behavioral, and meteorological factors; estimated leukocyte proportions; and technical covariates. Then we combined estimates from the 12 subpopulations in inverse variance-weighted meta-analyses and characterized CpG sites associated with significant associations and little evidence of heterogeneity among subpopulations ( p -7 ; p Cochran’s Q >0.05). Results: Although we found no significant or suggestive CO-, O 3 -, or SO 2 -DNAm associations, we found a significant 28-day mean NO 2 -DNAm association at cg01885635 near ZNF621 on chr. 3 ( p =5.01x10 -8 ) and suggestive 365-day mean NO 2 -DNAm associations at cg12684684 near ARPC2 on chr. 2 ( p =9.3x10 -7 ), cg19693031 near TXNIP on chr. 1 ( p =7.3x10 -7 ), and cg01885635 near ZNF621 on chr. 3 ( p =6.7x10 -7 ). We also found 2- and 365-day mean NOx-DNAm associations at cg27032760 near KCTD16 on chr. 5 ( p =4.1x10 -7 ) and cg15008743 near ZNF83 on chr. 19 ( p =2.8x10 -7 ), respectively. ZNF621 and ZNF83 encode zinc finger proteins that possess transcription factor activity. ARPC2 encodes an actin-related protein complex subunit that has been associated with mean platelet volume, a known risk factor for myocardial infarction (MI) and post-MI mortality. TXNIP encodes a thioredoxin-binding protein that protects cells from oxidative stress, is highly glucose responsive, and has been associated with triglycerides, blood pressure, diabetes, and CAD. KCTD16 encodes a potassium channel tetramerization domain-containing protein. Conclusions: Pending replication, the preliminary findings suggest that biologically plausible epigenetic mechanisms may underlie associations between nitrogen oxide exposures and CAD in multi-racial/ethnic populations.

Full genome replication in eukaryotes depends on the function of thousands of DNA replication origins (ORIs) that constitute the originome. The identification of ORIs in cultured cells has served to define their basic DNA and chromatin features. However, a major challenge is to learn the biology of ORIs in adult organisms to understand their developmental plasticity. Here, we have determined the originome and chromatin landscape in Arabidopsis thaliana at two stages of vegetative development. We found that ORIs associate with multiple chromatin signatures including the most frequent at TSS but also at proximal and distal gene regulatory regions or repressed Polycomb (PcG) domains. In constitutive heterochromatin, a high fraction of ORIs colocalize with GC-rich retrotransposons. Quantitative analysis of ORI activity led us to conclude that strong ORIs possess high scores of local GC content and clusters of GGN trinucleotides that may form G quadruplexes and other G-rich structures. We also found that development primarily influences ORI firing strength rather than ORI location. Moreover, ORIs that preferentially fire at early vegetative stages colocalize with GC-rich heterochromatin whereas those at later stages associate with transcribed genes. Our study provides the first originome of an adult organism, which is a developmentally and genetically tractable, thus opening new avenues of studying the biology of ORIs in response to developmental cues, transcriptional programs, environmental challenges and mutant backgrounds.

Sulfonylureas, a commonly-used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In eleven ethnically diverse cohorts that included 71 857 European, African American, and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT, and QRS intervals. In ancestry-specific meta-analyses, 8 novel pharmacogenomic loci met the threshold for genome-wide significance (P < 5 x 10−8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

QT interval prolongation is a heritable risk factor for ventricular arrhythmias and can predispose to sudden death. Most genome-wide association studies (GWAS) of QT were performed in European ancestral populations, leaving other groups uncharacterized. Herein we present the first QT GWAS of Hispanic/Latinos using data on 15,997 participants from four studies. Study-specific summary results of the association between 1000 Genomes Project (1000G) imputed SNPs and electrocardiographically measured QT were combined using fixed-effects meta-analysis. We identified 41 genome-wide significant SNPs that mapped to 13 previously identified QT loci. Conditional analyses distinguished six secondary signals at NOS1AP (n = 2), ATP1B1 (n = 2), SCN5A (n = 1), and KCNQ1 (n = 1). Comparison of linkage disequilibrium patterns between the 13 lead SNPs and six secondary signals with previously reported index SNPs in 1000G super populations suggested that the SCN5A and KCNE1 lead SNPs were potentially novel and population-specific. Finally, of the 42 suggestively associated loci, AJAP1 was suggestively associated with QT in a prior East Asian GWAS; in contrast BVES and CAP2 murine knockouts caused cardiac conduction defects. Our results indicate that whereas the same loci influence QT across populations, population-specific variation exists, motivating future trans-ethnic and ancestrally diverse QT GWAS.

Background Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals. Methods and results We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, p interaction =3.9e −9 ) and rs9830388 in UBE2E2 (β=25.2, p interaction =1.7e −8 ). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, p interaction =2.55e −8 ). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (p interaction >0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries. Conclusions Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

The pioneer transcription factor FOXA1 is a critical determinant for estrogen receptor (ER) function in hormone-dependent breast cancers. Upon estrogen stimulation, liganded ER binds to poised enhancer regions across the genome that are demarcated by FOXA1 and histone modifications such as H3K4me1 and H3K27ac. In a recent publication, we show that proinflammatory signaling, caused by the cytokine TNFa, drives FOXA1 to latent enhancer binding sites to promote chromatin accessibility for subsequent ER binding upon estrogen ligation. These latent enhancers, activated by the combined treatment of estrogen and TNFa, induced the expression of a unique transcriptome with clinical significance. The effects of TNFa treatment on FOXA1 chromatin redistribution and subsequent gene expression occur within 40 minutes, which points to a rapid signaling cascade that culminates in either changes in FOXA1's posttranslational modifications (PTMs) or its binding partners. To understand how proinflammatory TNFa signaling can redirect FOXA1 to new sites across the genome, we started by characterizing the posttranslational modifications (PTMs) of FOXA1. We immunoprecipitated FOXA1 from MCF-7 breast cancer cells that were treated by E2, TNFa or E2+ TNFa, and then examined their posttranslational status using semi-quantitative and quantitative mass spectrometry approaches. Several phosphorylation sites and acetylation sites have been identified near the DNA binding domain of FOXA1, and acetylation of lysine 295 (K295) was found specifically enriched in TNFa treatment. To test if acetylation of FOXA1 at K295 changes its binding preference and genomic distribution, we used the programmable properties of CRISPR/Cas9 to create specific knockin mutations to mimic or prevent acetylation of K295 in MCF-7 cells. More specifically, we mutated K295 to glutamine (K295Q) to mimic acetylation and essentially “lock” FOXA1 into a permanently acetylated state and, for comparison, we created another cell line where K295 was mutated to arginine (K295R) to prevent acetylation of FOXA1. Our preliminary data shows changes in the genomic redistribution of FOXA1 in the knock-in cell lines resulting in altered gene expression programs. These data suggest that inflammation-based acetylation of FOXA1 can affect estrogen signaling pathways in breast cancer cells by altering the enhancer landscape of FOXA1 and consequently the estrogen receptor. Supported by a grant from the NIH/NCI (R00 CA204628) to H.L.F Citation Format: Shen Li, Raul Mendez-Giraldez, Joseph P. Garay, Kamila Wisniewska, Colby A. Tubbs, Charles M. Perou, Hector L. Franco. Cytokine-induced post-translational modifications of FOXA1 affect enhancer selection and estrogen signaling in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4496.