Lineage-determining transcription factor-driven promoters regulate cell type-specific macrophage gene expression

Nucleic Acids Research, Год журнала: 2024, Номер 52(8), С. 4234 - 4256

Опубликована: Фев. 13, 2024

Abstract Mammalian promoters consist of multifarious elements, which make them unique and support the selection proper transcript variants required under diverse conditions in distinct cell types. However, their direct DNA-transcription factor (TF) interactions are mostly unidentified. Murine bone marrow-derived macrophages (BMDMs) a widely used model for studying gene expression regulation. Thus, this serves as rich source various next-generation sequencing data sets, including large number TF cistromes. By processing integrating available cistromic, epigenomic transcriptomic from BMDMs, we characterized macrophage-specific DNA-TF interactions, with particular emphasis on those specific promoters. Whilst active enriched certain types typically methylatable more than half contain non-methylatable prototypically promoter-distal elements. In addition, circa 14% promoters—including that Csf1r—are composed exclusively ‘distal’ elements provide type-specific regulation by specialized TFs. Similar to CG-rich promoters, these also CG sites demethylated significant portion show high polymerase activity. We conclude unusual class regulates macrophages, such mechanism might exist other too.

Язык: Английский

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Epigenetic Effects of Resveratrol on Oncogenic Signaling in Breast Cancer

Nutrients, Год журнала: 2024, Номер 16(5), С. 699 - 699

Опубликована: Фев. 29, 2024

The crosstalk between oncogenic signaling pathways plays a crucial role in driving cancer development. We previously demonstrated that dietary polyphenols, specifically resveratrol (RSV) and other stilbenoids, epigenetically target oncogenes for silencing via DNA hypermethylation breast cancer. In the present study, we identify signal transduction regulators among RSV-hypermethylated targets investigate functional of RSV-mediated regulation Hedgehog Wnt signaling. Non-invasive ER-positive MCF-7 highly invasive triple-negative MCF10CA1a human cell lines were used as experimental models. Upon 9-day exposure to 15 µM RSV, pyrosequencing qRT-PCR performed assess methylation expression GLI2 WNT4, which are upstream pathways, respectively. Our results showed RSV led increase within WNT4 enhancers, was accompanied by decreases gene expression. Consistently, observed downregulation genes downstream signaling, including common shared both CCND1 CYR61. Further analysis using chromatin immunoprecipitation identified increased H3K27 trimethylation decreased H3K9 acetylation, along with abolishing OCT1 transcription factor binding. Those changes indicate transcriptionally silent state at enhancers. inhibition confirmed phospho-antibody array suppression positive stimulation negative regulators. conclusion, our provide scientific evidence polyphenols epigenetics-modulating agents act re-methylate silence oncogenes, reducing transduction. Targeting such an action could be effective strategy prevention and/or adjuvant therapy.

Язык: Английский

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Factors that determine cell type–specific CTCF binding in health and disease

Current Opinion in Genetics & Development, Год журнала: 2024, Номер 88, С. 102244 - 102244

Опубликована: Авг. 14, 2024

Язык: Английский

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DNA methylation-environment interactions in the human genome

eLife, Год журнала: 2024, Номер 12

Опубликована: Фев. 26, 2024

Previously, we showed that a massively parallel reporter assay, mSTARR-seq, could be used to simultaneously test for both enhancer-like activity and DNA methylation-dependent enhancer millions of loci in single experiment (Lea et al., 2018). Here, apply mSTARR-seq query nearly the entire human genome, including almost all CpG sites profiled either on commonly Illumina Infinium MethylationEPIC array or via reduced representation bisulfite sequencing. We show fragments containing these are enriched regulatory capacity, is turn sensitive cellular environment. In particular, responses interferon alpha (IFNA) stimulation strongly attenuated by methyl marks, indicating widespread methylation-environment interactions. agreement, IFNA identified predict transcriptional challenge with influenza virus macrophages. Our observations support idea pre-existing methylation patterns can influence response subsequent environmental exposures—one tenets biological embedding. However, also find that, average, previously associated early life adversity not more likely functionally gene regulation than expected chance.

Язык: Английский

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Osteoarthritis as an Enhanceropathy: Gene Regulation in Complex Musculoskeletal Disease

Current Rheumatology Reports, Год журнала: 2024, Номер 26(6), С. 222 - 234

Опубликована: Март 2, 2024

Abstract Purpose of Review Osteoarthritis is a complex and highly polygenic disease. Over 100 reported osteoarthritis risk variants fall in non-coding regions the genome, ostensibly conferring functional effects through disruption regulatory elements impacting target gene expression. In this review, we summarise progress that has advanced our knowledge enhancers both within field more broadly diseases. Recent Findings Advances technologies such as ATAC-seq have facilitated understanding chromatin states specific cell types, bolstering interpretation GWAS identification effector genes. Their application to research revealed principal element driving disease-associated changes However, tissue-specific mechanisms can contribute added complexity biological interpretation. Summary Understanding their altered activity tissue types key unlocking genetic osteoarthritis. The use single-cell still its infancy. tools offer great promise improving druggable targets. Large-scale collaborative efforts will be imperative understand cell-type molecular underlying enhancer function

Язык: Английский

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Paired yeast one-hybrid assays to detect DNA-binding cooperativity and antagonism across transcription factors

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Окт. 18, 2023

Cooperativity and antagonism between transcription factors (TFs) can drastically modify their binding to regulatory DNA elements. While mapping these relationships TFs is important for understanding context-specific functions, existing approaches either rely on motif predictions, interrogate one TF at a time, or study individual in parallel. Here, we introduce paired yeast one-hybrid (pY1H) assays detect cooperativity across hundreds of TF-pairs regions interest. We provide evidence that wide variety are subject modulation by other region-specific manner. also demonstrate TF-TF often affected alternative isoform usage identify human viral proteins from papillomaviruses, Epstein-Barr virus, viruses. Altogether, pY1H broadly applicable framework how different functional affect protein occupancy regions.

Язык: Английский

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The impact of the embryonic DNA methylation program on CTCF-mediated genome regulation

Nucleic Acids Research, Год журнала: 2024, Номер 52(18), С. 10934 - 10950

Опубликована: Авг. 23, 2024

Abstract During mammalian embryogenesis, both the 5-cytosine DNA methylation (5meC) landscape and three dimensional (3D) chromatin architecture are profoundly remodeled during a process known as ‘epigenetic reprogramming.’ An understudied aspect of epigenetic reprogramming is how 5meC flux, per se, affects 3D genome. This pertinent given 5meC-sensitivity binding for key regulator chromosome folding: CTCF. We profiled CTCF using mouse embryonic stem cell (ESC) differentiation protocol that models dynamics. Mouse ESCs lacking machinery able to exit naive pluripotency, thus allowing dissection subtle effects on gene expression. performed HiChIP in wild-type mutant conditions assess gained CTCF–CTCF contacts absence 5meC. H3K27ac determine impact ectopic has cis-regulatory contacts. Using epigenome editing, we demonstrated methyl-mark impair at select loci. Finally, detailed imprinted Zdbf2 locus showed 5meC-antagonism allows proper regulation differentiation. work provides comprehensive overview impacts genome relevant model early events.

Язык: Английский

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Biochemical and Epigenetic Regulation of Glutamate Metabolism in Maize (Zea mays L.) Leaves under Salt Stress

Plants, Год журнала: 2024, Номер 13(18), С. 2651 - 2651

Опубликована: Сен. 21, 2024

The effect of salt stress (150 mM NaCl) on the expression genes, methylation their promoters, and enzymatic activity glutamate dehydrogenase (GDH), decarboxylase (GAD), 2-oxoglutarate (2-OG)-dehydrogenase (2-OGDH) complex was studied in maize (

Язык: Английский

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MethylGPT: a foundation model for the DNA methylome

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 3, 2024

Abstract DNA methylation serves as a powerful biomarker for disease diagnosis and biological age assessment. However, current analytical approaches often rely on linear models that cannot capture the complex, context-dependent nature of regulation. Here we present MethylGPT, transformer-based foundation model trained 226,555 (154,063 after QC deduplication) human profiles spanning diverse tissue types from 5,281 datasets, curated 49,156 CpG sites, 7.6 billion training tokens. MethylGPT learns biologically meaningful representations capturing both local genomic context higher-order chromosomal features without external supervision. The demonstrates robust value prediction (Pearson R=0.929) maintains stable performance in downstream tasks with up to 70% missing data. Applied across multiple types, achieves superior accuracy compared existing methods. Analysis model’s attention patterns reveals distinct signatures between young old samples, differential enrichment developmental aging-associated pathways. When finetuned mortality 60 major conditions using 18,859 samples Generation Scotland, predictive enables systematic evaluation intervention effects risks, demonstrating potential clinical applications. Our results demonstrate transformer architectures can effectively while preserving interpretability, suggesting broad utility epigenetic analysis

Язык: Английский

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Genetic risk of osteoarthritis operates during human skeletogenesis

Human Molecular Genetics, Год журнала: 2022, Номер 32(13), С. 2124 - 2138

Опубликована: Окт. 7, 2022

Osteoarthritis (OA) is a polygenic disease of older people resulting in the breakdown cartilage within articular joints. Although it leading cause disability, there are no disease-modifying therapies. Evidence emerging to support origins OA skeletogenesis. Whereas methylation quantitative trait loci (mQTLs) co-localizing with genome-wide association study signals have been identified aged human and used identify effector genes variants, such analyses never conducted during development. Here, for first time, we investigated developmental genetic risk at seven well-characterized loci, comprising 39 OA-mQTL CpGs, fetal limb (FL) (FC) tissues using range molecular techniques. We significant OA-mQTLs 14 29 CpGs FL FC tissues, respectively, compared our results samples (AC). Differential was observed 26 sites between AC, majority becoming actively hypermethylated old age. Notably, 6/9 showed allelic expression imbalances Finally, ATAC-sequencing from developing hip knee accessible chromatin regions found enrichment transcription factor binding motifs including SOX9 FOS/JUN. For demonstrated activity imbalance show striking differences spatiotemporal function these contributing understanding aetiology, implications timing strategy pharmacological interventions.

Язык: Английский

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