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1.
BMC Genomics ; 23(1): 19, 2022 Jan 08.
Article in English | MEDLINE | ID: mdl-34996354

ABSTRACT

Chromatin accessibility is essential for transcriptional activation of genomic regions. It is well established that transcription factors (TFs) and histone modifications (HMs) play critical roles in chromatin accessibility regulation. However, there is a lack of studies that quantify these relationships. Here we constructed a two-layer model to predict chromatin accessibility by integrating DNA sequence, TF binding, and HM signals. By applying the model to two human cell lines (GM12878 and HepG2), we found that DNA sequences had limited power for accessibility prediction, while both TF binding and HM signals predicted chromatin accessibility with high accuracy. According to the HM model, HM features determined chromatin accessibility in a cell line shared manner, with the prediction power attributing to five core HM types. Results from the TF model indicated that chromatin accessibility was determined by a subset of informative TFs including both cell line-specific and generic TFs. The combined model of both TF and HM signals did not further improve the prediction accuracy, indicating that they provide redundant information in terms of chromatin accessibility prediction. The TFs and HM models can also distinguish the chromatin accessibility of proximal versus distal transcription start sites with high accuracy.


Subject(s)
Chromatin , Epigenomics , Binding Sites , Chromatin/genetics , Chromatin Immunoprecipitation , Computer Simulation , Humans , Protein Binding
2.
Biosens Bioelectron ; 195: 113644, 2022 Jan 01.
Article in English | MEDLINE | ID: mdl-34571478

ABSTRACT

Cancer epigenomic-environment is a core center of a tumor's genetic and epigenetic configuration. Surveying epigenomic-environment of cancer stem-like cells (CSC) is vital for developing novel diagnostic methods and improving current therapies since CSCs are among the most challenging clinical hurdles. To date, there exists no technique which can successfully monitor the epigenomics of CSC. Here, we have developed unique sub-10 nm Self-functional Gold Nanoprobes (GNP) as a CSC epigenomic monitoring platform that can easily maneuver into the nucleus while not producing any conformal changes to the genomic DNA. The GNP was synthesized using physical synthesis method of pulsed laser multiphoton ionization, which enabled the shrinking of GNP to 2.69 nm which helped us achieve two critical parameters for epigenomics monitoring: efficient nuclear uptake (98%) without complex functionalization and no conformational nuclear changes. The GNP efficiently generated SERS for structural, functional, molecular epigenetics, and nuclear proteomics in preclinical models of breast and lung CSCs. To the best of knowledge, this study is first to utilize the intranuclear epigenomic signal to distinguish between CSC from different tissues with >99% accuracy and specificity. Our findings are anticipated to help advance real-time epigenomics surveillance technologies such as nucleus-targeted drug surveillance and epigenomic prognosis and diagnostics.


Subject(s)
Biosensing Techniques , Neoplasms , Epigenomics , Gold , Humans , Neoplastic Stem Cells
3.
Environ Pollut ; 292(Pt A): 118279, 2022 Jan 01.
Article in English | MEDLINE | ID: mdl-34619179

ABSTRACT

Arsenic (As) contamination in groundwater is responsible for numerous adverse health outcomes among millions of people. Epigenetic alterations are among the most widely studied mechanisms of As toxicity. To understand how As exposure alters gene expression through epigenetic modifications, a systematic genome-wide study was designed to address the impact of multiple important single nucleotide polymorphisms (SNPs) related to As exposure on the methylome of drinking water As-exposed rural subjects from Pakistan. Urinary As levels were used to stratify subjects into low, medium and high exposure groups. Genome-wide DNA methylation was investigated using MeDIP in combination with NimbleGen 2.1 M Deluxe Promotor arrays. Transcriptome levels were measured using Agilent 8 × 60 K expression arrays. Genotyping of selected SNPs (As3MT, DNMT1a, ERCC2, EGFR and MTHFR) was measured and an integrated genetic risk factor for each respondent was calculated by assigning a specific value to the measured genotypes based on known risk allele numbers. To select a representative model related to As exposure we compared 9 linear mixed models comprising of model 1 (including the genetic risk factor), model 2 (without the genetic risk factor) and models with individual SNPs incorporated into the methylome data. Pathway analysis was performed using ConsensusPathDB. Model 1 comprising the integrated genetic risk factor disclosed biochemical pathways including muscle contraction, cardio-vascular diseases, ATR signaling, GPCR signaling, methionine metabolism and chromatin modification in association with hypo- and hyper-methylated gene targets. A unique pathway (direct P53 effector) was found associated with the individual DNMT1a polymorphism due to hyper-methylation of CSE1L and TRRAP. Most importantly, we provide here the first evidence of As-associated DNA methylation in relation with gene expression of ATR, ATF7IP, TPM3, UBE2J2. We report the first evidence that integrating SNPs data with methylome data generates a more representative epigenome profile and discloses a better insight in disease risks of As-exposed individuals.


Subject(s)
Arsenic , DNA Methylation , Epigenomics , Genome-Wide Association Study , Humans , Methyltransferases/genetics , Polymorphism, Single Nucleotide , Risk Factors , Ubiquitin-Conjugating Enzymes , Xeroderma Pigmentosum Group D Protein
4.
Biochim Biophys Acta Mol Basis Dis ; 1868(1): 166284, 2022 01 01.
Article in English | MEDLINE | ID: mdl-34626773

ABSTRACT

Chromatin alterations brought by histone variants and modifications potentially regulate gene transcription from tumor initiation to progression. Histone H3.3 variant is one such epigenetic player important for disease progression and development. Though many studies have implicated H3.3 role in cancer progression and metastasis, its regulation, importance of specific modifications and chaperones have been not understood yet. We report DNA methylation mediated downregulation of histone H3 variant H3.3 in HCC and a concomitant increase in the level of the H3.2 variant. The loss of H3.3 in cancer tissues correlates with a decrease in the histone modifications associated with active transcription like H3K9/K14/K27Ac and H3K4Me3. The ectopic overexpression of H3.3 and H3.2 did not affect global PTMs and cell physiology, probably owing to the deregulation of specific histone chaperones CAF-1 (for H3.2) and HIRA (for H3.3) as observed in HCC tissues. Notably, knockdown of P150, a subunit of CAF-1 leads to a cell cycle arrest in S-phase in a neoplastic rat liver cell line, possibly due to the decrease in the histone levels necessary for DNA packaging. Remarkably, modulation of H3.3 in pre-neoplastic rat liver cells lead to an increase in cell proliferation and a decreased transcription of tumor suppressor genes, recapitulating the tumor cell phenotype. Our data suggests, inhibition of DNA methylation and histone deacetylation leads to the restoration of histone H3 variant expression in tumor cells.


Subject(s)
Carcinoma, Hepatocellular/genetics , Cell Cycle Proteins/genetics , Histone Chaperones/genetics , Histones/genetics , Liver Neoplasms/genetics , Transcription Factors/genetics , Animals , Carcinogenesis/genetics , Carcinoma, Hepatocellular/pathology , Cell Proliferation/genetics , Chromatin/genetics , Chromatin Assembly Factor-1/genetics , DNA Methylation/genetics , Epigenomics , Gene Expression Regulation, Neoplastic/genetics , Gene Knockdown Techniques , Humans , Liver Neoplasms/pathology , Protein Kinases/genetics , Rats
5.
Biol Psychiatry ; 91(1): 36-42, 2022 01 01.
Article in English | MEDLINE | ID: mdl-33602500

ABSTRACT

Both history of early-life stress (ELS) and female sex are associated with increased risk for depression. The complexity of how ELS interacts with brain development and sex to impart risk for multifaceted neuropsychiatric disorders is also unlikely to be understood by examining changes in single genes. Here, we review an emerging literature on genome-wide transcriptional and epigenetic signatures of ELS and the potential moderating influence of sex. We discuss evidence both that there are latent sex differences revealed by ELS and that ELS itself produces latent transcriptomic changes revealed by adult stress. In instances where there are broad similarities in global signatures of ELS among females and males, genes that contribute to these patterns are largely distinct based on sex. As this area of investigation grows, an effort should be made to better understand the sex-specific impact of ELS within the human brain, specific contributions of chromosomal versus hormonal sex, how ELS alters the time course of normal transcriptional development, and the cell-type specificity of transcriptomic and epigenomic changes in the brain. A better understanding of how ELS interacts with sex to alter transcriptomic and epigenomic signatures in the brain will inform individualized therapeutic strategies to prevent or ameliorate depression and other psychiatric disorders in this vulnerable population.


Subject(s)
Adverse Childhood Experiences , Brain , Epigenomics , Female , Humans , Male , Sex Characteristics , Stress, Psychological/genetics
6.
Cancer Lett ; 525: 115-130, 2022 01 28.
Article in English | MEDLINE | ID: mdl-34736960

ABSTRACT

Hepatocellular carcinoma (HCC) is a major cancer burden worldwide with increasing incidence in many developed countries. Super-enhancers (SEs) drive gene expressions required for cell type-specificity and tumor cell identity. However, their roles in HCC remain unclear because of data scarcity from primary tumors. Herein, chromatin profiling of non-alcoholic fatty liver disease (NAFLD)-associated HCCs and matched liver tissues uncovered an average of ∼500 somatically-acquired SEs per patient. The identified SE-target genes were functionally enriched for aberrant metabolism and cancer phenotypes, especially chromatin regulators including deacetylases and Polycomb repressive complexes. Notably, all examined tumors exhibited SE activation of Sirtuin 7 (SIRT7), genome-wide promoter H3K18 deacetylation and concurrent H3K27me3, as well as tumor-suppressor gene silencing. Depletion of SIRT7 SE in hepatoma cells induced global H3K18 acetylation and reactivated key metabolic and immune regulators, leading to marked suppression of tumorigenicity in vitro and in vivo. In concordance, SIRT7 physically interacted with the methyltransferase EZH2, and they were co-expressed in primary HCCs. In summary, our integrative analysis establishes a compendium of SEs in NAFLD-associated HCCs and uncovers SIRT7-driven chromatin regulatory network as potential druggable vulnerability of this increasingly prevalent cancer.


Subject(s)
Carcinoma, Hepatocellular/genetics , Enhancer Elements, Genetic/genetics , Liver Neoplasms/genetics , Sirtuins/genetics , Carcinogenesis/genetics , Carcinoma, Hepatocellular/pathology , Cellular Reprogramming/genetics , Epigenomics , Female , Gene Silencing , Humans , Liver Neoplasms/pathology , Male , Sirtuins/antagonists & inhibitors
7.
Methods Mol Biol ; 2301: 97-132, 2022.
Article in English | MEDLINE | ID: mdl-34415532

ABSTRACT

Epigenomics studies require the combined analysis and integration of multiple types of data and annotations to extract biologically relevant information. In this context, sophisticated data visualization techniques are fundamental to identify meaningful patterns in the data in relation to the genomic coordinates. Data visualization for Hi-C contact matrices is even more complex as each data point represents the interaction between two distant genomic loci and their three-dimensional positioning must be considered. In this chapter we illustrate how to obtain sophisticated plots showing Hi-C data along with annotations for other genomic features and epigenomics data. For the example code used in this chapter we rely on a Bioconductor package able to handle even high-resolution Hi-C datasets. The provided examples are explained in details and highly customizable, thus facilitating their extension and adoption by end users for other studies.


Subject(s)
Software , Chromatin , Epigenomics , Genome , Genomics
8.
Article in English | MEDLINE | ID: mdl-34948764

ABSTRACT

Atherosclerosis is a pathological vascular state caused by the interaction of environmental and hereditary factors. Epigenetic modifications may be the bridge connecting environmental factors and genetic factors. A search for publications on the Web of Science database in the field of atherosclerosis related to epigenetics was conducted from the earliest mention to 31 December 2020. Data on total and annual publications, citations, impact factors, Hirsch (H)-index, citation times, most prolific authors, and frequently published journals were collected for quantitative and qualitative comparison. A total of 1848 publications related to epigenetics and atherosclerosis were found. The major contributing countries were the China (522, 28.23%), United States (485, 26.23%), and Germany (119, 6.44%). The greatest number of retrieved publications were published in the journal, "Arteriosclerosis, Thrombosis, and Vascular Biology" (62, 3.66%). The publication "Oxidative Stress and Diabetic Complications" was cited 2370 times. The most frequent keywords were "DNA methylation" and "LncRNA". Publications on epigenetic research in the atherosclerosis field have increased significantly every year, indicating that the study of epigenetic modifications plays an increasingly important role in understanding the pathology of atherosclerosis.


Subject(s)
Atherosclerosis , Bibliometrics , Atherosclerosis/epidemiology , Atherosclerosis/genetics , Epigenesis, Genetic , Epigenomics , Germany , Humans , Publications , United States
9.
Proc Natl Acad Sci U S A ; 118(51)2021 12 21.
Article in English | MEDLINE | ID: mdl-34911760

ABSTRACT

Epigenetic changes have been consistently detected in different cell types in multiple sclerosis (MS). However, their contribution to MS pathogenesis remains poorly understood partly because of sample heterogeneity and limited coverage of array-based methods. To fill this gap, we conducted a comprehensive analysis of genome-wide DNA methylation patterns in four peripheral immune cell populations isolated from 29 MS patients at clinical disease onset and 24 healthy controls. We show that B cells from new-onset untreated MS cases display more significant methylation changes than other disease-implicated immune cell types, consisting of a global DNA hypomethylation signature. Importantly, 4,933 MS-associated differentially methylated regions in B cells were identified, and this epigenetic signature underlies specific genetic programs involved in B cell differentiation and activation. Integration of the methylome to changes in gene expression and susceptibility-associated regions further indicates that hypomethylated regions are significantly associated with the up-regulation of cell activation transcriptional programs. Altogether, these findings implicate aberrant B cell function in MS etiology.


Subject(s)
B-Lymphocytes/metabolism , Lymphocyte Activation , Multiple Sclerosis/metabolism , B-Lymphocytes/pathology , Cell Differentiation , DNA Methylation , Epigenesis, Genetic , Epigenomics , Female , Gene Expression Profiling , Genome-Wide Association Study , Humans , Multiple Sclerosis/genetics , Multiple Sclerosis/pathology , Transcriptional Activation
10.
Commun Biol ; 4(1): 1412, 2021 12 17.
Article in English | MEDLINE | ID: mdl-34921240

ABSTRACT

Effective conservation and management of threatened wildlife populations require an accurate assessment of age structure to estimate demographic trends and population viability. Epigenetic aging models are promising developments because they estimate individual age with high accuracy, accurately predict age in related species, and do not require invasive sampling or intensive long-term studies. Using blood and biopsy samples from known age plains zebras (Equus quagga), we model epigenetic aging using two approaches: the epigenetic clock (EC) and the epigenetic pacemaker (EPM). The plains zebra EC has the potential for broad application within the genus Equus given that five of the seven extant wild species of the genus are threatened. We test the EC's ability to predict age in sister taxa, including two endangered species and the more distantly related domestic horse, demonstrating high accuracy in all cases. By comparing chronological and estimated age in plains zebras, we investigate age acceleration as a proxy of health status. An interaction between chronological age and inbreeding is associated with age acceleration estimated by the EPM, suggesting a cumulative effect of inbreeding on biological aging throughout life.


Subject(s)
Age Distribution , Epigenesis, Genetic , Equidae/genetics , Animals , Endangered Species , Epigenomics , Equidae/physiology , Horses/physiology , Models, Genetic , Population Dynamics , Species Specificity
11.
Cancer Cell ; 39(12): 1573-1575, 2021 12 13.
Article in English | MEDLINE | ID: mdl-34906316

ABSTRACT

Two recent reports in Nature highlight a novel mechanism of immunoevasion that relies on the SET domain bifurcated histone lysine methyltransferase 1 (SETDB1)-dependent epigenetic suppression of endogenous retroelements in melanoma cells. Because SETDB1 is highly expressed by the stem cell compartment, these findings delineate an innovative strategy for restoring cancer stem cell immunosurveillance.


Subject(s)
Neoplasms , Epigenesis, Genetic , Epigenomics , Humans , Neoplastic Stem Cells
12.
BMC Genomics ; 22(1): 904, 2021 Dec 18.
Article in English | MEDLINE | ID: mdl-34920711

ABSTRACT

BACKGROUND: Liver fibrosis is a wound-healing response to tissue injury and inflammation hallmarked by the extracellular matrix (ECM) protein deposition in the liver parenchyma and tissue remodelling. Different cell types of the liver are known to play distinct roles in liver injury response. Hepatocytes and liver endothelial cells receive molecular signals indicating tissue injury and activate hepatic stellate cells which produce ECM proteins upon their activation. Despite the growing knowledge on the molecular mechanism underlying hepatic fibrosis in general, the cell-type-specific gene regulatory network associated with the initial response to hepatotoxic injury is still poorly characterized. RESULTS: In this study, we used thioacetamide (TAA) to induce hepatic injury in adult zebrafish. We isolated three major liver cell types - hepatocytes, endothelial cells and hepatic stellate cells - and identified cell-type-specific chromatin accessibility and transcriptional changes in an early stage of liver injury. We found that TAA induced transcriptional shifts in all three cell types hallmarked by significant alterations in the expression of genes related to fatty acid and carbohydrate metabolism, as well as immune response-associated and vascular-specific genes. Interestingly, liver endothelial cells exhibit the most pronounced response to liver injury at the transcriptome and chromatin level, hallmarked by the loss of their angiogenic phenotype. CONCLUSION: Our results uncovered cell-type-specific transcriptome and epigenome responses to early stage liver injury, which provide valuable insights into understanding the molecular mechanism implicated in the early response of the liver to pro-fibrotic signals.


Subject(s)
Endothelial Cells , Epigenomics , Animals , Liver , Zebrafish/genetics
13.
BMC Genomics ; 22(1): 906, 2021 Dec 18.
Article in English | MEDLINE | ID: mdl-34922464

ABSTRACT

BACKGROUND: Disruption of alveolar epithelial cell (AEC) differentiation is implicated in distal lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung adenocarcinoma that impact morbidity and mortality worldwide. Elucidating underlying disease pathogenesis requires a mechanistic molecular understanding of AEC differentiation. Previous studies have focused on changes of individual transcription factors, and to date no study has comprehensively characterized the dynamic, global epigenomic alterations that facilitate this critical differentiation process in humans. RESULTS: We comprehensively profiled the epigenomic states of human AECs during type 2 to type 1-like cell differentiation, including the methylome and chromatin functional domains, and integrated this with transcriptome-wide RNA expression data. Enhancer regions were drastically altered during AEC differentiation. Transcription factor binding analysis within enhancer regions revealed diverse interactive networks with enrichment for many transcription factors, including NKX2-1 and FOXA family members, as well as transcription factors with less well characterized roles in AEC differentiation, such as members of the MEF2, TEAD, and AP1 families. Additionally, associations among transcription factors changed during differentiation, implicating a complex network of heterotrimeric complex switching in driving differentiation. Integration of AEC enhancer states with the catalog of enhancer elements in the Roadmap Epigenomics Mapping Consortium and Encyclopedia of DNA Elements (ENCODE) revealed that AECs have similar epigenomic structures to other profiled epithelial cell types, including human mammary epithelial cells (HMECs), with NKX2-1 serving as a distinguishing feature of distal lung differentiation. CONCLUSIONS: Enhancer regions are hotspots of epigenomic alteration that regulate AEC differentiation. Furthermore, the differentiation process is regulated by dynamic networks of transcription factors acting in concert, rather than individually. These findings provide a roadmap for understanding the relationship between disruption of the epigenetic state during AEC differentiation and development of lung diseases that may be therapeutically amenable.


Subject(s)
Epigenomics , Transcription Factors , Cell Differentiation/genetics , Epigenesis, Genetic , Humans , Lung , Transcription Factors/genetics
15.
Biomolecules ; 11(12)2021 12 03.
Article in English | MEDLINE | ID: mdl-34944472

ABSTRACT

DNA methylation plays important roles in prostate cancer (PCa) development and progression. African American men have higher incidence and mortality rates of PCa than other racial groups in U.S. The goal of this study was to identify differentially methylated CpG sites and genes between clinically defined aggressive and nonaggressive PCa in African Americans. We performed genome-wide DNA methylation profiling in leukocyte DNA from 280 African American PCa patients using Illumina MethylationEPIC array that contains about 860K CpG sties. There was a slight increase of overall methylation level (mean ß value) with the increasing Gleason scores (GS = 6, GS = 7, GS ≥ 8, P for trend = 0.002). There were 78 differentially methylated CpG sites with P < 10-4 and 9 sites with P < 10-5 in the trend test. We also found 77 differentially methylated regions/genes (DMRs), including 10 homeobox genes and six zinc finger protein genes. A gene ontology (GO) molecular pathway enrichment analysis of these 77 DMRs found that the main enriched pathway was DNA-binding transcriptional factor activity. A few representative DMRs include HOXD8, SOX11, ZNF-471, and ZNF-577. Our study suggests that leukocyte DNA methylation may be valuable biomarkers for aggressive PCa and the identified differentially methylated genes provide biological insights into the modulation of immune response by aggressive PCa.


Subject(s)
African Americans/genetics , Biomarkers, Tumor/genetics , DNA Methylation , Epigenomics/methods , Prostatic Neoplasms/pathology , Adult , Aged , Aged, 80 and over , CpG Islands , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Promoter Regions, Genetic , Prostatic Neoplasms/genetics
16.
Nurs Clin North Am ; 56(4): 465-478, 2021 12.
Article in English | MEDLINE | ID: mdl-34749888

ABSTRACT

As obesity continues a relentless march across the globe, researchers are beginning to unlock the complicated interplay among obesity, its ensuing inflammation, and downstream complications. It is becoming clear that obesity is a chronic, multifactorial, inflammatory disease of maladaptive adipose tissue mass involving complex links among genetics, hormonal-signaling, and the environment. Understanding the intricate pathogenesis of obesity and its sequela will go a long way to discovering better treatment options and lessen anti-obesity bias.


Subject(s)
Adipose Tissue/physiopathology , Appetite Regulation , Epigenomics , Inflammation/physiopathology , Obesity/physiopathology , Humans
17.
Eur J Ophthalmol ; 31(6): 2856-2867, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34798695

ABSTRACT

Epigenetics is characterized by molecular modifications able to shape gene expression profiles in response to inner and external stimuli. Therefore, epigenetic elements are able to provide intriguing and useful information for the comprehension and management of different human conditions, including aging process, and diseases. On this subject, Age-related Macular Degeneration (AMD) represents one of the most frequent age-related disorders, dramatically affecting the quality of life of older adults worldwide. The etiopathogenesis is characterized by an interplay among multiple genetic and non-genetic factors, which have been extensively studied. Nevertheless, a deeper dissection of molecular machinery associated with risk, onset, progression and effectiveness of therapies is still missing. In this regard, epigenetic signals may be further explored to disentangle disease etiopathogenesis, the possible therapeutic avenues and the differential response to AMD treatment. This review will discuss the epigenomic signatures mostly investigated in AMD, which could be applied to improve the knowledge of disease mechanisms and to set-up novel or modified treatment options.


Subject(s)
Epigenomics , Macular Degeneration , Aged , Epigenesis, Genetic , Humans , Macular Degeneration/drug therapy , Macular Degeneration/genetics , Quality of Life
18.
Adv Exp Med Biol ; 1344: 43-53, 2021.
Article in English | MEDLINE | ID: mdl-34773225

ABSTRACT

The circadian clock governs multiple biological functions at the molecular level and plays an essential role in providing temporal diversity of behavior and physiology including neuronal activity. Studies spanning the past two decades have deciphered the molecular mechanisms of the circadian clock, which appears to operate as an essential interface in linking cellular metabolism to epigenetic control. Accumulating evidence illustrates that disruption of circadian rhythms through jet lag, shift work, and temporary irregular life-style could lead to depression-like symptoms. Remarkably, abnormal neuronal activity and depression-like behavior appear in animals lacking elements of the molecular clock. Recent studies demonstrate that neuronal and synaptic gene induction is under epigenetic control, and robust epigenetic remodeling is observed under depression and related psychiatric disorders. Thus, the intertwined links between the circadian clock and epigenetics may point to novel approaches for antidepressant treatments, epigenetic therapy, and chronotherapy. In this chapter we summarize how the circadian clock is involved in neuronal functions and depressive-like behavior and propose that potential strategies for antidepressant therapy by incorporating circadian genomic and epigenetic rewiring of neuronal signaling pathways.


Subject(s)
Circadian Clocks , Animals , Circadian Clocks/genetics , Circadian Rhythm/genetics , Depression/genetics , Epigenesis, Genetic , Epigenomics , Humans
19.
OMICS ; 25(11): 681-692, 2021 11.
Article in English | MEDLINE | ID: mdl-34678084

ABSTRACT

Multiomics study designs have significantly increased understanding of complex biological systems. The multiomics literature is rapidly expanding and so is their heterogeneity. However, the intricacy and fragmentation of omics data are impeding further research. To examine current trends in multiomics field, we reviewed 52 articles from PubMed and Web of Science, which used an integrated omics approach, published between March 2006 and January 2021. From studies, data regarding investigated loci, species, omics type, and phenotype were extracted, curated, and streamlined according to standardized terminology, and summarized in a previously developed graphical summary. Evaluated studies included 21 omics types or applications of omics technology such as genomics, transcriptomics, metabolomics, epigenomics, environmental omics, and pharmacogenomics, species of various phyla including human, mouse, Arabidopsis thaliana, Saccharomyces cerevisiae, and various phenotypes, including cancer and COVID-19. In the analyzed studies, diverse methods, protocols, results, and terminology were used and accordingly, assessment of the studies was challenging. Adoption of standardized multiomics data presentation in the future will further buttress standardization of terminology and reporting of results in systems science. This shall catalyze, we suggest, innovation in both science communication and laboratory medicine by making available scientific knowledge that is easier to grasp, share, and harness toward medical breakthroughs.


Subject(s)
Computational Biology/trends , Genomics/trends , Metabolomics/trends , Proteomics/trends , Animals , COVID-19 , Computer Graphics , Epigenomics/trends , Gene Expression Profiling/trends , Humans , Pharmacogenetics/trends , Publications , SARS-CoV-2 , Terminology as Topic
20.
PLoS Genet ; 17(10): e1009865, 2021 10.
Article in English | MEDLINE | ID: mdl-34699533

ABSTRACT

Chromatin accessibility and gene expression in relevant cell contexts can guide identification of regulatory elements and mechanisms at genome-wide association study (GWAS) loci. To identify regulatory elements that display differential activity across adipocyte differentiation, we performed ATAC-seq and RNA-seq in a human cell model of preadipocytes and adipocytes at days 4 and 14 of differentiation. For comparison, we created a consensus map of ATAC-seq peaks in 11 human subcutaneous adipose tissue samples. We identified 58,387 context-dependent chromatin accessibility peaks and 3,090 context-dependent genes between all timepoint comparisons (log2 fold change>1, FDR<5%) with 15,919 adipocyte- and 18,244 preadipocyte-dependent peaks. Adipocyte-dependent peaks showed increased overlap (60.1%) with Roadmap Epigenomics adipocyte nuclei enhancers compared to preadipocyte-dependent peaks (11.5%). We linked context-dependent peaks to genes based on adipocyte promoter capture Hi-C data, overlap with adipose eQTL variants, and context-dependent gene expression. Of 16,167 context-dependent peaks linked to a gene, 5,145 were linked by two or more strategies to 1,670 genes. Among GWAS loci for cardiometabolic traits, adipocyte-dependent peaks, but not preadipocyte-dependent peaks, showed significant enrichment (LD score regression P<0.005) for waist-to-hip ratio and modest enrichment (P < 0.05) for HDL-cholesterol. We identified 659 peaks linked to 503 genes by two or more approaches and overlapping a GWAS signal, suggesting a regulatory mechanism at these loci. To identify variants that may alter chromatin accessibility between timepoints, we identified 582 variants in 454 context-dependent peaks that demonstrated allelic imbalance in accessibility (FDR<5%), of which 55 peaks also overlapped GWAS variants. At one GWAS locus for palmitoleic acid, rs603424 was located in an adipocyte-dependent peak linked to SCD and exhibited allelic differences in transcriptional activity in adipocytes (P = 0.003) but not preadipocytes (P = 0.09). These results demonstrate that context-dependent peaks and genes can guide discovery of regulatory variants at GWAS loci and aid identification of regulatory mechanisms.


Subject(s)
Cell Differentiation/genetics , Chromatin/genetics , Gene Expression/genetics , Quantitative Trait Loci/genetics , Adipocytes/metabolism , Adipose Tissue/metabolism , Alleles , Allelic Imbalance/genetics , Binding Sites/genetics , Cardiovascular Diseases/genetics , Cardiovascular Diseases/metabolism , Chromatin/metabolism , Chromatin Immunoprecipitation Sequencing/methods , Epigenomics/methods , Genetic Techniques , Genome-Wide Association Study/methods , Humans , Metabolic Diseases/genetics , Metabolic Diseases/metabolism , Promoter Regions, Genetic/genetics , Regulatory Sequences, Nucleic Acid/genetics
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