scholarly journals m6A-TSHub: unveiling the context-specific m6A methylation and m6A-affecting mutations in 23 human tissues

2022 ◽  
Author(s):  
Bowen Song ◽  
Daiyun Huang ◽  
Yuxin Zhang ◽  
Zhen Wei ◽  
Jionglong Su ◽  
...  
Keyword(s):  
Web Server ◽  
Rna Modification ◽  
Epigenetic Mark ◽  
Cancer Type ◽  
Human Tissues ◽  
Rna Sequences ◽  
Tissue Specific ◽  
Specific Tissue ◽  
Context Specific ◽  
The Impact

As the most pervasive epigenetic marker present on mRNA and lncRNA, N6-methyladenosine (m6A) RNA methylation has been shown to participate in essential biological processes. Recent studies revealed the distinct patterns of m6A methylome across human tissues, and a major challenge remains in elucidating the tissue-specific presence and circuitry of m6A methylation. We present here a comprehensive online platform m6A-TSHub for unveiling the context-specific m6A methylation and genetic mutations that potentially regulate m6A epigenetic mark. m6A-TSHub consists of four core components, including (1) m6A-TSDB: a comprehensive database of 184,554 functionally annotated m6A sites derived from 23 human tissues and 499,369 m6A sites from 25 tumor conditions, respectively; (2) m6A-TSFinder: a web server for high-accuracy prediction of m6A methylation sites within a specific tissue from RNA sequences, which was constructed using multi-instance deep neural networks with gated attention; (3) m6A-TSVar: a web server for assessing the impact of genetic variants on tissue-specific m6A RNA modification; and (4) m6A-CAVar: a database of 587,983 TCGA cancer mutations (derived from 27 cancer types) that were predicted to affect m6A modifications in the primary tissue of cancers. The database should make a useful resource for studying the m6A methylome and genetic factor of epitranscriptome disturbance in a specific tissue (or cancer type). m6A-TSHub is accessible at: www.xjtlu.edu.cn/biologicalsciences/m6ats.

scholarly journals Tissue-specific 5-hydroxymethylcytosine landscape of the human genome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Bo He ◽  
Chao Zhang ◽  
Xiaoxue Zhang ◽  
Yu Fan ◽  
Hu Zeng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Genome ◽  
Association Studies ◽  
Specific Gene ◽  
Epigenetic Mark ◽  
Genome Wide Association Studies ◽  
Human Tissues ◽  
Tissue Specific ◽  
Tissue Specific Gene ◽  
Specific Gene Expression

Abstract5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark that regulates gene expression. Charting the landscape of 5hmC in human tissues is fundamental to understanding its regulatory functions. Here, we systematically profiled the whole-genome 5hmC landscape at single-base resolution for 19 types of human tissues. We found that 5hmC preferentially decorates gene bodies and outperforms gene body 5mC in reflecting gene expression. Approximately one-third of 5hmC peaks are tissue-specific differentially-hydroxymethylated regions (tsDhMRs), which are deposited in regions that potentially regulate the expression of nearby tissue-specific functional genes. In addition, tsDhMRs are enriched with tissue-specific transcription factors and may rewire tissue-specific gene expression networks. Moreover, tsDhMRs are associated with single-nucleotide polymorphisms identified by genome-wide association studies and are linked to tissue-specific phenotypes and diseases. Collectively, our results show the tissue-specific 5hmC landscape of the human genome and demonstrate that 5hmC serves as a fundamental regulatory element affecting tissue-specific gene expression programs and functions.

scholarly journals Tissue-specific 5-hydroxymethylcytosine landscape of the human genome

2020 ◽  
Author(s):  
Bo He ◽  
Chao Zhang ◽  
Xiaoxue Zhang ◽  
Yu Fan ◽  
Hu Zeng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Genome ◽  
Genome Wide Association Study ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Epigenetic Mark ◽  
Human Tissues ◽  
Tissue Specific ◽  
Regulatory Functions

Abstract 5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark that regulates gene expression. Charting the landscape of 5hmC in human tissues is fundamental to understand its regulatory functions. Here, we systematically profiled the whole-genome 5hmC landscape at single-base resolution for 19 types of human tissues. We found that 5hmC preferentially decorates gene bodies and outperforms gene body 5mC in reflecting gene expression. Approximately one-third of 5hmC peaks are tissue-specific differentially hydroxymethylated regions (tsDhMRs), which are deposited in regulatory elements that regulate the expression of nearby tissue-specific functional genes. In addition, tsDhMRs are enriched with tissue-specific transcription-factor-binding sites and may rewire tissue-specific gene expression networks. Moreover, tsDhMRs are associated with SNPs identified by genome-wide association study (GWAS), linked to tissue-specific phenotypes and diseases. Collectively, our results show the tissue-specific 5hmC landscape of the human genome and demonstrate that 5hmC serves as a fundamental regulatory element affecting tissue-specific development and diseases.

scholarly journals Impact of anatomic site on antigen-presenting cells in cancer

2020 ◽  
Vol 8 (2) ◽  
pp. e001204
Author(s):  
Maria Zagorulya ◽  
Ellen Duong ◽  
Stefani Spranger
Keyword(s):  
Immune Responses ◽  
Antitumor Immunity ◽  
Myeloid Cells ◽  
Antigen Presenting Cells ◽  
Cancer Type ◽  
Anatomic Site ◽  
Tissue Specific ◽  
Antigen Presenting ◽  
The Impact ◽  
Tissue Site

Checkpoint blockade immunotherapy (CBT) can induce long-term clinical benefits in patients with advanced cancer; however, response rates to CBT vary by cancer type. Cancers of the skin, lung, and kidney are largely responsive to CBT, while cancers of the pancreas, ovary, breast, and metastatic lesions to the liver respond poorly. The impact of tissue-resident immune cells on antitumor immunity is an emerging area of investigation. Recent evidence indicates that antitumor immune responses and efficacy of CBT depend on the tissue site of the tumor lesion. As myeloid cells are predominantly tissue-resident and can shape tumor-reactive T cell responses, it is conceivable that tissue-specific differences in their function underlie the tissue-site-dependent variability in CBT responses. Understanding the roles of tissue-specific myeloid cells in antitumor immunity can open new avenues for treatment design. In this review, we discuss the roles of tissue-specific antigen-presenting cells (APCs) in governing antitumor immune responses, with a particular focus on the contributions of tissue-specific dendritic cells. Using the framework of the Cancer-Immunity Cycle, we examine the contributions of tissue-specific APC in CBT-sensitive and CBT-resistant carcinomas, highlight how these cells can be therapeutically modulated, and identify gaps in knowledge that remain to be addressed.

scholarly journals Sex biases in cancer and autoimmune disease incidence are correlated across human tissues

2021 ◽  
Author(s):  
David R. Crawford ◽  
Sanju Sinha ◽  
Nishanth Ulhas Nair ◽  
Bríd M. Ryan ◽  
Jill S. Barnholtz-Sloan ◽  
...  
Keyword(s):  
Incidence Rate ◽  
Disease Incidence ◽  
Sex Bias ◽  
Cancer Type ◽  
Human Tissues ◽  
Key Factors ◽  
Common Basis ◽  
Incidence Studies ◽  
Specific Tissue ◽  
Sex Biases

AbstractCancer occurs more frequently in men while autoimmune diseases (AIDs) occur more frequently in women. To explore whether these sex biases have a common basis, we collected 170 AID incidence studies from many countries for tissues that have both a cancer type and an AID that arise from that tissue. Analyzing a total of 182 country-specific, tissue-matched cancer-AID incidence rate sex bias data pairs, we find that the sex biases observed in the incidence of AIDs and cancers that occur in the same tissue are correlated across human tissues. Among key factors that have been previously associated with sex bias in either AID or cancer incidence, we find that the sex bias in the expression of the 37 genes encoded in the mitochondrial genome and the expression of a few immune pathways stand out as common key factors whose levels across human tissues are strongly associated with these incidence rate sex biases.

scholarly journals Decoding the epitranscriptional landscape from native RNA sequences

2020 ◽  
Author(s):  
Piroon Jenjaroenpun ◽  
Thidathip Wongsurawat ◽  
Taylor D Wadley ◽  
Trudy M Wassenaar ◽  
Jun Liu ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
In Vitro Transcription ◽  
Rna Modification ◽  
Differential Analysis ◽  
Rna Sequences ◽  
Background Error ◽  
Sequencing Errors ◽  
Oxford Nanopore ◽  
The Impact

Abstract Traditional epitranscriptomics relies on capturing a single RNA modification by antibody or chemical treatment, combined with short-read sequencing to identify its transcriptomic location. This approach is labor-intensive and may introduce experimental artifacts. Direct sequencing of native RNA using Oxford Nanopore Technologies (ONT) can allow for directly detecting the RNA base modifications, although these modifications might appear as sequencing errors. The percent Error of Specific Bases (%ESB) was higher for native RNA than unmodified RNA, which enabled the detection of ribonucleotide modification sites. Based on the %ESB differences, we developed a bioinformatic tool, epitranscriptional landscape inferring from glitches of ONT signals (ELIGOS), that is based on various types of synthetic modified RNA and applied to rRNA and mRNA. ELIGOS is able to accurately predict known classes of RNA methylation sites (AUC > 0.93) in rRNAs from Escherichiacoli, yeast, and human cells, using either unmodified in vitro transcription RNA or a background error model, which mimics the systematic error of direct RNA sequencing as the reference. The well-known DRACH/RRACH motif was localized and identified, consistent with previous studies, using differential analysis of ELIGOS to study the impact of RNA m6A methyltransferase by comparing wild type and knockouts in yeast and mouse cells. Lastly, the DRACH motif could also be identified in the mRNA of three human cell lines. The mRNA modification identified by ELIGOS is at the level of individual base resolution. In summary, we have developed a bioinformatic software package to uncover native RNA modifications.

scholarly journals ResponseNet v.3: revealing signaling and regulatory pathways connecting your proteins and genes across human tissues

2019 ◽  
Vol 47 (W1) ◽  
pp. W242-W247 ◽  
Author(s):  
Omer Basha ◽  
Omry Mauer ◽  
Eyal Simonovsky ◽  
Rotem Shpringer ◽  
Esti Yeger-Lotem
Keyword(s):  
Human Tissue ◽  
Interaction Network ◽  
Tissue Expression ◽  
Patient Specific ◽  
Optimization Approach ◽  
Human Tissues ◽  
Regulatory Pathways ◽  
Specific Analysis ◽  
Specific Tissue ◽  
Context Specific

Abstract ResponseNet v.3 is an enhanced version of ResponseNet, a web server that is designed to highlight signaling and regulatory pathways connecting user-defined proteins and genes by using the ResponseNet network optimization approach (http://netbio.bgu.ac.il/respnet). Users run ResponseNet by defining source and target sets of proteins, genes and/or microRNAs, and by specifying a molecular interaction network (interactome). The output of ResponseNet is a sparse, high-probability interactome subnetwork that connects the two sets, thereby revealing additional molecules and interactions that are involved in the studied condition. In recent years, massive efforts were invested in profiling the transcriptomes of human tissues, enabling the inference of human tissue interactomes. ResponseNet v.3 expands ResponseNet2.0 by harnessing ∼11,600 RNA-sequenced human tissue profiles made available by the Genotype-Tissue Expression consortium, to support context-specific analysis of 44 human tissues. Thus, ResponseNet v.3 allows users to illuminate the signaling and regulatory pathways potentially active in the context of a specific tissue, and to compare them with active pathways in other tissues. In the era of precision medicine, such analyses open the door for tissue- and patient-specific analyses of pathways and diseases.

scholarly journals Outcomes Related to Percutaneous Nephrostomies (PCN) in Malignancy-Associated Ureteric Obstruction: A Systematic Review of the Literature

2021 ◽  
Vol 10 (11) ◽  
pp. 2354
Author(s):  
Francesca J. New ◽  
Sally J. Deverill ◽  
Bhaskar K. Somani
Keyword(s):  
Quality Of Life ◽  
Advanced Cancer ◽  
Previous Treatment ◽  
Cochrane Library ◽  
Cancer Type ◽  
Ureteric Obstruction ◽  
Survival Times ◽  
Advanced Malignancies ◽  
The Impact

Background: Malignant ureteric obstruction occurs in a variety of cancers and has been typically associated with a poor prognosis. Percutaneous nephrostomy (PCN) can potentially help increase patient longevity by establishing urinary drainage and treating renal failure. Our aim was to look at the outcomes of PCN in patients with advanced cancer and the impact on the patients’ lifespan and quality of life. Materials and Methods: A literature review was carried out for articles from 2000 to 2020 on PCN in patients with advanced malignancies, using MEDLINE, EMBASE, Scopus, CINAHL, Cochrane Library, clinicaltrials.gov, and Google Scholar. All English-language articles reporting on a minimum of 20 patients who underwent PCN for malignancy-associated ureteric obstruction were included. Results: A total of 21 articles (1674 patients) met the inclusion criteria with a mean of 60.2 years (range: 21–102 years). PCN was performed for ureteric obstruction secondary to urological malignancies (n = −633, 37.8%), gynaecological malignancies (n = 437, 26.1%), colorectal and GI malignancies (n = 216, 12.9%), and other specified malignancies (n = 205, 12.2%). The reported mean survival times varied from 2 to 8.5 months post PCN insertion, with an average survival time of 5.6 months, which depended on the cancer type, stage, and previous treatment. Conclusions: Patients with advanced malignancies who need PCN tend to have a survival rate under 12 months and spend a large proportion of this time in the hospital. Although the advent of newer chemotherapy and immunotherapy options has changed the landscape of managing advanced cancer, decisions on nephrostomy must be balanced with their survival and quality of life, which must be discussed with the patient.

scholarly journals Current insights into the implications of m6A RNA methylation and autophagy interaction in human diseases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xuechai Chen ◽  
Jianan Wang ◽  
Muhammad Tahir ◽  
Fangfang Zhang ◽  
Yuanyuan Ran ◽  
...  
Keyword(s):  
Intervertebral Disc Degeneration ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Degradation Process ◽  
Human Diseases ◽  
Rna Modification ◽  
Rna Methylation ◽  
M6a Rna Methylation ◽  
The Impact

AbstractAutophagy is a conserved degradation process crucial to maintaining the primary function of cellular and organismal metabolism. Impaired autophagy could develop numerous diseases, including cancer, cardiomyopathy, neurodegenerative disorders, and aging. N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells, and the fate of m6A modified transcripts is controlled by m6A RNA binding proteins. m6A modification influences mRNA alternative splicing, stability, translation, and subcellular localization. Intriguingly, recent studies show that m6A RNA methylation could alter the expression of essential autophagy-related (ATG) genes and influence the autophagy function. Thus, both m6A modification and autophagy could play a crucial role in the onset and progression of various human diseases. In this review, we summarize the latest studies describing the impact of m6A modification in autophagy regulation and discuss the role of m6A modification-autophagy axis in different human diseases, including obesity, heart disease, azoospermatism or oligospermatism, intervertebral disc degeneration, and cancer. The comprehensive understanding of the m6A modification and autophagy interplay may help in interpreting their impact on human diseases and may aid in devising future therapeutic strategies.

scholarly journals Estimating the burden of cardiovascular risk in community dwellers over 40 years old in South Africa, Kenya, Burkina Faso and Ghana

2021 ◽  
Vol 6 (1) ◽  
pp. e003499
Author(s):  
Ryan G Wagner ◽  
Nigel J Crowther ◽  
Lisa K Micklesfield ◽  
Palwende Romauld Boua ◽  
Engelbert A Nonterah ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
South African ◽  
Sub Saharan Africa ◽  
African Countries ◽  
Cvd Risk ◽  
Genomic Studies ◽  
Sub Saharan ◽  
Context Specific ◽  
The Impact

IntroductionCardiovascular disease (CVD) risk factors are increasing in sub-Saharan Africa. The impact of these risk factors on future CVD outcomes and burden is poorly understood. We examined the magnitude of modifiable risk factors, estimated future CVD risk and compared results between three commonly used 10-year CVD risk factor algorithms and their variants in four African countries.MethodsIn the Africa-Wits-INDEPTH partnership for Genomic studies (the AWI-Gen Study), 10 349 randomly sampled individuals aged 40–60 years from six sites participated in a survey, with blood pressure, blood glucose and lipid levels measured. Using these data, 10-year CVD risk estimates using Framingham, Globorisk and WHO-CVD and their office-based variants were generated. Differences in future CVD risk and results by algorithm are described using kappa and coefficients to examine agreement and correlations, respectively.ResultsThe 10-year CVD risk across all participants in all sites varied from 2.6% (95% CI: 1.6% to 4.1%) using the WHO-CVD lab algorithm to 6.5% (95% CI: 3.7% to 11.4%) using the Framingham office algorithm, with substantial differences in risk between sites. The highest risk was in South African settings (in urban Soweto: 8.9% (IQR: 5.3–15.3)). Agreement between algorithms was low to moderate (kappa from 0.03 to 0.55) and correlations ranged between 0.28 and 0.70. Depending on the algorithm used, those at high risk (defined as risk of 10-year CVD event >20%) who were under treatment for a modifiable risk factor ranged from 19.2% to 33.9%, with substantial variation by both sex and site.ConclusionThe African sites in this study are at different stages of an ongoing epidemiological transition as evidenced by both risk factor levels and estimated 10-year CVD risk. There is low correlation and disparate levels of population risk, predicted by different risk algorithms, within sites. Validating existing risk algorithms or designing context-specific 10-year CVD risk algorithms is essential for accurately defining population risk and targeting national policies and individual CVD treatment on the African continent.

scholarly journals Prediction of genome-wide effects of single nucleotide variants on transcription factor binding

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sebastian Carrasco Pro ◽  
Katia Bulekova ◽  
Brian Gregor ◽  
Adam Labadorf ◽  
Juan Ignacio Fuxman Bass
Keyword(s):  
Binding Sites ◽  
Cancer Type ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Regulatory Regions ◽  
Genome Wide ◽  
Transcriptional Regulatory ◽  
Gene Regulatory ◽  
The Impact ◽  
The Relationship

Abstract Single nucleotide variants (SNVs) located in transcriptional regulatory regions can result in gene expression changes that lead to adaptive or detrimental phenotypic outcomes. Here, we predict gain or loss of binding sites for 741 transcription factors (TFs) across the human genome. We calculated ‘gainability’ and ‘disruptability’ scores for each TF that represent the likelihood of binding sites being created or disrupted, respectively. We found that functional cis-eQTL SNVs are more likely to alter TF binding sites than rare SNVs in the human population. In addition, we show that cancer somatic mutations have different effects on TF binding sites from different TF families on a cancer-type basis. Finally, we discuss the relationship between these results and cancer mutational signatures. Altogether, we provide a blueprint to study the impact of SNVs derived from genetic variation or disease association on TF binding to gene regulatory regions.

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