California Santa Cruz Genome Browser Research Articles

Trackplot: a fast and lightweight R script for epigenomic enrichment plots.

BigWig files serve as essential inputs in epigenomic data visualization. However, current R packages for visualizing these files are limited, slow, and burdened by numerous dependencies. We introducetrackplot, a minimal R script designed for the rapid generation of integrative genomics viewer (IGV) style track plots, profile plots, and heatmaps from bigWig files. This script offers speed, owing to its reliance onbwtool, resulting in performance gains ofseveral magnitudescompared to equivalentpackages.The script is lightweight, requiring only thedata.tableandbwtoolpackages as primary dependencies. Notably, the plots are generated in base R graphics,eliminatingthe need for additional packages.trackplotqueries the University of California Santa Cruz (UCSC) genome browser for gene models thereby enhancing the reproducibility of analyses. The script extends its support to general transfer format (GTF) further enhancing its versatility. This tool addresses the gaps in existing bigWig visualization approaches by offering speed, simplicity, and minimal dependencies, thereby presenting a valuable asset to researchers in the fields of epigenomics. trackplot is implemented in R is made available under MIT license at https://github.com/PoisonAlien/trackplot.

Multi‑dimensional analysis reveals NCKAP5L is a promising biomarker for the diagnosis and prognosis of human cancers, especially colorectal cancer.

The Nck-associated protein 5-like (NCKAP5L) gene, also known as Cep169, is associated with certain cancers. However, the diagnosis and prognosis value of NCKAP5L in several types of human cancer, including colorectal cancer, is not fully understood. In the present study, a comprehensive pan-cancer analysis of NCKAP5L was performed using several approaches, including gene expression and alteration, protein phosphorylation, immune infiltration, survival prognosis analyses and gene enrichment using the following: The University of California Santa Cruz Genome Browser Human Dec. 2013 (GRCh38/hg38) Assembly, Tumor Immune Estimation Resource (version 2), Human Protein Atlas, Gene Expression Profiling Interactive Analysis (version 2), University of Alabama at Birmingham Cancer Data Analysis portal, the Kaplan-Meier Plotter, cBioportal, Search Tool for the Retrieval of Interacting Genes/Proteins, Jvenn and the Metascape server. The role of NCKAP5L in colorectal cancer was further assessed by reverse transcription-quantitative PCR. The results demonstrated that NCKAP5L was upregulated in the majority of cancer types, including colorectal cancer. The high expression of NCKAP5L was significantly correlated with patient survival prognosis and immune infiltration of cancer-associated fibroblasts in numerous types of cancer, including colorectal cancer. Furthermore, Gene Ontology analysis identified that NCKAP5L may serve an important role in metabolic and cellular processes in human cancers. In summary, the data from the present study demonstrate that NCKAP5L is a potential tumor biomarker for the diagnosis and prognosis of human cancers, especially colorectal cancer.

Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple-negative breast cancer to immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) shed new light on triple-negative breast cancer (TNBC), but only a minority of patients demonstrate response. Therefore, adaptive immune resistance (AIR) needs to be further defined to guide the development of ICI regimens. Databases, including The Cancer Genome Atlas, Gene Ontology Resource, University of California Santa Cruz Genome Browser, and Pubmed, were used to screen epigenetic modulators, regulators for CD8+ T cells, and transcriptional regulators of programmed cell death-ligand 1 (PD-L1). Human peripheral blood mononuclear cell (Hu-PBMC) reconstruction mice were adopted for xenograft transplantation. Tumor specimens from a TNBC cohort and the clinical trial CTR20191353 were retrospectively analyzed. RNA-sequencing, Western blotting, qPCR and immunohistochemistry were used to assess gene expression. Coculture assays were performed to evaluate the regulation of TNBC cells on T cells. Chromatin immunoprecipitation and transposase-accessible chromatin sequencing were used to determine chromatin-binding and accessibility. The epigenetic modulator AT-rich interaction domain 1A (ARID1A) gene demonstrated the highest expression association with AIR relative to other epigenetic modulators in TNBC patients. Low ARID1A expression in TNBC, causing an immunosuppressive microenvironment, promoted AIR and inhibited CD8+ T cell infiltration and activity through upregulating PD-L1. However, ARID1A did not directly regulate PD-L1 expression. We found that ARID1A directly bound the promoter of nucleophosmin 1 (NPM1) and that low ARID1A expression increased NPM1 chromatin accessibility as well as gene expression, further activating PD-L1 transcription. In Hu-PBMC mice, atezolizumab demonstrated the potential to reverse ARID1A deficiency-induced AIR in TNBC by reducing tumor malignancy and activating anti-tumor immunity. In CTR20191353, ARID1A-low patients derived more benefit from pucotenlimab compared to ARID1A-high patients. In AIR epigenetics, low ARID1A expression in TNBC contributed to AIR via the ARID1A/NPM1/PD-L1 axis, leading to poor outcome but sensitivity to ICI treatment.

Family hypercholesterolemia and LDLR mutations in communities of european origin in southern Brazil: a prospective observational cohort study

Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by high levels of circulating low-density lipoprotein (LDL) and premature coronary heart events. A quarter of the population of Southern Brazil is affected by hypercholesterolemia and the region has the highest mortality rates due to cardiovascular disease in the country. The aim of this study was to describe LDLR mutations in European descendants with FH living in Southern Brazil. Ten mL of venous blood were taken from 40 patients and used for DNA extraction and subsequent Polymerase Chain Reaction (PCR). The DNA fragments were sequenced and analyzed and the data obtained were compared to reference values from the University of California Santa Cruz (UCSC) Genome Browser. A total of 15 mutations were identified in 38 patients (95% of the total samples). These mutations were located in exons 11 (P518L) and 15 (D727G) in Italian, Portuguese and Spanish descendants and the *105T>G mutation, still undescribed, should be critically evaluated by means of mRNA alteration studies. The present study demonstrated for the first time the presence of the P518L mutation located in exon 11 of the LDLR gene in European descendants living in southern Brazil. This mutation has a high potential to be pathogenic since it is located in a domain responsible for LDLR release from the endoplasmic reticulum (ER).

An Integrated Approach for Microprotein Identification and Sequence Analysis.

Next-generation sequencing (NGS) has propelled the field of genomics forward and produced whole genome sequences for numerous animal species and model organisms. However, despite this wealth of sequence information, comprehensive gene annotation efforts have proven challenging, especially for small proteins. Notably, conventional protein annotation methods were designed to intentionally exclude putative proteins encoded by short open reading frames (sORFs) less than 300 nucleotides in length to filter out the exponentially higher number of spurious noncoding sORFs throughout the genome. As a result, hundreds of functional small proteins called microproteins (<100 amino acids in length) have been incorrectly classified as noncoding RNAs or overlooked entirely. Here we provide a detailed protocol to leverage free, publicly available bioinformatic tools to query genomic regions for microprotein-coding potential based on evolutionary conservation. Specifically, we provide step-by-step instructions on how to examine sequence conservation and coding potential using Phylogenetic Codon Substitution Frequencies (PhyloCSF) on the user-friendly University of California Santa Cruz (UCSC) Genome Browser. Additionally, we detail steps to efficiently generate multiple species alignments of identified microprotein sequences to visualize amino acid sequence conservation and recommend resources to analyze microprotein characteristics, including predicted domain structures. These powerful tools can be used to help identify putative microprotein-coding sequences in noncanonical genomic regions or to rule out the presence of a conserved coding sequence with translational potential in a noncoding transcript of interest.

Predicting Parkinson disease related genes based on PyFeat and gradient boosted decision tree

Identifying genes related to Parkinson’s disease (PD) is an active research topic in biomedical analysis, which plays a critical role in diagnosis and treatment. Recently, many studies have proposed different techniques for predicting disease-related genes. However, a few of these techniques are designed or developed for PD gene prediction. Most of these PD techniques are developed to identify only protein genes and discard long noncoding (lncRNA) genes, which play an essential role in biological processes and the transformation and development of diseases. This paper proposes a novel prediction system to identify protein and lncRNA genes related to PD that can aid in an early diagnosis. First, we preprocessed the genes into DNA FASTA sequences from the University of California Santa Cruz (UCSC) genome browser and removed the redundancies. Second, we extracted some significant features of DNA FASTA sequences using the PyFeat method with the AdaBoost as feature selection. These selected features achieved promising results compared with extracted features from some state-of-the-art feature extraction techniques. Finally, the features were fed to the gradient-boosted decision tree (GBDT) to diagnose different tested cases. Seven performance metrics were used to evaluate the performance of the proposed system. The proposed system achieved an average accuracy of 78.6%, the area under the curve equals 84.5%, the area under precision-recall (AUPR) equals 85.3%, F1-score equals 78.3%, Matthews correlation coefficient (MCC) equals 0.575, sensitivity (SEN) equals 77.1%, and specificity (SPC) equals 80.2%. The experiments demonstrate promising results compared with other systems. The predicted top-rank protein and lncRNA genes are verified based on a literature review.

De Novo Assembly of the Nearly Complete Fathead Minnow Reference Genome Reveals a Repetitive but Compact Genome.

The fathead minnow is a widely used model organism in environmental toxicology. The lack of a high-quality fathead minnow reference genome, however, has severely hampered its uses in toxicogenomics. We present the de novo assembly and annotation of the fathead minnow genome using long PacBio reads, Bionano and Hi-C scaffolding data, and large RNA-sequencing data sets from different tissues and life stages. The new annotated fathead minnow reference genome has a scaffold N50 of 12.0 Mbp and a complete benchmarking universal single-copy orthologs score of 95.1%. The completeness of annotation for the new reference genome is comparable to that of the zebrafish GRCz11 reference genome. The fathead minnow genome, revealed to be highly repetitive and sharing extensive syntenic regions with the zebrafish genome, has a much more compact gene structure than the zebrafish genome. Particularly, comparative genomic analysis with zebrafish, mouse, and human showed that fathead minnow homologous genes are relatively conserved in exon regions but had strikingly shorter intron regions. The new fathead minnow reference genome and annotation data, publicly available from the National Center for Biotechnology Information and the University of California Santa Cruz genome browser, provides an essential resource for aquatic toxicogenomic studies in ecotoxicology and public health. Environ Toxicol Chem 2022;41:448-461. Published 2021. This article is a U.S. Government work and is in the public domain in the USA.

Genomic resources for rhesus macaques (Macaca mulatta).

Rhesus macaques (Macaca mulatta) are among the most extensively studied of nonhuman primates. This species has been the subject of many investigations concerning basic primate biology and behavior, including studies of social organization, developmental psychology, physiology, endocrinology, and neurodevelopment. Rhesus macaques are also critically important as a nonhuman primate model of human health and disease, including use in studies of infectious diseases, metabolic diseases, aging, and drug or alcohol abuse. Current research addressing fundamental biological and/or applied biomedical questions benefits from various genetic and genomic analyses. As a result, the genome of rhesus macaques has been the subject of more study than most nonhuman primates. This paper briefly discusses a number of information resources that can provide interested researchers with access to genetic and genomic data describing the content of the rhesus macaque genome, available information regarding genetic variation within the species, results from studies of gene expression, and other aspects of genomic analysis. Specific online databases are discussed, including the US National Center for Biotechnology Information, the University of California Santa Cruz genome browser, Ensembl genome browser, the Macaque Genotype and Phenotype database (mGAP), Rhesusbase, and others.

Annotation Parasitoid Wasp Venom Transcripts

Parasitoid wasps infect other arthropod species to complete their life cycle by laying their eggs on the surface or body cavity of their host. Many species inject a venom that alters host physiology to allow eggs to complete their development. The venom contains toxins that can disrupt host immune cell signaling, metabolism, and gene regulation. Recent venom studies used an approach that combines transcriptome or genome sequencing with the purification of venom proteins and mass spectrometry to identify venom proteins. In the Genomics Education Partnership (GEP), we are annotating parasitoid wasp genes from three parasitoid species that infect fruit flies (Drosophila melanogaster). Here, I used the University of California Santa Cruz Genome Browser mirror that combines genome, transcriptome, and proteome data, along with sequence alignment tools, to map precise coding regions of three venom gland transcripts from Leptopilina boulardi, L. heterotoma, and Ganapsis species. Each of these transcripts aligned with the jewel wasp (Nasonia vitrepennis) ortholog for MDH2 and have a similar predicted gene structure to the Nasonia and Drosophila MDH2 orthologs. Additionally, the L. heterotoma transcript aligned to a predicted uncharacterized Nasonia gene. The C-terminus of this predicted L. heterotoma protein has some similarity to the gene Shootin1 but the N-terminus of the protein has no homology to other known proteins as determined by BLAST. These gene models will be used to further investigate venom evolution and function of venom proteins in host-pathogen interactions.

Annotation and Comparison of Parasitoid Wasp GAPDH Gene

Endoparasitoid wasps are members of the hymenoptera superfamily that are dependent on other arthropod species for reproduction, consisting of the host's exploitation after the first sting for the preparation of egg insertion. The element that allows the manipulation of host biology is the introduction of venom gland derived proteins into their host. This venom has the ability to alter the host's gene expression and paralyze the arthropod to allow the wasp's eggs to develop inside the host without a fight. Once the eggs begin to develop, they become completely dependent on the host for their nourishment and development, meaning that the host will lack its nourishment and what is needed to continue living. A painful and quiet death awaits the host while it is being eaten alive from the inside out for the benefit of the parasitoid wasp. This research project focuses on the evolutionary relationships between venom proteins from three different endoparasitoid wasps: Leptolina. heterotoma, L. boulardi, and Ganaspis. The genes aligning to the venom transcriptome of the following species were identified with the help of the University of California Santa Cruz Genome Browser, allowing easy identification of precise and accurate coding regions through comparison with other insect orthologs. The goal of this research project is the annotation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the three parasitoid species. GAPDH is a glycolytic enzyme that has significant cellular functions in glycolysis and gluconeogenesis, responsible for the interconversion of 1,3-diphosphoglycerate and glyceraldehyde-3-phosphate. This enzyme catalyzes the conversion of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate, producing ATP and pyruvate in the Cytoplasm of the cell through anaerobic glycolysis. RNA-seq data from the venom transcriptome suggests that the three GAPDH orthologs have a similar gene structure and are highly homologous to the Nasonia vitripennis predicted GAPDH peptide sequence. The GAPDH peptide from Ganapsis species has shares 93% identity and 97% similarity to N. vitripennis ortholog, whereas the L. boulardi ortholog is more divergent with 88.4% identity and 93.1% identity. These gene models will be used in a comparative genomics study to investigate parasitoid wasp venom evolution.

Dysregulation of hsa-miR-34a and hsa-miR-449a leads to overexpression of PACS-1 and loss of DNA damage response (DDR) in cervical cancer

We have observed overexpression of PACS-1, a cytosolic sorting protein in primary cervical tumors. Absence of exonic mutations and overexpression at the RNA level suggested a transcriptional and/or posttranscriptional regulation. University of California Santa Cruz genome browser analysis of PACS-1 micro RNAs (miR), revealed two 8-base target sequences at the 3' terminus for hsa-miR-34a and hsa-miR-449a. Quantitative RT-PCR and Northern blotting studies showed reduced or loss of expression of the two microRNAs in cervical cancer cell lines and primary tumors, indicating dysregulation of these two microRNAs in cervical cancer. Loss of PACS-1 with siRNA or exogenous expression of hsa-miR-34a or hsa-miR-449a in HeLa and SiHa cervical cancer cell lines resulted in DNA damage response, S-phase cell cycle arrest, and reduction in cell growth. Furthermore, the siRNA studies showed that loss of PACS-1 expression was accompanied by increased nuclear γH2AX expression, Lys382-p53 acetylation, and genomic instability. PACS-1 re-expression through LNA-hsa-anti-miR-34a or -449a or through PACS-1 cDNA transfection led to the reversal of DNA damage response and restoration of cell growth. Release of cells post 24-h serum starvation showed PACS-1 nuclear localization at G1-S phase of the cell cycle. Our results therefore indicate that the loss of hsa-miR-34a and hsa-miR-449a expression in cervical cancer leads to overexpression of PACS-1 and suppression of DNA damage response, resulting in the development of chemo-resistant tumors.

In silico investigation of heparanase-correlated genes in breast cancer subtypes.

ABSTRACTObjective To investigate the possible genes that may be related to the mechanisms that modulate heparanase-1.Methods The analysis was conducted at Universidade Federal de São Paulo, on the data provided by: The Cancer Genome Atlas, University of California Santa Cruz Genome Browser, Kyoto Encyclopedia of Genes and Genomes Pathway Database, Database for Annotation, Visualization and Integrated Discovery Bioinformatics Database and the softwares cBioPortal and Ingenuity Pathway Analysis.Results Using messenger RNA expression pattern of different molecular subtypes of breast cancer, we proposed that heparinase-1 was co-related with its progression. In addition, genes that were analyzed presented co-expression with heparanase-1. The results that showed that heparanase-1 co-expressed with phosphoinositide 3-kinase adapter protein 1, sialic acid-binding immunoglobulin-like lectin 7, and leukocyte-associated immunoglobulin-like receptor 1 are directed related with immune system evasion during breast cancer progression. Furthermore, cathepsin L was co-expressed with heparanase-1 and transformed inactive heparanase-1 form into active heparanase-1, triggering extracellular matrix remodeling, which contributes to enhanced tumor-host interaction of the tumor.Conclusion The signaling pathway analysis using bioinformatics tools gives supporting evidence of possible mechanisms related to breast cancer development. Evasion genes of the immune system co-expressed with heparanase-1, a enzyme related with tumor progression.

Detection and analysis of angiogenesis pathway‑associated lncRNA expression profiles in human skin fibroblasts under high‑glucose conditions.

Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) have crucial roles in wound healing and that vascular lesions in diabetic wounds are frequently difficult to heal. However, the role of angiogenesis pathway-associated lncRNAs in wound healing in diabetic patients has remained to be fully elucidated. In the present study, human skin fibroblasts were cultured under high-glucose conditions in vitro to mimic a diabetic environment and the angiogenesis pathway-associated lncRNA expression profile in the high- and normal-glucose groups was examined. The microarray data indicated that 14 lncRNAs and 22 mRNAs were differentially expressed. Several candidate lncRNAs and mRNAs were then analyzed by reverse transcription-quantitative PCR and the results were consistent with the microarray data. Furthermore, the University of California Santa Cruz Genome Browser was used to identify mRNAs linked to angiogenesis pathways near the transcriptional region of lncRNAs. The results suggested that lncRNAs RP4-791C19.1 and CTD-2589O24.1 may act on their target genes epidermal growth factor receptor and p21 (RAC1) activated kinase 1, respectively, as enhancers and cis-regulate their expression. Therefore, the present study confirmed that several angiogenesis pathway-associated lncRNAs were differentially expressed under high-glucose conditions, which may have a key role in wound healing in patients with diabetes.

Bromodomain Epigenetic Protein Promotes Metastatic Potential in Melanoma Cells through Increased Invasiveness and Decreased Macrophage-Mediated Phagocytosis

Bromodomain Epigenetic Protein Promotes Metastatic Potential in Melanoma Cells through Increased Invasiveness and Decreased Macrophage-Mediated Phagocytosis

UCSC Genome Browser enters 20th year.

The University of California Santa Cruz Genome Browser website (https://genome.ucsc.edu) enters its 20th year of providing high-quality genomics data visualization and genome annotations to the research community. In the past year, we have added a new option to our web BLAT tool that allows search against all genomes, a single-cell expression viewer (https://cells.ucsc.edu), a ‘lollipop’ plot display mode for high-density variation data, a RESTful API for data extraction and a custom-track backup feature. New datasets include Tabula Muris single-cell expression data, GeneHancer regulatory annotations, The Cancer Genome Atlas Pan-Cancer variants, Genome Reference Consortium Patch sequences, new ENCODE transcription factor binding site peaks and clusters, the Database of Genomic Variants Gold Standard Variants, Genomenon Mastermind variants and three new multi-species alignment tracks.

Bioinformatics prediction and experimental validation of a novel microRNA: hsa-miR-B43 within human CDH4 gene with a potential metastasis-related function in breast cancer.

As a class of short noncoding RNAs, microRNAs (miRNAs) play a key role in the modulation of gene expression. Although, the regulatory roles of currently identified miRNAs in various cancer types including breast cancer have been well documented, there are many as yet undiscovered miRNAs. The aim of the current study was to bioinformatically reanalyze a list of 189 potentially new miRNAs introduced in a previously published paper (PMID: 21346806) and experimentally explore the existence and function of a candidate one: hsa-miR-B43 in breast cancer cells. The sequences of 189 potential miRNAs were re-checked in the miRbase database. Genomic location and conservation of them were assessed with the University of California Santa Cruz (UCSC) genome browser. SSC profiler, RNAfold, miRNAFold, MiPred, and FOMmiR bioinformatics tools were furthermore utilized to explore potential hairpin structures and differentiate real miRNA precursors from pseudo ones. hsa-miR-B43 was finally selected as one of the best candidates for laboratory verification. The expression and function of hsa-miR-B43 were examined by real-time polymerase chain reaction, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and wound-healing assays. DIANA-microT, RNAhybrid and Enrichr tools were used to predict the miRNA target genes and for further enrichment analysis. We could detect the exogenous and endogenous expression of hsa-miR-B43, as a real novel miRNA, in cancer cell lines. Gene Ontology enrichment, pathway analysis and wound-healing assay results furthermore confirmed that a metastasis-related function may be assigned to hsa-miR-B43. Our results introduced hsa-miR-B43, as a novel functional miRNA, which might play a role in the metastatic process. Further studies will be necessary to completely survey the existence and function of hsa-miR-B43 in other cancer types.

Conservation analysis and pathogenicity prediction of mutant genes of ectodysplasin a

BackgroundHypohidrotic ectodermal dysplasia (HED) is a common recessive X-linked hereditary disease that affects the development of ectoderm. Gene mutations of ectodysplasin A (EDA) play key roles in process of this disease. In our preliminary study, three unknown mutation sites (c.878 T > G, c.663-697del and c.587-615del) were detected from the pedigrees of HED.MethodsConservation analysis of the related homologous proteins in 3 unknown EDA gene mutation sites was conducted using the University of California Santa Cruz (UCSC) Genome Browser database. SIFT and PolyPhen-2, the online gene function prediction software, were utilized to predict the pathogenicity of point mutation of c.878 T > G.ResultsAll three unknown mutation sites were located in the highly-conserved region of EDA and possessed strong amino acid conservation among different species. In addition, the results of the pathogenicity prediction of point mutation of c.878 T > G by SIFT (P = 0.00) and PolyPhen-2 (S = 0.997) demonstrated that the mutation site had considerable pathogenicity theoretically.ConclusionsThe EDA mutations of c.878 T > G, c.663-697del and c.587-615del may be responsible for the pathogenesis of HED in their pedigrees.

Leveraging the power of new molecular technologies in the clinical setting requires unprecedented awareness of limitations and drawbacks: experience of one diagnostic laboratory.

Advances in molecular technologies and in-silico variant prediction tools offer wide-ranging opportunities in diagnostic settings, yet they also present with significant limitations. Here, we contextualise the limitations of next-generation sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA) and in-silico prediction tools routinely used by diagnostic laboratories by reviewing specific experiences from our diagnostic laboratory. We investigated discordant annotations and/or incorrect variant 'callings' in exons of 56 genes constituting our cardiomyopathy and connective tissue disorder NGS panels. Discordant variants and segmental duplications (SD) were queried using the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool and the University of California Santa Cruz genome browser, respectively, to identify regions of high homology. Discrepant variant analyses by in-silico models were re-evaluated using updated file entries. We observed a 5% error rate in MYH7 variant 'calling' using MLPA, which resulted from >90% homology of the MYH7 probe-binding site to MYH6. SDs were detected in TTN, PKP2 and MYLK. SDs in MYLK presented the highest risk (15.7%) of incorrect variant 'calling'. The inaccurate 'callings' and discrepant in-silico predictions were resolved following detailed investigation into the source of error. Recognising the limitations described here may help avoid incorrect diagnoses and leverage the power of new molecular technologies in diagnostic settings.

Sarcoidosis Related Novel Candidate Genes Identified by Multi-Omics Integrative Analyses

Sarcoidosis is a multifactorial systemic disease characterized by granulomatous inflammation and greatly impacting on global public health. The etiology and mechanisms of sarcoidosis are not fully understood. Recent high-throughput biological research has generated vast amounts of multi-omics big data on sarcoidosis, but their significance remains to be determined. We sought to identify novel candidate regions, and genes consistently altered in heterogeneous omics studies so as to reveal the underlying molecular mechanisms. We conducted a comprehensive integrative literature analysis on global data on sarcoidosis, including genomic, transcriptomic, proteomic, and phenomic studies. We performed positional integration analysis of 38 eligible datasets originating from 17 different biological layers. Using the integration interval length of 50 kb, we identified 54 regions reaching significance value p ≤ 0.0001 and 15 regions with significance value p ≤ 0.00001, when applying more stringent criteria. Secondary literature analysis of the top 20 regions, with the most significant accumulation of signals, revealed several novel candidate genes for which associations with sarcoidosis have not yet been established, but have considerable support for their involvement based on omic data. These new plausible candidate genes include NELFE, CFB, EGFL7, AGPAT2, FKBPL, NRC3, and NEU1. Furthermore, annotated data were prepared to enable custom visualization and browsing of these sarcoidosis related omics evidence in the University of California Santa Cruz (UCSC) Genome Browser. Further multi-omics approaches are called for sarcoidosis biomarkers and diagnostic and therapeutic innovation. Our approach for harnessing multi-omics data and the findings presented herein reflect important steps toward understanding the etiology and underlying pathological mechanisms of sarcoidosis.

The Pancancer DNA Methylation Trackhub: A Window to The Cancer Genome Atlas Epigenomics Data.

The Cancer Genome Atlas (TCGA) epigenome data includes the DNA methylation status of tumor and normal tissues of large cohorts for dozens of cancer types. Due to the moderately large data sizes, retrieving and analyzing them requires basic programming skills. Simple data browsing (e.g., candidate gene search) is hampered by the scarcity of easy-to-use data browsers addressed to the broad community of biomedical researchers. We propose a new visualization method depicting the overall DNA methylation status at each TCGA cohort while emphasizing its heterogeneity, thus facilitating the evaluation of the cohort variability and the normal versus tumor differences. Implemented as a trackhub integrated to the University of California Santa Cruz (UCSC) genome browser, it can be easily added to any genome-wide annotation layer.To exemplify the trackhub usage we evaluate local DNA methylation boundaries, the aberrant DNA methylation of a CpG island located at the estrogen receptor 1 (ESR1) in breast and colon cancer, and the hypermethylation of the Homeobox HOXA gene cluster and the EN1 gene in multiple cancer types. The DNA methylation pancancer trackhub is freely available at http://maplab.cat/tcga_450k_trackhub .