Biology subjects

Patil, S.

Publications and source records attributed to Patil, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Construction of an Immunoinformatics-Based Multi-Epitope Vaccine Candidate targeting Kyasanur Forest Disease Virus

Kyasanur Forest Disease (KFD) is one of the neglected tick-borne viral zoonoses. KFD virus was initially considered endemic to the Western Ghats region of Karnataka. Still, over the years, there have been reports of its spread to newer areas within and outside Karnataka. The absence of an effective treatment for KFD expedites the need for further research and development of novel vaccines. The present study was designed to develop a multi-epitope vaccine candidate against KFDV using immunoinformatic tools. After analyzing 74 complete KFDV genome sequences for genetic recombination and phylogeny, different prioritized B and T cell epitopes were combined using various linkers to construct the vaccine candidate. Docking analysis of the designed vaccine construct revealed a stable interaction with the TLR2-TLR6 receptor complex. After confirming the stability of the vaccine receptor complex, codon optimization was done to ensure the efficient translation of the designed multi-epitope vaccine in the prokaryotic host system, and the subsequent in-silico cloning into the pET30b(+) expression vector was carried out. Immunoinformatics analysis of the multi-epitope vaccine in the current study is satisfactory as it can significantly accelerate the initial stages of vaccine development by narrowing down potential vaccine candidates and providing insights into their design. Experimental validation of the potential multi-epitope vaccine candidate remains crucial to confirm effectiveness and safety in real-world conditions.

bioinformatics↗

bioRxiv2024

Towards Generative RNA Design With Tertiary Interactions

AO_SCPLOWBSTRACTC_SCPLOWThe function of an RNA molecule depends on its structure and a strong structure-to-function relationship is already achieved on the secondary structure level of RNA. Therefore, the secondary structure based design of RNAs is one of the major challenges in computational biology. A common approach to RNA design is inverse RNA folding. However, existing RNA design methods cannot invert all folding algorithms because they cannot represent all types of base interactions. In this work, we propose RNAinformer, a novel generative transformer based approach to the inverse RNA folding problem. Leveraging axial-attention, we directly model the secondary structure input represented as an adjacency matrix in a 2D latent space, which allows us to invert all existing secondary structure prediction algorithms. Consequently, RNAinformer is the first model capable of designing RNAs from secondary structures with all base interactions, including non-canonical base pairs and tertiary interactions like pseudoknots and base multiplets. We demonstrate RNAinformers state-of-the-art performance across different RNA design benchmarks and showcase its novelty by inverting different RNA secondary structure prediction algorithms.

bioinformatics↗

bioRxiv2023

Preventing evolutionary rescue in cancer

AO_SCPLOWBSTRACTC_SCPLOWFirst-line cancer treatment frequently fails due to initially rare therapeutic resistance. An important clinical question is then how to schedule subsequent treatments to maximize the probability of tumour eradication. Here, we provide a theoretical solution to this problem by using mathematical analysis and extensive stochastic simulations within the framework of evolutionary rescue theory to determine how best to exploit the vulnerability of small tumours to stochastic extinction. Whereas standard clinical practice is to wait for evidence of relapse, we confirm a recent hypothesis that the optimal time to switch to a second treatment is when the tumour is close to its minimum size before relapse, when it is likely undetectable. This optimum can lie slightly before or slightly after the nadir, depending on tumour parameters. Given that this exact time point may be difficult to determine in practice, we study windows of high extinction probability that lie around the optimal switching point, showing that switching after the relapse has begun is typically better than switching too early. We further reveal how treatment dose and tumour demographic and evolutionary parameters influence the predicted clinical outcome, and we determine how best to schedule drugs of unequal efficacy. Our work establishes a foundation for further experimental and clinical investigation of this evolutionarily-informed "extinction therapy" strategy.

cancer biology↗

bioRxiv2023

Outer membrane proteins in Mycobacterium tuberculosis and its potential role in small molecule permeation

Increased resistance to current anti-mycobacterial and a potential bias towards relatively hydrophobic chemical entities highlight an urgent need to understand how current anti-TB drugs enter the tubercle bacilli. While inner membrane proteins are well-studied, how small molecules cross the impenetrable outer membrane remains unknown. Here we employed mass spectrometry-based proteomics to show that octyl-{beta}-glucopyranoside selectively extracts the outer membrane proteins of Mycobacterium tuberculosis. Differentially expressed proteins between nutrient replete and depleted conditions were enriched to identify proteins involved in nutrient uptake. We demonstrate cell surface localization of seven new proteins using immunofluorescence and show that overexpression of the proteins LpqY and ProX leads to hypersensitivity towards streptomycin, while expression of SubI, FecB2, and Rv0999 exhibited higher membrane permeability, assessed through EtBr accumulation assay. Further, proton NMR metabolomics suggests the role of four outer membrane proteins in glycerol uptake. This study identifies several outer membrane proteins that are involved in the permeation of small hydrophilic molecules and are potential targets for enhancing uptake and efficacy of anti-TB drugs.

microbiology↗

bioRxiv2023

The effects of phenylalanine and tyrosine levels on dopamine production in rat PC12 cells. Implications for treatment of phenylketonuria and tyrosinemia type 1

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, resulting in phenylalanine accumulation and impaired tyrosine production. In Tyrosinemia type 1 (TYRSN1) mutations affect fumarylacetoacetate hydrolase, leading to accumulation of toxic intermediates of tyrosine catabolism. Treatment of TYRSN1 with nitisinone results in extreme tissue levels of tyrosine. Although PKU and TYRSN1 have opposite effects on tyrosine levels, both conditions have been associated with neuro- psychiatric symptoms indicative of impaired dopamine (DA) synthesis. However, concrete in vivo data on the possible molecular basis for disrupted DA production under disease mimicking conditions have been lacking. In pursuit to uncover associated molecular mechanisms, we exposed an established, DA producing cell line (PC12) to different concentrations of phenylalanine and tyrosine in culture media. We measured the effects on viability, proteomic composition, tyrosine, DA and tyrosine hydroxylase (TH) levels and TH phosphorylation. TH catalyzes the rate-limiting step in DA synthesis. High extracellular levels of phenylalanine rapidly depleted cells of intracellular tyrosine and DA. Compared to physiological levels (75 {micro}M), either low (35 {micro}M) or high concentrations of tyrosine (275 or 835 {micro}M) decreased cellular DA, TH protein, and its phosphorylation levels. Using deep proteomic analysis, we identified multiple proteins, biological processes and pathways that were altered, including enzymes and transporters involved in amino acid metabolism. Specifically, levels of the broad specificity transporter of neutral amino acids LAT1 and the branched-chain amino-acid-transporter BCAT2 were both similarly increased. Using this information and published data, we developed a mathematical model to predict how extracellular levels of aromatic amino acids can affect the cellular synthesis of DA via different mechanisms. Together, these data provide new information about the normal regulation of neurotransmitter synthesis and how this may be altered on the molecular level in neurometabolic disorders, such as PKU and TYRSN1. HighlightsTyrosinemia type I and phenylketonuria are rare metabolic disorders, characterized by extremely elevated plasma levels of the aromatic amino acids tyrosine and phenylalanine, respectively. To study the molecular consequences of dysregulated amino acid uptake on dopamine homeostasis, we simulated these conditions using rat pheochromocytoma (PC12) cells, an established model system for investigating catecholamine production. Non-physiological tyrosine levels induced a broad cellular response, including reduced protein level and phosphorylation stoichiometry for tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, which in turn resulted in decreases in both intra- and extracellular dopamine levels. Similarly, dopamine content was also decreased when cells were exposed to high phenylalanine levels characteristic of phenylketonuria, although the underlying molecular mechanism for this response appears to differ.

molecular biology↗

bioRxiv2023

Acvr1b loss promotes formation of precancerous lesions from acinar and ductal cells of origin

Background & AimsPancreatic ductal adenocarcinoma (PDAC) can develop from precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). Previous studies indicated that loss of Acvr1b accelerates the Kras-mediated development of papillary IPMN in the mouse pancreas, however, the cell type predominantly affected by these genetic changes remains unclear. MethodsWe investigated the contribution of cellular origin by inducing IPMN associated mutations-KRASG12D expression and Acvr1b loss - specifically in acinar (Ptf1aCreER;KrasLSL-G12D;Acvr1bfl/flmice) or ductal (Sox9CreER;KrasLSL- G12D;Acvr1bfl/flmice) cells in mice. We then performed MRI imaging and a thorough histopathological analysis of their pancreatic tissues. ResultsThe loss of Acvr1b increased the development of PanIN and IPMN-like lesions when either acinar and ductal cells expressed a Kras mutation. MRI, immunohistochemistry and histology revealed large IPMN-like lesions in these mice that exhibited features of flat, gastric epithelium. In addition, cyst formation in both mouse models was accompanied by chronic pancreatitis. Experimental acute pancreatitis accelerated the development of large mucinous cysts and PanIN when acinar, but not ductal, cells expressed mutant Kras and lost Acvr1b. ConclusionThese findings indicate that loss of Acvr1b in the presence of the Kras oncogene promotes the development of large and small precancerous lesions from both ductal and acinar cells. However, the IPMN-like phenotype was not equivalent to that observed when these mutations were made in all pancreatic cells during development. Our study underscores the significance of the cellular context in the initiation and progression of precursor lesions from exocrine cells.

cancer biology↗

bioRxiv2023

Illuminating Dark Chemical Matter using the Cell Painting Assay

The identification of bioactive small molecules is at the heart of chemical biology and medicinal research. The screening for modulators of disease-relevant targets and phenotypes is the first step on the way to new drugs. Therefore, large compound libraries have been synthesized and employed by academia and, particularly, pharmaceutical companies to meet the need for chemical entities that are as diverse as possible. Extensive screening of these compound libraries revealed a portion of small molecules that is inactive in more than 100 different assays and was therefore termed dark chemical matter (DCM). Deorphanization of DCM promises to yield very selective compounds as they, by definition, should have less off-target effects. We employed morphological profiling using the Cell painting assay (CPA) to detect bioactive DCM compounds. CPA is not biased to a given target or phenotype and can detect various unrelated mechanisms and modes of action. Within the DCM collection, we identified bioactive compounds and confirmed several modulators of microtubules, DNA synthesis and pyrimidine biosynthesis. Profiling approaches are therefore powerful tools to probe compound collections for bioactivity in an unbiased manner and particularly suitable for deorphanization of DCM.

cell biology↗

bioRxiv2023

Androgen Receptor driven gene score identifies tumors with Epithelial to Mesenchymal Transition features in triple negative breast cancer

BackgroundAndrogen receptor (AR) is considered marker associated with better prognosis within hormone receptor positive tumors. Its role in triple negative tumors however is controversial showing both better and worse prognosis and different methods are used for identification of AR driven tumors. Conflicting results could be due to intrinsic molecular differences or scoring method for AR positivity. We attempted to develop an AR driven gene score and examined its utility in subtypes of breast cancer (BC). MethodsA bioinformatic pipeline was constructed and applied on publicly available microarray data sets obtained from AR positive BC cell lines treated with dihydrotestosterone (DHT). Expression levels of genes identified through the pipeline along with set of epithelial mesenchymal transition (EMT) markers, proliferation associated genes and enzymes involved in intracrinal androgen metabolism was evaluated in a cohort of Indian Breast cancer patients. Tumors were divided into AR high and low based on the gene score and association with clinical parameters, circulating androgens, disease free survival, proliferation and EMT markers were examined, all results were further validated in external public datasets. ResultsAR driven gene score was calculated as average expression of the 6 genes selected through bioinformatic analysis. 53% (133/249) tumors were classified as AR high by the gene score and had significantly better clinical parameters such as higher age, smaller tumor size, lower grade and lower proliferation. Tumors with high AR driven gene score had significantly better disease-free survival (mean survival time of 86.13 vs 72.69 months, log rank p=0.032) when compared to the AR low tumors. A subset analysis within TNBC (N=66) showed 36% (24/66) were AR high and had significantly higher expression of EMT markers (p=0.024). Though circulating levels of total testosterone was not different between the groups, intratumoral levels of 5 alfa reductase (SRD5A1) was significantly high in tumors with high AR driven score. ConclusionRole of AR in breast cancer is debatable and difficult to decipher with protein detection alone. Our results support the context dependent function of AR in driving better prognosis, while identifying its role in driving EMT within TNBC tumors.

cancer biology↗

bioRxiv2023

BRCA1 expression, its correlation with clinicopathological features and response to neoadjuvant chemotherapy in high grade serous ovarian cancer from an Indian centre

In high grade serous ovarian cancers (HG-SOC), BRCA1/2 mutations have been reported as the most predominant mutations by various studies. However, the non-mutational mechanisms of BRCA pathway inactivation in HG-SOC are unclear. We aimed to evaluate BRCA1 inactivation by estimating its expression along with its repressor in primary and neoadjuvant chemotherapy (NACT) treated HG-SOC tumors with known therapeutic response. The expression pattern of BRCA1 protein was evaluated by immunohistochemistry (IHC) in 119 cases of HG-SOC from a hospital cohort consisting of primary (N= 69) and NACT treated (N=50) tumors. Histological patterns (SET), stromal infiltration by lymphocytes (sTILs) and chemotherapy response score (CRS) were estimated by microscopic examination. Gene expression levels of BRCA1, and its repressor ID4 was estimated by qPCR. Association of BRCA1 protein and mRNA with clinicopathological features was studied. Relevance of the BRCA1/ID4 ratio was evaluated in tumors with different CRS. BRCA1 protein expression was observed in 12% of primary and 19% of NACT treated HG-SOC tumors. Moderate concordance was observed between BRCA1 protein and mRNA expression (AUC-0.677). High BRCA1 mRNA expression was significantly associated with more frequent SET pattern (p=0.024), higher sTILs density (p=0.042), increased mitosis (p=0.028). BRCA1 negative tumors showed higher expression of ID4 though not statistically significant. Higher BRCA1/ID4 ratio was associated with high sTILs density in primary (p=0.042) and NACT treated tumors (p=0.040). Our findings show the utility of BRCA1/ID4 ratio to predict neoadjuvant therapy response, which needs further evaluation in larger cohort with long term outcomes.

cancer biology↗

bioRxiv2022

eIF4E phosphorylation recruits β-catenin to mRNA cap and selectively promotes Wnt pathway translation in dentate gyrus LTP maintenance in vivo

The mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E), is crucial for translation and regulated by Ser209 phosphorylation. However, the biochemical and physiological role of eIF4E phosphorylation in translational control of long-term synaptic plasticity is unknown. We demonstrate that phospho-ablated Eif4eS209A knockin mice are profoundly impaired in dentate gyrus LTP maintenance in vivo, while basal perforant path-evoked transmission and LTP induction are intact. mRNA cap-pulldown assays show that phosphorylation is required for synaptic activity-induced removal of translational repressors from eIF4E, allowing initiation complex formation. Using ribosome profiling, we identified selective, phospho-eIF4E-dependent translation of the Wnt signaling pathway in in vivo LTP. Surprisingly, the canonical Wnt effector, {beta}-catenin, was massively recruited to the eIF4E cap complex following LTP induction in wild-type, but not Eif4eS209A, mice. These results demonstrate a critical role for activity-evoked eIF4E phosphorylation in dentate gyrus LTP maintenance, bidirectional remodeling of the mRNA cap-binding complex, and mRNA-specific translational control linked to Wnt pathway. Key highlightsO_LISynaptic activity-induced eIF4E phosphorylation controls DG-LTP maintenance in vivo C_LIO_LIeIF4E phosphorylation triggers release of translational repressors from cap complex C_LIO_LIeIF4E phosphorylation recruits {beta}-catenin to cap complex C_LIO_LIeIF4E phosphorylation selectively enhances translation of Wnt pathway C_LI

neuroscience↗

bioRxiv2022

Genome characterization of monkeypox cases detected in India: Identification of three sub clusters among A.2 lineage

Since May 2022, Monkeypox, a zoonotic Orthopox DNA virus was reported in more than 102 countries indicating expansion of its geographic range. We analyzed the complete genomes sequences of Monkeypox cases from Kerala (n=5 travelled from UAE) and Delhi (n=5 no travel history), India confirmed during July to August 2022. All the retrieved MPXV sequences from India covering 90 to 99% genome belong to A.2 lineage of clade IIb. The A.2 MPXV lineage divided in three sub clusters; first cluster Kerala n=5, Delhi n=2 aligned with the USA-2022 ON674051.1; while second of Delhi n=3 aligned with USA-2022 ON675438.1 and third consists of the UK, USA and Thailand. Recent update in MPXV lineage designated all the five sequences from Kerala as A.2.1. In addition to known 16 single nucleotide polymorphisms (SNPs) along with 13 APOBEC3 cytosine deaminase activity determined specific lineage defining mutations in A.2 lineage, 25 additional APOBEC3 mutations were found in 10 reported sequences. The study emphasizes need of enhancing genomic surveillance to understand the mutation and its linkage.

microbiology↗

bioRxiv2022

Impact of female mate copying on male morph dynamics

Mate copying (MC), a type of non-independent mate choice, is a behaviour observed in many vertebrate and few invertebrate species. It occurs when an individuals sexual preference gets socially inclined toward those of its conspecifics. Theoretical models and experimental studies of MC have been limited to choice between two options (or morphs). In this study we model the evolution of morphology in a population under varying extents of mate copying. Multiple morphs and multiple observations are considered and a generalisable model is presented. We quantify the level of copying needed to achieve pseudo-stable equilibria in the presence of multiple morphs. Moving closer to realistic scenarios we support our theoretical development with simulations and discuss relevance for empirical model systems.

animal behavior and cognition↗

bioRxiv2022

Insulin receptors in pancreatic acinar cells contribute to KrasG12D-driven cancer initiation in the context of diet-induced obesity

The rising pancreatic cancer incidence due to obesity and type 2 diabetes is closely tied to hyperinsulinemia, an independent cancer risk factor. Previous studies demonstrated reducing insulin production suppressed pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in Kras-mutant mice. However, the pathophysiological and molecular mechanisms remained unknown and in particular it was unclear whether hyperinsulinemia affected PanIN precursor cells directly or indirectly. Here, we demonstrate that insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are dispensable for glucose homeostasis, but necessary for hyperinsulinemia-driven PanIN formation in the context of diet-induced hyperinsulinemia and obesity. Mechanistically, this was attributed to amplified digestive enzyme protein translation, triggering of local inflammation and PanIN metaplasia in vivo. In vitro, insulin dose-dependently increased acinar-to-ductal metaplasia formation in a trypsin- and Insr-dependent manner. Collectively, our data shed light on the mechanisms connecting obesity-driven hyperinsulinemia and pancreatic cancer development.

cancer biology↗

bioRxiv2022

An in vitro and in vivo approach for the isolation of Omicron variant from human clinical specimens

Due to failure of virus isolation of Omicron variant in Vero CCL-81 from the clinical specimens of COVID-19 cases, we infected Syrian hamsters and then passage into Vero CCL-81 cells. The Omicron sequences were studied to assess if hamster could incorporate any mutation to changes its susceptibility. L212C mutation, Tyrosine 69 deletion, and C25000T nucleotide change in spike gene and absence of V17I mutation in E gene was observed in sequences of hamster passage unlike human clinical specimen and Vero CCL-81 passages. No change was observed in the furin cleavage site in any of the specimen sequence which suggests usefulness of these isolates in future studies.

microbiology↗

bioRxiv2021

Using Progressive Context Encoders for Anomaly Detection in Digital Pathology Images

Whole slide imaging (WSI) is transforming the practice of pathology, converting a qualitative discipline into a quantitative one. However, one must exercise caution in interpreting algorithm assertions, particularly in pathology where an incorrect classification could have profound impacts on a patient, and rare classes exist that may not have been seen by the algorithm during training. A more robust approach would be to identify areas of an image for which the pathologist should concentrate their effort to make a final diagnosis. This anomaly detection strategy would be ideal for WSI, but given the extremely high resolution and large file sizes, such an approach is difficult. Here, we combine progressive generative adversarial networks with a flexible adversarial autoencoder architecture capable of learning the "normal distribution" of WSIs of normal skin tissue at extremely high resolution and demonstrate its anomaly detection performance. Our approach yielded pixel-level accuracy of 89% for identifying melanoma, suggesting that our label-free anomaly detection pipeline is a viable strategy for generating high quality annotations - without tedious manual segmentation by pathologists. The code is publicly available at https://github.com/Steven-N-Hart/P-CEAD.

pathology↗

bioRxiv2021

Possible role of accessory proteins in the viral replication for the 20I/501Y.V1 (B.1.1.7) SARS-CoV-2 variant

The study investigates the replication cycle and transcriptional pattern of the B.1.1.7 variant. It was observed that the B.1.1.7 variant required a longer maturation time. The transcriptional response demonstrated higher expression of ORF6 and ORF8 compared to nucleocapsid transcript till the eclipse period which might influence higher viral replication. The number of infectious viruses titer is higher in the B.1.1.7, despite a lesser copy number than B.1, indicating higher infectivity.

microbiology↗

bioRxiv2020

Identification of potential and novel target genes in pituitary prolactinoma by bioinformatics analysis

Pituitary prolactinoma is one of the most complicated and fatally pathogenic pituitary adenomas. Therefore, there is an urgent need to improve our understanding of the underlying molecular mechanism that drives the initiation, progression, and metastasis of pituitary prolactinoma. The aim of the present study was to identify the key genes and signaling pathways associated with pituitary prolactinoma using bioinformatics analysis. Transcriptome microarray dataset GSE119063 was acquired from Gene Expression Omnibus datasets, which included 5 pituitary prolactinoma samples and 4 normal pituitaries samples. We screened differentially expressed genes (DEGs) with limma and investigated their biological function by pathway and Gene Ontology (GO) enrichment analysis. A protein-protein interaction (PPI) network of the up and down DEGs were constructed and analyzed by HIPPIE and Cytoscape software. Module analyses were performed. In addition, a target gene - miRNA network and target gene - TF network of the up and down DEGs were constructed by NetworkAnalyst and Cytoscape software. The set of DEGs exhibited an intersection consisting of 989 genes (461 up-regulated and 528 down-regulated), which may be associated with pituitary prolactinoma. Pathway enrichment analysis showed that the 989 DEGs were significantly enriched in the retinoate biosynthesis II, signaling pathways regulating pluripotency of stem cells, ALK2 signaling events, vitamin D3 biosynthesis, cell cycle and aurora B signaling. Gene Ontology (GO) enrichment analysis also showed that sensory organ morphogenesis, extracellular matrix, hormone activity, nuclear division, condensed chromosome and microtubule binding. In the PPI network and modules, SOX2, PRSS45, CLTC, PLK1, B4GALT6, RUNX1 and GTSE1 were considered as hub genes. In the target gene miRNA network and target gene - TF network, LINC00598, SOX4, IRX1 and UNC13A were considered as hub genes. Using integrated bioinformatics analysis, we identified candidate genes in pituitary prolactinoma, which may improve our understanding of the mechanisms of the pathogenesis and integration; genes may be therapeutic targets and prognostic markers for pituitary prolactinoma.

genomics↗

bioRxiv2020

Comprehensive enhancer-target gene assignments improve gene set level interpretation of genome-wide regulatory data

Revealing the gene targets of distal regulatory elements is challenging yet critical for interpreting regulome data. Experiment-derived enhancer-gene links are restricted to a small set of enhancers and/or cell types, while the accuracy of genome-wide approaches remains elusive due to the lack of a systematic evaluation. We combined multiple spatial and in silico approaches for defining enhancer locations and linking them to their target genes aggregated across >500 cell types, generating 1,860 human genome-wide distal Enhancer to Target gene Definitions (EnTDefs). To evaluate performance, we used gene set enrichment testing on 87 independent ENCODE ChIP-seq datasets of 34 transcription factors (TFs) and assessed concordance of results with known TF Gene Ontology (GO) annotations., assuming that greater concordance with TF-GO annotation signifies better enrichment results and thus more accurate enhancer-to-gene assignments. Notably, the top ranked 741 (40%) EnTDefs significantly outperformed the common, naive approach of linking distal regions to the nearest genes (FDR < 0.05), and the top 10 ranked EnTDefs performed well when applied to ChIP-seq data of other cell types. These general EnTDefs also showed comparable performance to EnTDefs generated using cell-type-specific data. Our findings illustrate the power of our approach to provide genome-wide interpretation regardless of cell type.

bioinformatics↗