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Article: Towards a Synthesis of the Non-Genetic and Genetic Views of Cancer in Understanding Pancreatic Ductal Adenocarcinoma Initiation and Prevention.

Gopalan, Vishaka / Hannenhalli, Sridhar

2023 Volume 15, Issue 7

Abstract: While much of the research in oncogenesis and cancer therapy has focused on mutations in key cancer driver genes, more recent work suggests a complementary non-genetic paradigm. This paradigm focuses on how transcriptional and phenotypic heterogeneity, ... ...

Abstract	While much of the research in oncogenesis and cancer therapy has focused on mutations in key cancer driver genes, more recent work suggests a complementary non-genetic paradigm. This paradigm focuses on how transcriptional and phenotypic heterogeneity, even in clonally derived cells, can create sub-populations associated with oncogenesis, metastasis, and therapy resistance. We discuss this complementary paradigm in the context of pancreatic ductal adenocarcinoma. A better understanding of cellular transcriptional heterogeneity and its association with oncogenesis can lead to more effective therapies that prevent tumor initiation and slow progression.
Language	English
Publishing date	2023-04-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15072159
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Predicting gene expression changes upon epigenomic drug treatment.

Agrawal, Piyush / Gopalan, Vishaka / Hannenhalli, Sridhar

bioRxiv : the preprint server for biology

2023

Abstract: Background: Tumors are characterized by global changes in epigenetic changes such as DNA methylation and histone modifications that are functionally linked to tumor progression. Accordingly, several drugs targeting the epigenome have been proposed for ... ...

Abstract	Background: Tumors are characterized by global changes in epigenetic changes such as DNA methylation and histone modifications that are functionally linked to tumor progression. Accordingly, several drugs targeting the epigenome have been proposed for cancer therapy, notably, histone deacetylase inhibitors (HDACi) such as Methods: Given the pre-treatment transcriptome and epigenomic profile of a sample, we assessed the extent of predictability of locus-specific changes in gene expression upon treatment with HDACi using machine learning. Results: We found that in two cell lines (HCT116 treated with Largazole at 8 doses and RH4 treated with Entinostat at 1μM) where the appropriate data (pre-treatment transcriptome and epigenome as well as post-treatment transcriptome) is available, our model distinguished the post-treatment up versus downregulated genes with high accuracy (up to ROC of 0.89). Furthermore, a model trained on one cell line is applicable to another cell line suggesting generalizability of the model. Conclusions: Here we present a first assessment of the predictability of genome-wide transcriptomic changes upon treatment with HDACi. Lack of appropriate omics data from clinical trials of epigenetic drugs currently hampers the assessment of applicability of our approach in clinical setting.
Language	English
Publishing date	2023-07-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.07.20.549955
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Article ; Online: De novo human brain enhancers created by single-nucleotide mutations.

Li, Shan / Hannenhalli, Sridhar / Ovcharenko, Ivan

Science advances

2023 Volume 9, Issue 7, Page(s) eadd2911

Abstract: Advanced human cognition is attributed to increased neocortex size and complexity, but the underlying evolutionary and regulatory mechanisms are largely unknown. Using human and macaque embryonic neocortical H3K27ac data coupled with a deep learning ... ...

Abstract	Advanced human cognition is attributed to increased neocortex size and complexity, but the underlying evolutionary and regulatory mechanisms are largely unknown. Using human and macaque embryonic neocortical H3K27ac data coupled with a deep learning model of enhancers, we identified ~4000 enhancer gains in humans, which, per our model, can often be attributed to single-nucleotide essential mutations. Our analyses suggest that functional gains in embryonic brain development are associated with de novo enhancers whose putative target genes exhibit increased expression in progenitor cells and interneurons and partake in critical neural developmental processes. Essential mutations alter enhancer activity through altered binding of key transcription factors (TFs) of embryonic neocortex, including ISL1, POU3F2, PITX1/2, and several SOX TFs, and are associated with central nervous system disorders. Overall, our results suggest that essential mutations lead to gain of embryonic neocortex enhancers, which orchestrate expression of genes involved in critical developmental processes associated with human cognition.
MeSH term(s)	Humans ; Enhancer Elements, Genetic ; Nucleotides ; Transcription Factors/genetics ; Brain ; Mutation ; Gene Expression Regulation, Developmental
Chemical Substances	Nucleotides ; Transcription Factors
Language	English
Publishing date	2023-02-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.add2911
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Article: Transcription factors organize into functional groups on the linear genome and in 3D chromatin.

Vadnala, Rakesh Netha / Hannenhalli, Sridhar / Narlikar, Leelavati / Siddharthan, Rahul

Heliyon

2023 Volume 9, Issue 8, Page(s) e18211

Abstract: Transcription factors (TFs) and their binding sites have evolved to interact cooperatively or competitively with each other. Here we examine in detail, across multiple cell lines, such cooperation or competition among TFs both in sequential and spatial ... ...

Abstract	Transcription factors (TFs) and their binding sites have evolved to interact cooperatively or competitively with each other. Here we examine in detail, across multiple cell lines, such cooperation or competition among TFs both in sequential and spatial proximity (using chromatin conformation capture assays), considering in vivo binding data as well as TF binding motifs in DNA. We ascertain significantly co-occurring ("attractive") or avoiding ("repulsive") TF pairs using robust randomized models that retain the essential characteristics of the experimental data. Across human cell lines TFs organize into two groups, with intra-group attraction and inter-group repulsion. This is true for both sequential and spatial proximity, and for both in vivo binding and sequence motifs. Attractive TF pairs exhibit significantly more physical interactions suggesting an underlying mechanism. The two TF groups differ significantly in their genomic and network properties, as well in their function-while one group regulates housekeeping function, the other potentially regulates lineage-specific functions, that are disrupted in cancer. Weaker binding sites tend to occur in spatially interacting regions of the genome. Our results suggest that a complex pattern of spatial cooperativity of TFs and chromatin has evolved with the genome to support housekeeping and lineage-specific functions.
Language	English
Publishing date	2023-07-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2023.e18211
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Article ; Online: miRSCAPE - inferring miRNA expression from scRNA-seq data.

Olgun, Gulden / Gopalan, Vishaka / Hannenhalli, Sridhar

iScience

2022 Volume 25, Issue 9, Page(s) 104962

Abstract: Our understanding of miRNA activity at cellular resolution is thwarted by the inability of standard scRNA-seq protocols to capture miRNAs. We introduce a novel tool, miRSCAPE, to infer miRNA expression in a sample from its RNA-seq profile. We establish ... ...

Abstract	Our understanding of miRNA activity at cellular resolution is thwarted by the inability of standard scRNA-seq protocols to capture miRNAs. We introduce a novel tool, miRSCAPE, to infer miRNA expression in a sample from its RNA-seq profile. We establish miRSCAPE's accuracy in 10 tumor and normal cohorts demonstrating its superiority over alternatives. miRSCAPE accurately infers cell type-specific miRNA activities (predicted versus observed fold-difference correlation ∼0.81) in two independent scRNA-seq datasets. We apply miRSCAPE to infer miRNA activities in scRNA clusters in pancreatic and lung adenocarcinomas, as well as in 56 cell types in the human cell landscape (HCL). In pancreatic and breast cancer scRNA-seq data, miRSCAPE recapitulates miRNAs associated with stemness and epithelial-mesenchymal transition (EMT) cell states, respectively. Overall, miRSCAPE recapitulates and refines miRNA biology at cellular resolution. miRSCAPE is freely available and is easily applicable to scRNA-seq data to infer miRNA activities at cellular resolution.
Language	English
Publishing date	2022-08-17
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2022.104962
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Article: A path-based analysis of infected cell line and COVID-19 patient transcriptome reveals novel potential targets and drugs against SARS-CoV-2.

Agrawal, Piyush / Sambaturu, Narmada / Olgun, Gulden / Hannenhalli, Sridhar

Research square

2022

Abstract: Most transcriptomic studies of SARS-CoV-2 infection have focused on differentially expressed genes, which do not necessarily reveal the genes mediating the transcriptomic changes. In contrast, exploiting curated biological network, our PathExt tool ... ...

Abstract	Most transcriptomic studies of SARS-CoV-2 infection have focused on differentially expressed genes, which do not necessarily reveal the genes mediating the transcriptomic changes. In contrast, exploiting curated biological network, our PathExt tool identifies central genes from the differentially active paths mediating global transcriptomic response. Here we apply PathExt to multiple cell line infection models of SARS-CoV-2 and other viruses, as well as to COVID-19 patient-derived PBMCs. The central genes mediating SARS-CoV-2 response in cell lines were uniquely enriched for ATP metabolic process, G1/S transition, leukocyte activation and migration. In contrast, PBMC response reveals dysregulated cell-cycle processes. In PBMC, the most frequently central genes are associated with COVID-19 severity. Importantly, relative to differential genes, PathExt-identified genes show greater concordance with several benchmark anti-COVID-19 target gene sets. We propose six novel anti-SARS-CoV-2 targets ADCY2, ADSL, OCRL, TIAM1, PBK, and BUB1, and potential drugs targeting these genes, such as Bemcentinib, Phthalocyanine, and Conivaptan.
Language	English
Publishing date	2022-03-21
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-1474136/v1
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Article ; Online: A Path-Based Analysis of Infected Cell Line and COVID-19 Patient Transcriptome Reveals Novel Potential Targets and Drugs Against SARS-CoV-2.

Agrawal, Piyush / Sambaturu, Narmada / Olgun, Gulden / Hannenhalli, Sridhar

Frontiers in immunology

2022 Volume 13, Page(s) 918817

Abstract	Most transcriptomic studies of SARS-CoV-2 infection have focused on differentially expressed genes, which do not necessarily reveal the genes mediating the transcriptomic changes. In contrast, exploiting curated biological network, our PathExt tool identifies central genes from the differentially active paths mediating global transcriptomic response. Here we apply PathExt to multiple cell line infection models of SARS-CoV-2 and other viruses, as well as to COVID-19 patient-derived PBMCs. The central genes mediating SARS-CoV-2 response in cell lines were uniquely enriched for ATP metabolic process, G1/S transition, leukocyte activation and migration. In contrast, PBMC response reveals dysregulated cell-cycle processes. In PBMC, the most frequently central genes are associated with COVID-19 severity. Importantly, relative to differential genes, PathExt-identified genes show greater concordance with several benchmark anti-COVID-19 target gene sets. We propose six novel anti-SARS-CoV-2 targets ADCY2, ADSL, OCRL, TIAM1, PBK, and BUB1, and potential drugs targeting these genes, such as Bemcentinib, Phthalocyanine, and Conivaptan.
MeSH term(s)	COVID-19/genetics ; Cell Line ; Humans ; Leukocytes, Mononuclear ; SARS-CoV-2 ; Transcriptome ; COVID-19 Drug Treatment
Language	English
Publishing date	2022-07-01
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.918817
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Article ; Online: Network-based approach elucidates critical genes in BRCA subtypes and chemotherapy response in triple negative breast cancer.

Agrawal, Piyush / Jain, Navami / Gopalan, Vishaka / Timon, Annan / Singh, Arashdeep / Rajagopal, Padma S / Hannenhalli, Sridhar

iScience

2024 Volume 27, Issue 5, Page(s) 109752

Abstract: Breast cancers (BRCA) exhibit substantial transcriptional heterogeneity, posing a significant clinical challenge. The global transcriptional changes in a disease context, however, are likely mediated by few key genes which reflect disease etiology better ...

Abstract	Breast cancers (BRCA) exhibit substantial transcriptional heterogeneity, posing a significant clinical challenge. The global transcriptional changes in a disease context, however, are likely mediated by few key genes which reflect disease etiology better than the differentially expressed genes (DEGs). We apply our network-based tool PathExt to 1,059 BRCA tumors across 4 subtypes to identify key mediator genes in each subtype. Compared to conventional differential expression analysis, PathExt-identified genes exhibit greater concordance across tumors, revealing shared and subtype-specific biological processes; better recapitulate BRCA-associated genes in multiple benchmarks, and are more essential in BRCA subtype-specific cell lines. Single-cell transcriptomic analysis reveals a subtype-specific distribution of PathExt-identified genes in multiple cell types from the tumor microenvironment. Application of PathExt to a TNBC chemotherapy response dataset identified subtype-specific key genes and biological processes associated with resistance. We described putative drugs that target key genes potentially mediating drug resistance.
Language	English
Publishing date	2024-04-16
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2024.109752
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Article ; Online: Protocol for using single-cell sequencing to study the heterogeneity of NF1 nerve sheath tumors from clinical biospecimens.

Zhang, Xiyuan / Gopalan, Vishaka / Syed, Neeraja / Hannenhalli, Sridhar / Shern, Jack F

STAR protocols

2023 Volume 4, Issue 2, Page(s) 102297

Abstract: Single-cell sequencing is a powerful technology to understand the heterogeneity of clinical biospecimens. Here, we present a protocol for obtaining single-cell suspension from neurofibromatosis type 1-associated nerve sheath tumors for transcriptomic ... ...

Abstract	Single-cell sequencing is a powerful technology to understand the heterogeneity of clinical biospecimens. Here, we present a protocol for obtaining single-cell suspension from neurofibromatosis type 1-associated nerve sheath tumors for transcriptomic profiling on the 10x platform. We describe steps for clinical sample collection, generation of single-cell suspension, and cell capture and sequencing. We then detail methods for integrative analysis, developmental Schwann cell trajectory building using bioinformatic tools, and comparative analysis. This protocol can be adapted for single-cell sequencing using mouse nerve tumors. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2022).
Language	English
Publishing date	2023-05-10
Publishing country	United States
Document type	Journal Article
ISSN	2666-1667
ISSN (online)	2666-1667
DOI	10.1016/j.xpro.2023.102297
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Article ; Online: Transcription factors organize into functional groups on the linear genome and in 3D chromatin

Rakesh Netha Vadnala / Sridhar Hannenhalli / Leelavati Narlikar / Rahul Siddharthan

Heliyon, Vol 9, Iss 8, Pp e18211- (2023)

2023

Abstract	Transcription factors (TFs) and their binding sites have evolved to interact cooperatively or competitively with each other. Here we examine in detail, across multiple cell lines, such cooperation or competition among TFs both in sequential and spatial proximity (using chromatin conformation capture assays), considering in vivo binding data as well as TF binding motifs in DNA. We ascertain significantly co-occurring (“attractive”) or avoiding (“repulsive”) TF pairs using robust randomized models that retain the essential characteristics of the experimental data. Across human cell lines TFs organize into two groups, with intra-group attraction and inter-group repulsion. This is true for both sequential and spatial proximity, and for both in vivo binding and sequence motifs. Attractive TF pairs exhibit significantly more physical interactions suggesting an underlying mechanism. The two TF groups differ significantly in their genomic and network properties, as well in their function—while one group regulates housekeeping function, the other potentially regulates lineage-specific functions, that are disrupted in cancer. Weaker binding sites tend to occur in spatially interacting regions of the genome. Our results suggest that a complex pattern of spatial cooperativity of TFs and chromatin has evolved with the genome to support housekeeping and lineage-specific functions.
Keywords	Chromatin ; Transcription factors ; Science (General) ; Q1-390 ; Social sciences (General) ; H1-99
Subject code	571
Language	English
Publishing date	2023-08-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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