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Artikel ; Online: No Dataset Left Behind: Mechanistic Insights into Thyroid Receptor Signaling Through Transcriptomic Consensome Meta-Analysis.

Ochsner, Scott A / McKenna, Neil J

Thyroid : official journal of the American Thyroid Association

2020 Band 30, Heft 4, Seite(n) 621–639

Abstract: Background: ...

Abstract	Background:
Mesh-Begriff(e)	Computational Biology ; Gene Expression Profiling ; Humans ; Liver/metabolism ; Receptors, Thyroid Hormone/metabolism ; Signal Transduction/physiology ; Thyroid Gland/metabolism ; Thyroid Hormones/metabolism ; Transcriptome
Chemische Substanzen	Receptors, Thyroid Hormone ; Thyroid Hormones
Sprache	Englisch
Erscheinungsdatum	2020-01-29
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1086044-7
ISSN	1557-9077 ; 1050-7256
ISSN (online)	1557-9077
ISSN	1050-7256
DOI	10.1089/thy.2019.0307
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Research Resources for Nuclear Receptor Signaling Pathways.

McKenna, Neil J

Molecular pharmacology

2016 Band 90, Heft 2, Seite(n) 153–159

Abstract: Nuclear receptor (NR) signaling pathways impact cellular function in a broad variety of tissues in both normal physiology and disease states. The complex tissue-specific biology of these pathways is an enduring impediment to the development of clinical ... ...

Abstract	Nuclear receptor (NR) signaling pathways impact cellular function in a broad variety of tissues in both normal physiology and disease states. The complex tissue-specific biology of these pathways is an enduring impediment to the development of clinical NR small-molecule modulators that combine therapeutically desirable effects in specific target tissues with suppression of off-target effects in other tissues. Supporting the important primary research in this area is a variety of web-based resources that assist researchers in gaining an appreciation of the molecular determinants of the pharmacology of a NR pathway in a given tissue. In this study, selected representative examples of these tools are reviewed, along with discussions on how current and future generations of tools might optimally adapt to the future of NR signaling research.
Mesh-Begriff(e)	Biomedical Research ; Genomics ; Humans ; Ligands ; Models, Biological ; Receptors, Cytoplasmic and Nuclear/metabolism ; Signal Transduction
Chemische Substanzen	Ligands ; Receptors, Cytoplasmic and Nuclear
Sprache	Englisch
Erscheinungsdatum	2016-08
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Review
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
DOI	10.1124/mol.116.103713
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Transcriptional regulatory networks of circulating immune cells in type 1 diabetes: A community knowledgebase.

Ochsner, Scott A / Pillich, Rudolf T / Rawool, Deepali / Grethe, Jeffrey S / McKenna, Neil J

iScience

2022 Band 25, Heft 7, Seite(n) 104581

Abstract: Investigator-generated transcriptomic datasets interrogating circulating immune cell (CIC) gene expression in clinical type 1 diabetes (T1D) have underappreciated re-use value. Here, we repurposed these datasets to create an open science environment for ... ...

Abstract	Investigator-generated transcriptomic datasets interrogating circulating immune cell (CIC) gene expression in clinical type 1 diabetes (T1D) have underappreciated re-use value. Here, we repurposed these datasets to create an open science environment for the generation of hypotheses around CIC signaling pathways whose gain or loss of function contributes to T1D pathogenesis. We firstly computed sets of genes that were preferentially induced or repressed in T1D CICs and validated these against community benchmarks. We then inferred and validated signaling node networks regulating expression of these gene sets, as well as differentially expressed genes in the original underlying T1D case:control datasets. In a set of three use cases, we demonstrated how informed integration of these networks with complementary digital resources supports substantive, actionable hypotheses around signaling pathway dysfunction in T1D CICs. Finally, we developed a federated, cloud-based web resource that exposes the entire data matrix for unrestricted access and re-use by the research community.
Sprache	Englisch
Erscheinungsdatum	2022-06-11
Erscheinungsland	United States
Dokumenttyp	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2022.104581
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: A transcriptional regulatory atlas of coronavirus infection of human cells

Scott A Ochsner / Neil J McKenna

Abstract: AbstractIdentifying transcriptional responses that are most consistently associated with experimental coronavirus (CoV) infection can help illuminate human cellular signaling pathways impacted by CoV infection. Here, we distilled over 3,000,000 data ... ...

Abstract	AbstractIdentifying transcriptional responses that are most consistently associated with experimental coronavirus (CoV) infection can help illuminate human cellular signaling pathways impacted by CoV infection. Here, we distilled over 3,000,000 data points from publically archived CoV infection transcriptomic datasets into consensus regulatory signatures, or consensomes, that rank genes based on their transcriptional responsiveness to infection of human cells by MERS, SARS-CoV-1 and SARS-CoV-2 subtypes. We computed overlap between genes with elevated rankings in the CoV consensomes against those from transcriptomic and ChIP-Seq consensomes for nearly 880 cellular signaling pathway nodes. Validating the CoV infection consensomes, we identified robust overlap between their highly ranked genes and high confidence targets of signaling pathway nodes with known roles in CoV infection. We then developed a series of use cases that illustrate the utility of the CoV consensomes for hypothesis generation around mechanistic aspects of the cellular response to CoV infection. We make the CoV infection consensomes and their universe of underlying data points freely accessible through the Signaling Pathways Project web knowledgebase.
Schlagwörter	covid19
Verlag	biorxiv
Dokumenttyp	Artikel ; Online
DOI	10.1101/2020.04.24.059527
Datenquelle	COVID19

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Artikel ; Online: Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress.

Taylor, Bethany C / Steinthal, Loic H / Dias, Michelle / Yalamanchili, Hari Krishna / Ochsner, Scott A / Zapata, Gladys E / Mehta, Nitesh R / McKenna, Neil J / Young, Nicolas L / Nuotio-Antar, Alli M

Epigenetics & chromatin

2024 Band 17, Heft 1, Seite(n) 12

Abstract: Background: Regulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Our preliminary analyses of RNA-Seq data uncovered many nodes ... ...

Abstract	Background: Regulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Our preliminary analyses of RNA-Seq data uncovered many nodes representing epigenetic modifiers that are altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic thermogenic activation broadly alters epigenetic modifications of DNA and histones in BAT. Results: Motivated to understand how BAT function is regulated epigenetically, we developed a novel method for the first-ever unbiased top-down proteomic quantitation of histone modifications in BAT and validated our results with a multi-omic approach. To test our hypothesis, wildtype male C57BL/6J mice were housed under chronic conditions of thermoneutral temperature (TN, 28°C), mild cold/room temperature (RT, 22°C), or severe cold (SC, 8°C) and BAT was analyzed for DNA methylation and histone modifications. Methylation of promoters and intragenic regions in genomic DNA decrease in response to chronic cold exposure. Integration of DNA methylation and RNA expression datasets suggest a role for epigenetic modification of DNA in regulation of gene expression in response to cold. In response to cold housing, we observe increased bulk acetylation of histones H3.2 and H4, increased histone H3.2 proteoforms with di- and trimethylation of lysine 9 (K9me2 and K9me3), and increased histone H4 proteoforms with acetylation of lysine 16 (K16ac) in BAT. Conclusions: Our results reveal global epigenetically-regulated transcriptional "on" and "off" signals in murine BAT in response to varying degrees of chronic cold stimuli and establish a novel methodology to quantitatively study histones in BAT, allowing for direct comparisons to decipher mechanistic changes during the thermogenic response. Additionally, we make histone PTM and proteoform quantitation, RNA splicing, RRBS, and transcriptional footprint datasets available as a resource for future research.
Mesh-Begriff(e)	Animals ; Adipose Tissue, Brown/metabolism ; Mice ; Epigenesis, Genetic ; Male ; Histones/metabolism ; Cold-Shock Response ; Mice, Inbred C57BL ; DNA Methylation ; Histone Code ; Thermogenesis ; Cold Temperature
Chemische Substanzen	Histones
Sprache	Englisch
Erscheinungsdatum	2024-04-27
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2462129-8
ISSN	1756-8935 ; 1756-8935
ISSN (online)	1756-8935
ISSN	1756-8935
DOI	10.1186/s13072-024-00536-8
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress.

Taylor, Bethany C / Steinthal, Loic H / Dias, Michelle / Yalamanchili, Hari K / Ochsner, Scott A / Zapata, Gladys E / Mehta, Nitesh R / McKenna, Neil J / Young, Nicolas L / Nuotio-Antar, Alli M

bioRxiv : the preprint server for biology

2024

Abstract: Regulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Our preliminary analyses uncovered many nodes representing epigenetic ... ...

Abstract	Regulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Our preliminary analyses uncovered many nodes representing epigenetic modifiers that are altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic thermogenic activation broadly alters epigenetic modifications of DNA and histones in BAT. Motivated to understand how BAT function is regulated epigenetically, we developed a novel method for the first-ever unbiased top-down proteomic quantitation of histone modifications in BAT and validated our results with a multi-omic approach. To test our hypothesis, wildtype male C57BL/6J mice were housed under chronic conditions of thermoneutral temperature (TN, 28.8°C), mild cold/room temperature (RT, 22°C), or severe cold (SC, 8°C) and BAT was analyzed for DNA methylation and histone modifications. Methylation of promoters and intragenic regions in genomic DNA decrease in response to chronic cold exposure. Integration of DNA methylation and RNA expression data suggest a role for epigenetic modification of DNA in gene regulation in response to cold. In response to cold housing, we observe increased bulk acetylation of histones H3.2 and H4, increased histone H3.2 proteoforms with di- and trimethylation of lysine 9 (K9me2 and K9me3), and increased histone H4 proteoforms with acetylation of lysine 16 (K16ac) in BAT. Taken together, our results reveal global epigenetically-regulated transcriptional "on" and "off" signals in murine BAT in response to varying degrees of chronic cold stimuli and establish a novel methodology to quantitatively study histones in BAT, allowing for direct comparisons to decipher mechanistic changes during the thermogenic response. Additionally, we make histone PTM and proteoform quantitation, RNA splicing, RRBS, and transcriptional footprint datasets available as a resource for future research.
Sprache	Englisch
Erscheinungsdatum	2024-01-22
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2023.07.30.551059
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Consensus transcriptional regulatory networks of coronavirus-infected human cells.

Ochsner, Scott A / Pillich, Rudolf T / McKenna, Neil J

bioRxiv : the preprint server for biology

2020

Abstract: Establishing consensus around the transcriptional interface between coronavirus (CoV) infection and human cellular signaling pathways can catalyze the development of novel anti-CoV therapeutics. Here, we used publicly archived transcriptomic datasets to ... ...

Abstract	Establishing consensus around the transcriptional interface between coronavirus (CoV) infection and human cellular signaling pathways can catalyze the development of novel anti-CoV therapeutics. Here, we used publicly archived transcriptomic datasets to compute consensus regulatory signatures, or consensomes, that rank human genes based on their rates of differential expression in MERS-CoV (MERS), SARS-CoV-1 (SARS1) and SARS-CoV-2 (SARS2)-infected cells. Validating the CoV consensomes, we show that high confidence transcriptional targets (HCTs) of CoV infection intersect with HCTs of signaling pathway nodes with known roles in CoV infection. Among a series of novel use cases, we gather evidence for hypotheses that SARS2 infection efficiently represses E2F family target genes encoding key drivers of DNA replication and the cell cycle; that progesterone receptor signaling antagonizes SARS2-induced inflammatory signaling in the airway epithelium; and that SARS2 HCTs are enriched for genes involved in epithelial to mesenchymal transition. The CoV infection consensomes and HCT intersection analyses are freely accessible through the Signaling Pathways Project knowledgebase, and as Cytoscape-style networks in the Network Data Exchange repository.
Schlagwörter	covid19
Sprache	Englisch
Erscheinungsdatum	2020-07-15
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2020.04.24.059527
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Consensus transcriptional regulatory networks of coronavirus-infected human cells.

Ochsner, Scott A / Pillich, Rudolf T / McKenna, Neil J

Scientific data

2020 Band 7, Heft 1, Seite(n) 314

Abstract	Establishing consensus around the transcriptional interface between coronavirus (CoV) infection and human cellular signaling pathways can catalyze the development of novel anti-CoV therapeutics. Here, we used publicly archived transcriptomic datasets to compute consensus regulatory signatures, or consensomes, that rank human genes based on their rates of differential expression in MERS-CoV (MERS), SARS-CoV-1 (SARS1) and SARS-CoV-2 (SARS2)-infected cells. Validating the CoV consensomes, we show that high confidence transcriptional targets (HCTs) of MERS, SARS1 and SARS2 infection intersect with HCTs of signaling pathway nodes with known roles in CoV infection. Among a series of novel use cases, we gather evidence for hypotheses that SARS2 infection efficiently represses E2F family HCTs encoding key drivers of DNA replication and the cell cycle; that progesterone receptor signaling antagonizes SARS2-induced inflammatory signaling in the airway epithelium; and that SARS2 HCTs are enriched for genes involved in epithelial to mesenchymal transition. The CoV infection consensomes and HCT intersection analyses are freely accessible through the Signaling Pathways Project knowledgebase, and as Cytoscape-style networks in the Network Data Exchange repository.
Mesh-Begriff(e)	Betacoronavirus ; COVID-19 ; Cell Cycle ; Consensus ; Coronavirus Infections/genetics ; DNA Replication ; Datasets as Topic ; Epithelial-Mesenchymal Transition/genetics ; Gene Expression ; Humans ; Interferon Regulatory Factors/genetics ; Middle East Respiratory Syndrome Coronavirus ; Pandemics ; Pneumonia, Viral/genetics ; Receptors, Progesterone ; Severe acute respiratory syndrome-related coronavirus ; SARS-CoV-2 ; Signal Transduction ; Transcriptome
Chemische Substanzen	Interferon Regulatory Factors ; Receptors, Progesterone
Schlagwörter	covid19
Sprache	Englisch
Erscheinungsdatum	2020-09-22
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2775191-0
ISSN	2052-4463 ; 2052-4463
ISSN (online)	2052-4463
ISSN	2052-4463
DOI	10.1038/s41597-020-00628-6
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Consensus transcriptional regulatory networks of coronavirus-infected human cells

Scott A. Ochsner / Rudolf T. Pillich / Neil J. McKenna

Scientific Data, Vol 7, Iss 1, Pp 1-

2020 Band 20

Abstract: Abstract Establishing consensus around the transcriptional interface between coronavirus (CoV) infection and human cellular signaling pathways can catalyze the development of novel anti-CoV therapeutics. Here, we used publicly archived transcriptomic ... ...

Abstract	Abstract Establishing consensus around the transcriptional interface between coronavirus (CoV) infection and human cellular signaling pathways can catalyze the development of novel anti-CoV therapeutics. Here, we used publicly archived transcriptomic datasets to compute consensus regulatory signatures, or consensomes, that rank human genes based on their rates of differential expression in MERS-CoV (MERS), SARS-CoV-1 (SARS1) and SARS-CoV-2 (SARS2)-infected cells. Validating the CoV consensomes, we show that high confidence transcriptional targets (HCTs) of MERS, SARS1 and SARS2 infection intersect with HCTs of signaling pathway nodes with known roles in CoV infection. Among a series of novel use cases, we gather evidence for hypotheses that SARS2 infection efficiently represses E2F family HCTs encoding key drivers of DNA replication and the cell cycle; that progesterone receptor signaling antagonizes SARS2-induced inflammatory signaling in the airway epithelium; and that SARS2 HCTs are enriched for genes involved in epithelial to mesenchymal transition. The CoV infection consensomes and HCT intersection analyses are freely accessible through the Signaling Pathways Project knowledgebase, and as Cytoscape-style networks in the Network Data Exchange repository.
Schlagwörter	Science ; Q ; covid19
Thema/Rubrik (Code)	570
Sprache	Englisch
Erscheinungsdatum	2020-09-01T00:00:00Z
Verlag	Nature Publishing Group
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel ; Online: Transcriptional regulatory networks of circulating immune cells in type 1 diabetes

Scott A. Ochsner / Rudolf T. Pillich / Deepali Rawool / Jeffrey S. Grethe / Neil J. McKenna

iScience, Vol 25, Iss 7, Pp 104581- (2022)

A community knowledgebase

2022

Abstract: Summary: Investigator-generated transcriptomic datasets interrogating circulating immune cell (CIC) gene expression in clinical type 1 diabetes (T1D) have underappreciated re-use value. Here, we repurposed these datasets to create an open science ... ...

Abstract	Summary: Investigator-generated transcriptomic datasets interrogating circulating immune cell (CIC) gene expression in clinical type 1 diabetes (T1D) have underappreciated re-use value. Here, we repurposed these datasets to create an open science environment for the generation of hypotheses around CIC signaling pathways whose gain or loss of function contributes to T1D pathogenesis. We firstly computed sets of genes that were preferentially induced or repressed in T1D CICs and validated these against community benchmarks. We then inferred and validated signaling node networks regulating expression of these gene sets, as well as differentially expressed genes in the original underlying T1D case:control datasets. In a set of three use cases, we demonstrated how informed integration of these networks with complementary digital resources supports substantive, actionable hypotheses around signaling pathway dysfunction in T1D CICs. Finally, we developed a federated, cloud-based web resource that exposes the entire data matrix for unrestricted access and re-use by the research community.
Schlagwörter	Bioinformatics ; Biological database ; Transcriptomics ; Science ; Q
Thema/Rubrik (Code)	570
Sprache	Englisch
Erscheinungsdatum	2022-07-01T00:00:00Z
Verlag	Elsevier
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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