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Article ; Online: Compendium of human transcription factor effector domains.

Soto, Luis F / Li, Zhaorong / Santoso, Clarissa S / Berenson, Anna / Ho, Isabella / Shen, Vivian X / Yuan, Samson / Fuxman Bass, Juan I

Molecular cell

2021 Volume 82, Issue 3, Page(s) 514–526

Abstract: Transcription factors (TFs) regulate gene expression by binding to DNA sequences and modulating transcriptional activity through their effector domains. Despite the central role of effector domains in TF function, there is a current lack of a ... ...

Abstract	Transcription factors (TFs) regulate gene expression by binding to DNA sequences and modulating transcriptional activity through their effector domains. Despite the central role of effector domains in TF function, there is a current lack of a comprehensive resource and characterization of effector domains. Here, we provide a catalog of 924 effector domains across 594 human TFs. Using this catalog, we characterized the amino acid composition of effector domains, their conservation across species and across the human population, and their roles in human diseases. Furthermore, we provide a classification system for effector domains that constitutes a valuable resource and a blueprint for future experimental studies of TF effector domain function.
MeSH term(s)	Amino Acid Sequence ; Binding Sites ; DNA/genetics ; DNA/metabolism ; Evolution, Molecular ; Gene Expression Regulation ; Humans ; Mutation ; Protein Binding ; Protein Domains ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription, Genetic
Chemical Substances	Transcription Factors ; DNA (9007-49-2)
Language	English
Publishing date	2021-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2021.11.007
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Therapeutic Targeting of Transcription Factors to Control the Cytokine Release Syndrome in COVID-19.

Santoso, Clarissa S / Li, Zhaorong / Rottenberg, Jaice T / Liu, Xing / Shen, Vivian X / Fuxman Bass, Juan I

Frontiers in pharmacology

2021 Volume 12, Page(s) 673485

Abstract: Treatment of the cytokine release syndrome (CRS) has become an important part of rescuing hospitalized COVID-19 patients. Here, we systematically explored the transcriptional regulators of inflammatory cytokines involved in the COVID-19 CRS to identify ... ...

Abstract	Treatment of the cytokine release syndrome (CRS) has become an important part of rescuing hospitalized COVID-19 patients. Here, we systematically explored the transcriptional regulators of inflammatory cytokines involved in the COVID-19 CRS to identify candidate transcription factors (TFs) for therapeutic targeting using approved drugs. We integrated a resource of TF-cytokine gene interactions with single-cell RNA-seq expression data from bronchoalveolar lavage fluid cells of COVID-19 patients. We found 581 significantly correlated interactions, between 95 TFs and 16 cytokines upregulated in the COVID-19 patients, that may contribute to pathogenesis of the disease. Among these, we identified 19 TFs that are targets of FDA approved drugs. We investigated the potential therapeutic effect of 10 drugs and 25 drugs combinations on inflammatory cytokine production, which revealed two drugs that inhibited cytokine production and numerous combinations that show synergistic efficacy in downregulating cytokine production. Further studies of these candidate repurposable drugs could lead to a therapeutic regimen to treat the CRS in COVID-19 patients.
Language	English
Publishing date	2021-06-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2021.673485
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Compendium of human transcription factor effector domains

Soto, Luis F. / Li, Zhaorong / Santoso, Clarissa S. / Berenson, Anna / Ho, Isabella / Shen, Vivian X. / Yuan, Samson / Fuxman Bass, Juan I.

Molecular cell. 2022 Feb. 03, v. 82, no. 3

2022

Abstract	Transcription factors (TFs) regulate gene expression by binding to DNA sequences and modulating transcriptional activity through their effector domains. Despite the central role of effector domains in TF function, there is a current lack of a comprehensive resource and characterization of effector domains. Here, we provide a catalog of 924 effector domains across 594 human TFs. Using this catalog, we characterized the amino acid composition of effector domains, their conservation across species and across the human population, and their roles in human diseases. Furthermore, we provide a classification system for effector domains that constitutes a valuable resource and a blueprint for future experimental studies of TF effector domain function.
Keywords	DNA ; amino acid composition ; gene expression ; human population ; humans ; transcription (genetics) ; transcription factors
Language	English
Dates of publication	2022-0203
Size	p. 514-526.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2021.11.007
Database	NAL-Catalogue (AGRICOLA)

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Article: In vitro

Santoso, Clarissa S / Li, Zhaorong / Rottenberg, Jaice T / Liu, Xing / Shen, Vivian X / Bass, Juan I Fuxman

bioRxiv : the preprint server for biology

2020

Abstract	Treatment of the cytokine release syndrome (CRS) has become an important part of rescuing hospitalized COVID-19 patients. Here, we systematically explored the transcriptional regulators of inflammatory cytokines involved in the COVID-19 CRS to identify candidate transcription factors (TFs) for therapeutic targeting using approved drugs. We integrated a resource of TF-cytokine gene interactions with single-cell RNA-seq expression data from bronchoalveolar lavage fluid cells of COVID-19 patients. We found 581 significantly correlated interactions, between 95 TFs and 16 cytokines upregulated in the COVID-19 patients, that may contribute to pathogenesis of the disease. Among these, we identified 19 TFs that are targets of FDA approved drugs. We investigated the potential therapeutic effect of 10 drugs and 25 drug combinations on inflammatory cytokine production in peripheral blood mononuclear cells, which revealed two drugs that inhibited cytokine production and numerous combinations that show synergistic efficacy in downregulating cytokine production. Further studies of these candidate repurposable drugs could lead to a therapeutic regimen to treat the CRS in COVID-19 patients.
Language	English
Publishing date	2020-12-30
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.12.29.424728
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The ABC Transporter

Santoso, Clarissa S / Meehan, Tracy L / Peterson, Jeanne S / Cedano, Tiara M / Turlo, Christopher V / McCall, Kimberly

G3 (Bethesda, Md.)

2018 Volume 8, Issue 3, Page(s) 833–843

Abstract: The clearance of dead cells is a fundamental process in the maintenance of tissue homeostasis. Genetic studies ... ...

Abstract	The clearance of dead cells is a fundamental process in the maintenance of tissue homeostasis. Genetic studies in
MeSH term(s)	ATP Binding Cassette Transporter 1/chemistry ; ATP Binding Cassette Transporter 1/genetics ; ATP Binding Cassette Transporter 1/metabolism ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/metabolism ; Amino Acid Sequence ; Animals ; Animals, Genetically Modified ; Apoptosis/genetics ; Drosophila melanogaster/chemistry ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Female ; Genotype ; Mutation ; Ovarian Follicle/cytology ; Ovarian Follicle/metabolism ; Ovary/cytology ; Ovary/metabolism ; Phenotype
Chemical Substances	ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters
Language	English
Publishing date	2018-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2629978-1
ISSN	2160-1836 ; 2160-1836
ISSN (online)	2160-1836
ISSN	2160-1836
DOI	10.1534/g3.117.300427
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Enhanced Yeast One-hybrid Screens To Identify Transcription Factor Binding To Human DNA Sequences.

Shrestha, Shaleen / Liu, Xing / Santoso, Clarissa Stephanie / Fuxman Bass, Juan Ignacio

Journal of visualized experiments : JoVE

2019 , Issue 144

Abstract: Identifying the sets of transcription factors (TFs) that regulate each human gene is a daunting task that requires integrating numerous experimental and computational approaches. One such method is the yeast one-hybrid (Y1H) assay, in which interactions ... ...

Abstract	Identifying the sets of transcription factors (TFs) that regulate each human gene is a daunting task that requires integrating numerous experimental and computational approaches. One such method is the yeast one-hybrid (Y1H) assay, in which interactions between TFs and DNA regions are tested in the milieu of the yeast nucleus using reporter genes. Y1H assays involve two components: a 'DNA-bait' (e.g., promoters, enhancers, silencers, etc.) and a 'TF-prey,' which can be screened for reporter gene activation. Most published protocols for performing Y1H screens are based on transforming TF-prey libraries or arrays into DNA-bait yeast strains. Here, we describe a pipeline, called enhanced Y1H (eY1H) assays, where TF-DNA interactions are interrogated by mating DNA-bait strains with an arrayed collection of TF-prey strains using a high density array (HDA) robotic platform that allows screening in a 1,536 colony format. This allows for a dramatic increase in throughput (60 DNA-bait sequences against >1,000 TFs takes two weeks per researcher) and reproducibility. We illustrate the different types of expected results by testing human promoter sequences against an array of 1,086 human TFs, as well as examples of issues that can arise during screens and how to troubleshoot them.
MeSH term(s)	Base Sequence/genetics ; Humans ; Transcription Factors/genetics ; Two-Hybrid System Techniques/standards
Chemical Substances	Transcription Factors
Language	English
Publishing date	2019-02-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/59192
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Comprehensive mapping of the human cytokine gene regulatory network.

Santoso, Clarissa S / Li, Zhaorong / Lal, Sneha / Yuan, Samson / Gan, Kok Ann / Agosto, Luis M / Liu, Xing / Pro, Sebastian Carrasco / Sewell, Jared A / Henderson, Andrew / Atianand, Maninjay K / Fuxman Bass, Juan I

Nucleic acids research

2020 Volume 48, Issue 21, Page(s) 12055–12073

Abstract: Proper cytokine gene expression is essential in development, homeostasis and immune responses. Studies on the transcriptional control of cytokine genes have mostly focused on highly researched transcription factors (TFs) and cytokines, resulting in an ... ...

Abstract	Proper cytokine gene expression is essential in development, homeostasis and immune responses. Studies on the transcriptional control of cytokine genes have mostly focused on highly researched transcription factors (TFs) and cytokines, resulting in an incomplete portrait of cytokine gene regulation. Here, we used enhanced yeast one-hybrid (eY1H) assays to derive a comprehensive network comprising 1380 interactions between 265 TFs and 108 cytokine gene promoters. Our eY1H-derived network greatly expands the known repertoire of TF-cytokine gene interactions and the set of TFs known to regulate cytokine genes. We found an enrichment of nuclear receptors and confirmed their role in cytokine regulation in primary macrophages. Additionally, we used the eY1H-derived network as a framework to identify pairs of TFs that can be targeted with commercially-available drugs to synergistically modulate cytokine production. Finally, we integrated the eY1H data with single cell RNA-seq and phenotypic datasets to identify novel TF-cytokine regulatory axes in immune diseases and immune cell lineage development. Overall, the eY1H data provides a rich resource to study cytokine regulation in a variety of physiological and disease contexts.
MeSH term(s)	Cell Lineage/genetics ; Cell Lineage/immunology ; Cytokines/classification ; Cytokines/genetics ; Cytokines/immunology ; Datasets as Topic ; Dendritic Cells/cytology ; Dendritic Cells/immunology ; Gene Expression Profiling ; Gene Expression Regulation ; Gene Ontology ; Gene Regulatory Networks/immunology ; HEK293 Cells ; High-Throughput Nucleotide Sequencing ; Humans ; Lymphocytes/classification ; Lymphocytes/cytology ; Lymphocytes/immunology ; Macrophages/cytology ; Macrophages/immunology ; Molecular Sequence Annotation ; Monocytes/cytology ; Monocytes/immunology ; Primary Cell Culture ; Promoter Regions, Genetic ; Protein Binding ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/immunology ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Single-Cell Analysis ; THP-1 Cells ; Transcription Factors/classification ; Transcription Factors/genetics ; Transcription Factors/immunology ; Transcription, Genetic ; Two-Hybrid System Techniques
Chemical Substances	Cytokines ; Receptors, Cytoplasmic and Nuclear ; Transcription Factors
Language	English
Publishing date	2020-11-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkaa1055
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: In vitro Targeting of Transcription Factors to Control the Cytokine Release Syndrome in COVID-19

Santoso, Clarissa S / Li, Zhaorong / Rottenberg, Jaice T / Liu, Xing / Shen, Vivian X / Fuxman Bass, Juan I

bioRxiv

Abstract	Treatment of the cytokine release syndrome (CRS) has become an important part of rescuing hospitalized COVID-19 patients. Here, we systematically explored the transcriptional regulators of inflammatory cytokines involved in the COVID-19 CRS to identify candidate transcription factors (TFs) for therapeutic targeting using approved drugs. We integrated a resource of TF-cytokine gene interactions with single-cell RNA-seq expression data from bronchoalveolar lavage fluid cells of COVID-19 patients. We found 581 significantly correlated interactions, between 95 TFs and 16 cytokines upregulated in the COVID-19 patients, that may contribute to pathogenesis of the disease. Among these, we identified 19 TFs that are targets of FDA approved drugs. We investigated the potential therapeutic effect of 10 drugs and 25 drug combinations on inflammatory cytokine production in peripheral blood mononuclear cells, which revealed two drugs that inhibited cytokine production and numerous combinations that show synergistic efficacy in downregulating cytokine production. Further studies of these candidate repurposable drugs could lead to a therapeutic regimen to treat the CRS in COVID-19 patients.
Keywords	covid19
Language	English
Publishing date	2020-12-30
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.12.29.424728
Database	COVID19

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Article ; Online: Paired yeast one-hybrid assays to detect DNA-binding cooperativity and antagonism across transcription factors.

Berenson, Anna / Lane, Ryan / Soto-Ugaldi, Luis F / Patel, Mahir / Ciausu, Cosmin / Li, Zhaorong / Chen, Yilin / Shah, Sakshi / Santoso, Clarissa / Liu, Xing / Spirohn, Kerstin / Hao, Tong / Hill, David E / Vidal, Marc / Fuxman Bass, Juan I

Nature communications

2023 Volume 14, Issue 1, Page(s) 6570

Abstract: Cooperativity and antagonism between transcription factors (TFs) can drastically modify their binding to regulatory DNA elements. While mapping these relationships between TFs is important for understanding their context-specific functions, existing ... ...

Abstract	Cooperativity and antagonism between transcription factors (TFs) can drastically modify their binding to regulatory DNA elements. While mapping these relationships between TFs is important for understanding their context-specific functions, existing approaches either rely on DNA binding motif predictions, interrogate one TF at a time, or study individual TFs in parallel. Here, we introduce paired yeast one-hybrid (pY1H) assays to detect cooperativity and antagonism across hundreds of TF-pairs at DNA regions of interest. We provide evidence that a wide variety of TFs are subject to modulation by other TFs in a DNA region-specific manner. We also demonstrate that TF-TF relationships are often affected by alternative isoform usage and identify cooperativity and antagonism between human TFs and viral proteins from human papillomaviruses, Epstein-Barr virus, and other viruses. Altogether, pY1H assays provide a broadly applicable framework to study how different functional relationships affect protein occupancy at regulatory DNA regions.
MeSH term(s)	Humans ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Epstein-Barr Virus Infections ; Protein Binding ; Herpesvirus 4, Human/genetics ; Herpesvirus 4, Human/metabolism ; DNA/metabolism ; Binding Sites
Chemical Substances	Transcription Factors ; DNA (9007-49-2)
Language	English
Publishing date	2023-10-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-42445-6
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Enhanced yeast one-hybrid screens to identify transcription factor binding to human dna sequences

Shrestha, Shaleen / Liu, Xing / Santoso, Clarissa Stephanie / Fuxman Bass, Juan Ignacio

Journal of visualized experiments. 2019 Feb. 11, , no. 144

2019

Abstract	Identifying the sets of transcription factors (TFs) that regulate each human gene is a daunting task that requires integrating numerous experimental and computational approaches. One such method is the yeast one-hybrid (Y1H) assay, in which interactions between TFs and DNA regions are tested in the milieu of the yeast nucleus using reporter genes. Y1H assays involve two components: a ‘DNA-bait’ (e.g., promoters, enhancers, silencers, etc.) and a ‘TF-prey,’ which can be screened for reporter gene activation. Most published protocols for performing Y1H screens are based on transforming TF-prey libraries or arrays into DNA-bait yeast strains. Here, we describe a pipeline, called enhanced Y1H (eY1H) assays, where TF-DNA interactions are interrogated by mating DNA-bait strains with an arrayed collection of TF-prey strains using a high density array (HDA) robotic platform that allows screening in a 1,536 colony format. This allows for a dramatic increase in throughput (60 DNA-bait sequences against >1,000 TFs takes two weeks per researcher) and reproducibility. We illustrate the different types of expected results by testing human promoter sequences against an array of 1,086 human TFs, as well as examples of issues that can arise during screens and how to troubleshoot them.
Keywords	DNA ; gene activation ; humans ; promoter regions ; reporter genes ; robots ; screening ; transcription factors ; yeasts
Language	English
Dates of publication	2019-0211
Size	p. e59192.
Publishing place	Journal of Visualized Experiments
Document type	Article
ZDB-ID	2259946-0
ISSN	1940-087X
ISSN	1940-087X
DOI	10.3791/59192
Database	NAL-Catalogue (AGRICOLA)

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