The hedgehog co-receptor BOC differentially regulates SHH signaling during craniofacial development

ABSTRACTThe Hedgehog (HH) pathway controls multiple aspects of craniofacial development. HH ligands signal through the canonical receptor PTCH1, and three co-receptors: GAS1, CDON and BOC. Together, these co-receptors are required during embryogenesis to mediate proper HH signaling. Here, we investigated the individual and combined contributions of GAS1, CDON and BOC to HH-dependent mammalian craniofacial development. Notably, individual deletion of either Gas1 or Cdon results in variable holoprosencephaly phenotypes in mice, even on a congenic background. In contrast, we find that Boc deletion results in facial widening that correlates with increased HH target gene expression. In addition, Boc deletion in a Gas1 null background partially ameliorates the craniofacial defects observed in Gas1 single mutants; a phenotype that persists over developmental time, resulting in significant improvements to a subset of craniofacial structures. This contrasts with HH-dependent phenotypes in other tissues that significantly worsen following combined deletion of Gas1 and Boc. Together, these data indicate that BOC acts as a multi-functional regulator of HH signaling during craniofacial development, alternately promoting or restraining HH pathway activity in a tissue-specific fashion.

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The Hedgehog Co-Receptor BOC Differentially Regulates SHH Signaling During Craniofacial Development

10.1101/2020.02.04.934497 ◽

2020 ◽

Author(s):

Martha L. Echevarría-Andino ◽

Benjamin L. Allen

Keyword(s):

Neural Crest ◽

Hedgehog Signaling ◽

Developmental Time ◽

Craniofacial Development ◽

Pathway Activity ◽

Tissue Specific ◽

Summary Statement ◽

Hh Signaling ◽

The Individual ◽

Craniofacial Defects

AbstractThe Hedgehog (HH) pathway controls multiple aspects of craniofacial development. HH ligands signal through the canonical receptor PTCH1, and three co-receptors– GAS1, CDON and BOC. Together, these co-receptors are required during embryogenesis to mediate proper HH signaling. Here we investigated the individual and combined contributions of GAS1, CDON and BOC to HH-dependent mammalian craniofacial development. Individual deletion of either Gas1 or Cdon results in variable holoprosencephaly phenotypes, characterized by the failure to divide and form the telencephalon and midfacial structures. In contrast, we find that Boc deletion results in facial widening consistent with increased HH pathway activity. Additionally, the deletion of Boc in a Gas1 null background partially rescues the craniofacial defects observed in Gas1 single mutants; a phenotype that persists over developmental time. This contrasts with HH-dependent phenotypes in other tissues that significantly worsen following combined deletion of Gas1 and Boc. Mechanistically, BOC selectively restricts neural crest-derived mesenchymal proliferation. Together, these data indicate that BOC acts as a multi-functional regulator of HH signaling during craniofacial development, alternately promoting or restraining HH pathway activity in a tissue-specific fashion.Summary statementHere we identify dual, tissue-specific roles for the Hedgehog co-receptor BOC in both the promotion and antagonism of Hedgehog signaling during craniofacial development.

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Assessment of Functional Phosphatidylinositol 3-Kinase Pathway Activity in Cancer Tissue Using Forkhead Box-O Target Gene Expression in a Knowledge-Based Computational Model

American Journal Of Pathology ◽

10.1016/j.ajpath.2018.05.020 ◽

2018 ◽

Vol 188 (9) ◽

pp. 1956-1972 ◽

Cited By ~ 16

Author(s):

Henk van Ooijen ◽

Marten Hornsveld ◽

Christa Dam-de Veen ◽

Rick Velter ◽

Meng Dou ◽

...

Keyword(s):

Gene Expression ◽

Computational Model ◽

Target Gene ◽

Cancer Tissue ◽

Phosphatidylinositol 3 Kinase ◽

Pathway Activity ◽

Target Gene Expression ◽

Knowledge Based ◽

Forkhead Box ◽

Kinase Pathway

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Non-coplanar polychlorinated biphenyls (PCBs) are direct agonists for the human pregnane-X receptor and constitutive androstane receptor, and activate target gene expression in a tissue-specific manner

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2012.05.016 ◽

2012 ◽

Vol 263 (1) ◽

pp. 7-13 ◽

Cited By ~ 56

Author(s):

Fadheela Al-Salman ◽

Nick Plant

Keyword(s):

Gene Expression ◽

Polychlorinated Biphenyls ◽

Target Gene ◽

Constitutive Androstane Receptor ◽

Pregnane X Receptor ◽

Tissue Specific ◽

Target Gene Expression ◽

Specific Manner ◽

Coplanar Polychlorinated Biphenyls

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An absolute requirement for Cubitus interruptus in Hedgehog signaling

Development ◽

10.1242/dev.128.5.733 ◽

2001 ◽

Vol 128 (5) ◽

pp. 733-742 ◽

Cited By ~ 4

Author(s):

N. Methot ◽

K. Basler

Keyword(s):

Gene Expression ◽

Signal Transduction ◽

Hedgehog Signaling ◽

Target Gene ◽

Target Genes ◽

Signal Transduction Pathway ◽

Transduction Pathway ◽

Cubitus Interruptus ◽

Target Gene Expression ◽

Hh Signaling

Hedgehog (Hh) proteins play diverse organizing roles in animal development by regulating gene expression in responding cells. Several components of the Hh signal transduction pathway have been identified, yet their precise role in mediating the various outputs of the pathway is still poorly understood. The Gli homolog Cubitus interruptus (Ci) is involved in controlling the transcription of Drosophila Hh target genes and thus represents the most downstream component known in this pathway. We address the question of whether the Hh pathway is distally branched or, in other words, whether the regulation of Ci activity is the sole output of Hh signaling. Putative Ci-independent branches of Hh signaling are explored by analyzing the behavior of cells that lack Ci but have undergone maximal activation of the Hh transduction pathway due to the removal of Patched (Ptc). The analysis of target gene expression and morphogenetic read-outs of Hh in embryonic, larval and adult stages indicates that Ci is absolutely required for all examined aspects of Hh outputs. We interpret this as evidence against the existence of Ci-independent branches in the Hh signal transduction pathway and propose that most cases of apparent Ci/Gli-independent Hh output can be attributed to the derepression of target gene expression in the absence of Ci/Gli repressor function.

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Enhancer RNA Expression in Response to Glucocorticoid Treatment in Murine Macrophages

Cells ◽

10.3390/cells11010028 ◽

2021 ◽

Vol 11 (1) ◽

pp. 28

Author(s):

Franziska Greulich ◽

Kirsten Adele Bielefeld ◽

Ronny Scheundel ◽

Aikaterini Mechtidou ◽

Benjamin Strickland ◽

...

Keyword(s):

Gene Expression ◽

Target Gene ◽

Metabolic Effects ◽

Cell Type ◽

Glucocorticoid Treatment ◽

Tissue Specific ◽

Murine Macrophages ◽

Target Gene Expression ◽

A Cell ◽

Cell Type Specific

Glucocorticoids are potent anti-inflammatory drugs; however, their molecular mode of action remains complex and elusive. They bind to the glucocorticoid receptor (GR), a nuclear receptor that controls gene expression in almost all tissues in a cell type-specific manner. While GR’s transcriptional targets mediate beneficial reactions in immune cells, they also harbor the potential of adverse metabolic effects in other cell types such as hepatocytes. Here, we have profiled nascent transcription upon glucocorticoid stimulation in LPS-activated primary murine macrophages using 4sU-seq. We compared our results to publicly available nascent transcriptomics data from murine liver and bioinformatically identified non-coding RNAs transcribed from intergenic GR binding sites in a tissue-specific fashion. These tissue-specific enhancer RNAs (eRNAs) correlate with target gene expression, reflecting cell type-specific glucocorticoid responses. We further associate GR-mediated eRNA expression with changes in H3K27 acetylation and BRD4 recruitment in inflammatory macrophages upon glucocorticoid treatment. In summary, we propose a common mechanism by which GR-bound enhancers regulate target gene expression by changes in histone acetylation, BRD4 recruitment and eRNA expression. We argue that local eRNAs are potential therapeutic targets downstream of GR signaling which may modulate glucocorticoid response in a cell type-specific way.

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2049-P: The Chd4 Helicase of the Nucleosome Remodeling and Deacetylase Complex Modulates Pdx1 Target Gene Expression In Vitro

Diabetes ◽

10.2337/db20-2049-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 2049-P

Author(s):

REBECCA K. DAVIDSON ◽

NOLAN CASEY ◽

JASON SPAETH

Keyword(s):

Gene Expression ◽

Target Gene ◽

Nucleosome Remodeling ◽

Target Gene Expression

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On the way toward regulatable expression systems in acetic acid bacteria: target gene expression and use cases

Applied Microbiology and Biotechnology ◽

10.1007/s00253-021-11269-z ◽

2021 ◽

Author(s):

Philipp Moritz Fricke ◽

Angelika Klemm ◽

Michael Bott ◽

Tino Polen

Keyword(s):

Gene Expression ◽

Acetic Acid ◽

Literature Search ◽

Target Gene ◽

Target Genes ◽

Recombinant Dna ◽

Acetic Acid Bacteria ◽

Homoserine Lactone ◽

Expression Systems ◽

Target Gene Expression

Abstract Acetic acid bacteria (AAB) are valuable biocatalysts for which there is growing interest in understanding their basics including physiology and biochemistry. This is accompanied by growing demands for metabolic engineering of AAB to take advantage of their properties and to improve their biomanufacturing efficiencies. Controlled expression of target genes is key to fundamental and applied microbiological research. In order to get an overview of expression systems and their applications in AAB, we carried out a comprehensive literature search using the Web of Science Core Collection database. The Acetobacteraceae family currently comprises 49 genera. We found overall 6097 publications related to one or more AAB genera since 1973, when the first successful recombinant DNA experiments in Escherichia coli have been published. The use of plasmids in AAB began in 1985 and till today was reported for only nine out of the 49 AAB genera currently described. We found at least five major expression plasmid lineages and a multitude of further expression plasmids, almost all enabling only constitutive target gene expression. Only recently, two regulatable expression systems became available for AAB, an N-acyl homoserine lactone (AHL)-inducible system for Komagataeibacter rhaeticus and an l-arabinose-inducible system for Gluconobacter oxydans. Thus, after 35 years of constitutive target gene expression in AAB, we now have the first regulatable expression systems for AAB in hand and further regulatable expression systems for AAB can be expected. Key points • Literature search revealed developments and usage of expression systems in AAB. • Only recently 2 regulatable plasmid systems became available for only 2 AAB genera. • Further regulatable expression systems for AAB are in sight.

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