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SMAD4 target genes are part of a transcriptional network that integrates the response to BMP and SHH signaling during early limb bud patterning

SMAD4 regulates gene expression in response to BMP and TGFβ signal transduction, and is required for diverse morphogenetic processes, but its target genes have remained largely elusive. Here, we identify the SMAD4 target genes in mouse limb buds using an epitope-tagged Smad4 allele for ChIP-seq anal...

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Autores principales: Gamart, Julie, Barozzi, Iros, Laurent, Frédéric, Reinhardt, Robert, Martins, Laurène Ramos, Oberholzer, Thomas, Visel, Axel, Zeller, Rolf, Zuniga, Aimée
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8714076/
https://www.ncbi.nlm.nih.gov/pubmed/34822715
http://dx.doi.org/10.1242/dev.200182
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author Gamart, Julie
Barozzi, Iros
Laurent, Frédéric
Reinhardt, Robert
Martins, Laurène Ramos
Oberholzer, Thomas
Visel, Axel
Zeller, Rolf
Zuniga, Aimée
author_facet Gamart, Julie
Barozzi, Iros
Laurent, Frédéric
Reinhardt, Robert
Martins, Laurène Ramos
Oberholzer, Thomas
Visel, Axel
Zeller, Rolf
Zuniga, Aimée
author_sort Gamart, Julie
collection PubMed
description SMAD4 regulates gene expression in response to BMP and TGFβ signal transduction, and is required for diverse morphogenetic processes, but its target genes have remained largely elusive. Here, we identify the SMAD4 target genes in mouse limb buds using an epitope-tagged Smad4 allele for ChIP-seq analysis in combination with transcription profiling. This analysis shows that SMAD4 predominantly mediates BMP signal transduction during early limb bud development. Unexpectedly, the expression of cholesterol biosynthesis enzymes is precociously downregulated and intracellular cholesterol levels are reduced in Smad4-deficient limb bud mesenchymal progenitors. Most importantly, our analysis reveals a predominant function of SMAD4 in upregulating target genes in the anterior limb bud mesenchyme. Analysis of differentially expressed genes shared between Smad4- and Shh-deficient limb buds corroborates this function of SMAD4 and also reveals the repressive effect of SMAD4 on posterior genes that are upregulated in response to SHH signaling. This analysis uncovers opposing trans-regulatory inputs from SHH- and SMAD4-mediated BMP signal transduction on anterior and posterior gene expression during the digit patterning and outgrowth in early limb buds.
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spelling pubmed-87140762022-01-07 SMAD4 target genes are part of a transcriptional network that integrates the response to BMP and SHH signaling during early limb bud patterning Gamart, Julie Barozzi, Iros Laurent, Frédéric Reinhardt, Robert Martins, Laurène Ramos Oberholzer, Thomas Visel, Axel Zeller, Rolf Zuniga, Aimée Development Research Article SMAD4 regulates gene expression in response to BMP and TGFβ signal transduction, and is required for diverse morphogenetic processes, but its target genes have remained largely elusive. Here, we identify the SMAD4 target genes in mouse limb buds using an epitope-tagged Smad4 allele for ChIP-seq analysis in combination with transcription profiling. This analysis shows that SMAD4 predominantly mediates BMP signal transduction during early limb bud development. Unexpectedly, the expression of cholesterol biosynthesis enzymes is precociously downregulated and intracellular cholesterol levels are reduced in Smad4-deficient limb bud mesenchymal progenitors. Most importantly, our analysis reveals a predominant function of SMAD4 in upregulating target genes in the anterior limb bud mesenchyme. Analysis of differentially expressed genes shared between Smad4- and Shh-deficient limb buds corroborates this function of SMAD4 and also reveals the repressive effect of SMAD4 on posterior genes that are upregulated in response to SHH signaling. This analysis uncovers opposing trans-regulatory inputs from SHH- and SMAD4-mediated BMP signal transduction on anterior and posterior gene expression during the digit patterning and outgrowth in early limb buds. The Company of Biologists Ltd 2021-12-03 /pmc/articles/PMC8714076/ /pubmed/34822715 http://dx.doi.org/10.1242/dev.200182 Text en © 2021. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Gamart, Julie
Barozzi, Iros
Laurent, Frédéric
Reinhardt, Robert
Martins, Laurène Ramos
Oberholzer, Thomas
Visel, Axel
Zeller, Rolf
Zuniga, Aimée
SMAD4 target genes are part of a transcriptional network that integrates the response to BMP and SHH signaling during early limb bud patterning
title SMAD4 target genes are part of a transcriptional network that integrates the response to BMP and SHH signaling during early limb bud patterning
title_full SMAD4 target genes are part of a transcriptional network that integrates the response to BMP and SHH signaling during early limb bud patterning
title_fullStr SMAD4 target genes are part of a transcriptional network that integrates the response to BMP and SHH signaling during early limb bud patterning
title_full_unstemmed SMAD4 target genes are part of a transcriptional network that integrates the response to BMP and SHH signaling during early limb bud patterning
title_short SMAD4 target genes are part of a transcriptional network that integrates the response to BMP and SHH signaling during early limb bud patterning
title_sort smad4 target genes are part of a transcriptional network that integrates the response to bmp and shh signaling during early limb bud patterning
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8714076/
https://www.ncbi.nlm.nih.gov/pubmed/34822715
http://dx.doi.org/10.1242/dev.200182
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