SMAD4 target genes are part of a transcriptional network that integrates the response to BMP and SHH signaling during early limb bud patterning.
Anterior
BMP
ChIP-seq
Cistrome
Limb development
Mouse
RNA-seq
SHH
SMAD4
Journal
Development (Cambridge, England)
ISSN: 1477-9129
Titre abrégé: Development
Pays: England
ID NLM: 8701744
Informations de publication
Date de publication:
01 12 2021
01 12 2021
Historique:
received:
08
09
2021
accepted:
03
11
2021
pubmed:
26
11
2021
medline:
3
2
2022
entrez:
25
11
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34822715
pii: 273522
doi: 10.1242/dev.200182
pmc: PMC8714076
pii:
doi:
Substances chimiques
Bone Morphogenetic Proteins
0
Hedgehog Proteins
0
Shh protein, mouse
0
Smad4 Protein
0
Smad4 protein, mouse
0
Types de publication
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.
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHGRI NIH HHS
ID : R01 HG003988
Pays : United States
Organisme : NHGRI NIH HHS
ID : U54 HG006997
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG009421
Pays : United States
Informations de copyright
© 2021. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing or financial interests.
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