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Histone arginine methylation by Prmt5 is required for lung branching morphogenesis through repression of BMP signaling

ABSTRACT: Branching morphogenesis is essential for the successful development of a functional lung to accomplish its gas exchange function. Although many studies have highlighted requirements for the bone morphogenetic protein (BMP) signaling pathway during branching morphogenesis, little is known about how BMP signalingis regulated. Here we report that the protein arginine methyltransferase 5 (Prmt5) and symmetric dimethylation at histone H4 arginine 3 (H4R3sme2) directly associate with chromatin of Bmp4 to suppress its transcription. Inactivation of Prmt5 in the lung epithelium results in halted branching morphogenesis, altered epithelial cell differentiation and neonatal lethality. These defects are accompanied by increased apoptosis and reduced proliferation of lung epithelium, as a consequence of elevated canonical BMP-Smad1/5/9 signaling. Inhibition of BMP signaling by Noggin rescues the lung branching defects of Prmt5 mutant in vitro. Taken together, our results identify a novel mechanism through which Prmt5-mediated histone arginine methylation represses canonical BMP signaling to regulate lung branching morphogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE229423 | GEO | 2024/05/23

REPOSITORIES: GEO

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Histone arginine methylation by Prmt controls lung branching morphogenesis through transcriptional repression of Bmp

Project description:We report that a protein arginine methyltransferase Prmt and symmetric dimethylation at histone H arginine (HRsme) directly associates with chromatin of Bmp to suppress its transcription. Inactivation of Prmt in the lung epithelium results in halted branching morphogenesis, altered P-D airway patterning and neonatal lethality.

2019-01-30 | GSE108934 | GEO

Wnt5a–Vangl1/2 signaling regulates the position and direction of lung branching through the cytoskeleton and focal adhesions

Project description:Lung branching morphogenesis requires reciprocal interactions between the epithelium and mesenchyme. How the lung branches are generated at a defined location and projected toward a specific direction remains a major unresolved issue. In this study, we investigated the function of Wnt signaling in lung branching in mice. We discovered that Wnt5a in both the epithelium and mesenchyme plays an essential role in controlling the position and direction of lung branching. The Wnt5a signal is mediated by Vangl1/2 to trigger a cascade of non-canonical or planar cell polarity (PCP) signaling. In response to non-canonical Wnt signaling, lung cells undergo cytoskeletal reorganization and change focal adhesions. Perturbed focal adhesions in lung explants are associated with defective branching. Moreover, we observed changes in the shape and orientation of the epithelial sheet and the underlying mesenchymal layer in regions of defective branching in the mutant lungs. Thus, PCP signaling helps define the position and orientation of the lung branches. We propose that mechanical force induced by non-canonical Wnt signaling mediates a coordinated alteration in the shape and orientation of a group of epithelial and mesenchymal cells. These results provide a new framework for understanding the molecular mechanisms by which a stereotypic branching pattern is generated.

2022-07-10 | GSE188993 | GEO

Smad1 and its target gene Wif1 coordinate BMP and Wnt signaling activities to regulate lung development

Project description:Bone morphogenetic protein 4 (BMP4) is essential for lung development. To define its intracellular signaling mechanisms by which BMP4 regulates lung development, BMP-specific Smad1 or Smad5 was selectively knocked out in fetal mouse lung epithelial cells. Abrogation of lung epithelial-specific Smad1, but not Smad5, resulted in retardation of lung branching morphogenesis and reduced sacculation, accompanied by altered distal lung epithelial cell proliferation and differentiation, and consequently severe neonatal respiratory failure. By combining cDNA microarray with ChIP-chip analyses, Wnt inhibitory factor-1 (Wif1) was identified as a novel target gene of Smad1 in the developing mouse lung epithelial cells. Loss of Smad1 transcriptional activation of Wif1 expression was associated with reduced Wif1 expression and increased Wnt/beta-catenin signaling activity in lung epithelia, resulting in specific fetal lung abnormalities. Therefore, a novel regulatory loop of BMP4-Smad1-Wif1-Wnt/beta-catenin in coordinating BMP and Wnt pathways to control fetal lung development is suggested. mRNA profiling: Total RNA was isolated from left lobe lungs of three pair of E18.5 wild type and Smad1 lung epithelium-specific conditional knockout mice

2011-01-07 | E-GEOD-26502 | biostudies-arrayexpress

Expression data from cultured fetal lung epithelium

Project description:Branching morphogenesis in lung development is regulate by growth factor signaling. Wnt signaling is one of the important singnaling pathway that is required for progenitor maintainance. In the presence of CHIR99021, an agonist for the beta-catenin pathway of Wnt signaling, specific group of genes are upregulated in cultured lung epithelium. RNAs were extracted from cultured epithelium and cDNAs were hybridized to Affymetrix microarrays.

2016-06-16 | E-GEOD-83391 | biostudies-arrayexpress

Histone arginine methylation by Prmt controls lung branching morphogenesis through transcriptional repression of Bmp

Project description:Histone arginine methylation by Prmt controls lung branching morphogenesis through transcriptional repression of Bmp

| PRJNA429192 | ENA

Expression data from cultured fetal lung epithelium

2016-06-16 | GSE83391 | GEO

Differential gene expression analysis of colonic epithelial cells from wildtype and PRMT5 heterozygote mice

Project description:PRMT5 is a type II arginine methyltransferase enzyme that is abundantly expressed in intestinal epithelial cells (IECs) of the colon. Here, we compared the transcriptome of the colonic epithelium from wildtype and PRMT5 heterozygote mice under steady state. We found that PRMT5-regulated genes are involved in anti-microbial responses and immune signaling.

2023-09-04 | GSE221566 | GEO

Mesenchymal proteases and tissue fluidity remodel the extracellular matrix during airway epithelial branching in the embryonic avian lung

Project description:Reciprocal signaling between an epithelium and its surrounding mesenchyme is common during morphogenesis. These epithelial-mesenchymal interactions are particularly evident in tissues that undergo branching morphogenesis, such as the airway epithelium of the lung. Here, we found that reciprocal interactions between the epithelium and mesenchyme drive remodeling of the extracellular matrix (ECM) during morphogenesis of the embryonic chicken lung. RNA-Seq analysis revealed changes in the expression of genes associated with integrin signaling and ECM remodeling. Consistently, we found that prior to branching, the basement membrane is a spatially uniform sheath that wraps the airway epithelium. After branch initiation, however, the basement membrane is significantly depleted from the tip of extending branches. Culturing embryonic lung explants revealed that this basement membrane thinning is mediated by matrix metalloproteinase-2 (MMP2), which is expressed in the mesenchyme. Inhibiting MMP activity suppresses branch extension but has no effect on branch initiation. As branches extend, we found that tenascin-C (TNC) accumulates in the mesenchyme several cell diameters away from the branch tip. Despite its pattern of accumulation, this mesenchymal ECM protein is expressed exclusively by airway epithelial cells, which activate focal adhesion kinase (FAK) to induce TNC expression. We found that branch extension coincides with the deformation of adjacent mesenchymal cells into elongated geometries, which correlates with an increase in the fluidity of the mesenchyme at branch tips. This local increase in mesenchymal movement transports TNC from the epithelial surface into the mesenchyme. These data reveal novel epithelial-mesenchymal interactions that direct ECM remodeling during airway branching morphogenesis.

2019-08-12 | GSE132478 | GEO

Smad1 and its target gene Wif1 coordinate BMP and Wnt signaling activities to regulate lung development

2011-01-07 | GSE26502 | GEO

Positional Identity of Branching-associated HOXB2 and B3 Gene Expression is Maintained by Adult Human Airway Epithelial Progenitor Cells

Project description:In the context that HOX mutant mice have profound deficits in airway branching morphogenesis, we asked whether the positional identity of HOX genes is maintained in the epithelium of the adult human tracheobronchial tree and if so, whether these positional differences are embedded in the stem/progenitor population derived from nonbranching vs branching airways. We found that 10 of 39 HOX genes are expressed in varying degrees in the nonbranching (trachea) or branching (large and small airways) human airway epithelium. Strikingly, HOXB2 and B3 were highly expressed in the trachea epithelium, but barely detectable in the branching airway epithelium. This difference in HOXB2 and B3 gene expression was embedded in the airway basal cell stem/progenitor population isolated from the trachea vs branching airways, and maintained during differentiation in vitro. Finally, HOXB2 and B3 expressions in the trachea vs branching airways correlated with the expression of a variety of other transcription and growth factors related to branching morphogenesis. The finding that the adult human airway epithelium expresses some HOX genes in a positional manner, with differences embedded in the transcriptomes of airway epithelial stem/progenitor cells, has implications for the use of stem/progenitor cells for applications relevant to lung regeneration.

2024-06-05 | GSE31449 | GEO

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