Histone arginine methylation by Prmt controls lung branching morphogenesis through transcriptional repression of Bmp
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ABSTRACT:
PROVIDER: PRJNA429192 | ENA |
REPOSITORIES: ENA
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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
Project description: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.
2024-05-23 | GSE229423 | GEO
Project description:Protein arginine methylation, catalyzed by the protein arginine methyltransferase (PRMT) family, is recognized as a widespread post-translational modification (PTM) with implications in a plethora of biological processes in eukaryotes. PRMT proteins were classified into three types, type I, II and III, according to the final methyl-arginine products generated. Despite that thousands of substrates have been identified for Type I and II PRMTs, a full scope of arginine methylation catalyzed by the only type III PRMT, PRMT7, as well as its connection with that of type I and II PRMTs remain unknown, limiting our understanding of the network of arginine methylation and its functions in cells. In this study, global profiling of PRMT4 (type I), PRMT5 (type II) and PRMT7 (type III) substrates (also referred as methylome) revealed that PRMT7 methylated a GAR (glycine and arginine) motif similar as PRMT5, while PRMT4 uniquely methylated a motif in which proline was highly enriched. PRMT4, 5 and 7-methylome were all enriched with proteins functioning in mRNA splicing, and knockdown of PRMT4, 5 or 7 led to a global change of alternative splicing events, among which a cohort with implications in cancer development was co-regulated by all three PRMTs. PRMT4, 5 and 7-mediated arginine methylation on splicing factors such as hnRNPA1, though at different status, were shown to enhance RNA binding in general and participate in the regulation of PRMT4, 5 and 7 co-regulated alternative splicing events.The clinical significance of PRMT4, 5 and 7-mediated arginine methylation was underscored by the fact that these three PRMTs as well as hnRNPA1 arginine methylation were over-represented in multiple types of cancers, which were associated with aberrant gene alternative splicing. Consistently, silencing or pharmacological inhibition of PRMT4, 5 and 7 altered gene alternative splicing and suppressed cancer cell growth, and co-treatment exhibited synergistic effects. Taken together, our study provided an integrative view of substrates for the three types of PRMTs, revealing the important function of arginine methylation in RNA splicing and cancer.
2021-01-23 | GSE150040 | GEO
Project description:Branching morphogenesis of the mammary gland is driven by the highly motile terminal end bud (TEB) throughout pubertal development. The stem cell enriched, proliferative TEB branches as it invades the mammary fat pad to create a complex network of ducts. The gene expression programs specific to the TEB and the differentiated duct are poorly understood. We conducted a time course analysis of gene expression in the TEB and duct throughout branching morphogenesis. Additionally, we determined the gene regulatory networks coordinated by the Co-factor of LIM domains (CLIM/LDB) transcriptional regulators and determined an essential function for CLIMs in branching morphogenesis by maintaining basal mammary epithelial stem cells and promoting cell proliferation. We used laser capture microdissection to isolate TEB and duct cells throughout branching morphogenesis. We then profiled gene expression in these cells to determine gene regulatory networks involved in branching morphogenesis, and specifically those regulated by CLIM transcriptional regulators. Mouse mammary glands from 4, 6, 8, and 10 week old mice (early puberty through early adulthood) were used for laser capture microdissection of TEB and duct cells from WT and K14-DN-Clim transgenic mice. RNA was isolated (Qiagen) and hybridized to Affymetrix MouseGene 1.0 ST arrays. In addition, basal (CD29HiCD24+Lin-) and Luminal (CD29LoCD24+Lin-) cells were sorted and RNA collected for hybridization to Affymetrix MouseGene 1.0ST arrays.
2014-07-07 | E-GEOD-57724 | biostudies-arrayexpress
Project description:Branching morphogenesis of the mammary gland is driven by the highly motile terminal end bud (TEB) throughout pubertal development. The stem cell enriched, proliferative TEB branches as it invades the mammary fat pad to create a complex network of ducts. The gene expression programs specific to the TEB and the differentiated duct are poorly understood. We conducted a time course analysis of gene expression in the TEB and duct throughout branching morphogenesis. Additionally, we determined the gene regulatory networks coordinated by the Co-factor of LIM domains (CLIM/LDB) transcriptional regulators and determined an essential function for CLIMs in branching morphogenesis by maintaining basal mammary epithelial stem cells and promoting cell proliferation. We used laser capture microdissection to isolate TEB and duct cells throughout branching morphogenesis. We then profiled gene expression in these cells to determine gene regulatory networks involved in branching morphogenesis, and specifically those regulated by CLIM transcriptional regulators.
2014-07-07 | GSE57724 | GEO
Project description:Protein arginine methylation, catalyzed by the protein arginine methyltransferase (PRMT) family, is recognized as a widespread post-translational modification (PTM) with implications in a plethora of biological processes in eukaryotes. PRMT proteins were classified into three types, type I, II and III, according to the final methyl-arginine products generated. Despite that thousands of substrates have been identified for Type I and II PRMTs, a full scope of arginine methylation catalyzed by the only type III PRMT, PRMT7, as well as its connection with that of type I and II PRMTs remain unknown, limiting our understanding of the network of arginine methylation and its functions in cells. In this study, global profiling of PRMT4 (type I), PRMT5 (type II) and PRMT7 (type III) substrates (also referred as methylome) revealed that PRMT7 methylated a GAR (glycine and arginine) motif similar as PRMT5, while PRMT4 uniquely methylated a motif in which proline was highly enriched. PRMT4, 5 and 7-methylome were all enriched with proteins functioning in mRNA splicing.
2021-01-27 | PXD022424 | Pride
Project description:Mechanical forces are increasingly recognized to regulate morphogenesis, but how this is accomplished in the context of the multiple tissues present within a developing organ remains unclear. Here we use bioengineered “microfluidic chest cavities” to precisely control the mechanical environment of the fetal lung. We show that transmural pressure controls airway branching morphogenesis and regulates the frequency of airway smooth muscle contraction. Next-generation sequencing analysis shows that lungs held at higher pressure are more mature than lungs held at lower pressure. Timelapse imaging reveals that branching events are synchronized across distant locations within the lung, and are preceded by long-duration waves of airway smooth muscle contraction. Higher transmural pressure decreases the interval between systemic smooth muscle contractions and increases the rate of morphogenesis of the airway epithelium. These data reveal that the mechanical properties of the microenvironment instruct crosstalk between tissues to control the rate of development of the embryonic lung.
2017-11-07 | GSE90148 | GEO
Project description:A Grhl2-dependent gene network controls trophoblast branching morphogenesis
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Project description:The transcriptional dynamics occurring at the self-organizing glandular epithelial during branching morphogenesis are pivotal for deciphering various processes ranging from normal tissue growth to cancer formation. For the past decade matrigel© has been widely used as extracellular matrix for the propagation of organoids, here we report that only in the presence of a higher than 70% collagen matrix symmetry breaking can be observed. Comparing the transcriptomic profile of collagen and matrigel grown-organoids we identified that matrigel organoids are more basal-like, have a higher EMT signature (GSEA) compared to the more classical collagen grown organoids. In this study we used single primary murine pancreatic ductal adenocarcinoma cells (PDAC) cells embedded in floating collagen gels and adapted the media supplementation, thus allowing organoids to self-organize into highly complex branched structures, replicating the in vivo tumour architecture. During organoid development we identified four distinct morphogenetic phases, each characterized by a unique pattern of cell proliferation, invasion, matrix deformation and protein expression. In our search for novel molecular drivers of branching morphogenesis we compared the transcriptome of two distinct phases, an early development (day 7) vs a late mature time point (day 13). We compared these two distinct developmental time points in using PCA, GSEA and respective heat maps of major processes illustrating the overexpression of genes associated with: proliferation, ECM interaction, signalling by Rho GTPases and EMT in day-7 organoids and genes associated with ion channel transport at day-13 organoids. An important aspect raised during our investigation was the effect of different genotypes (Ptf1aCre/+; KrasG12D/+, Pdx1Cre/+; KrasG12D/+; TP53fl/fl) on the branch formation of organoids. To this end we generated organoids derived from KC and KPC tumours, which interestingly gave rise to strikingly similar branching organoids. Although the morphology was not significantly altered the transcriptional profiling showed higher proliferation (Myc targets, E2F targets), EMT score for the KPC organoids. We propose that the spatiotemporal synchronized processes of cell proliferation, matrix remodeling, contraction and ion channel flux are key-events of the different morphogenic phases and lead to the formation of these complex structures. Importantly, these dynamic processes are accompanied by strong transcriptional profile changes, with the organoids undergoing de-differentiation during branch elongation and later on activating an epithelial gene expression program upon maturation. Taken together, these results illustrate the ability of tumour cells to self-organize in multicellular complex structures and provide with a novel system to study branching morphogenesis and tumour biology in vitro.
2022-08-02 | GSE200308 | GEO
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