Histone arginine methylation by Prmt5 is required for lung branching morphogenesis through repression of BMP signaling
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ABSTRACT:
PROVIDER: PRJNA954408 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24135557_1.fastq.gz | Fastqsanger.gz | |||
| SRR24135557_2.fastq.gz | Fastqsanger.gz | |||
| SRR24135558_1.fastq.gz | Fastqsanger.gz | |||
| SRR24135558_2.fastq.gz | Fastqsanger.gz | |||
| SRR24135559_1.fastq.gz | Fastqsanger.gz |
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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: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:Histone arginine methylation by Prmt controls lung branching morphogenesis through transcriptional repression of Bmp
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Project description:Protein arginine methyltransferases (PRMTs) catalyze arginine methylation, an abundant post-translational modification occurring on both chromatin-bound and cytoplasmic proteins. Growing evidence supports the involvement of PRMT5, the major Type II PRMT, in pro-survival and differentiation pathways, important during development and to promote tumorigenesis. Thus, PRMT5 emerges as an attractive drug target and inhibitors are currently in clinical trials for cancer therapy. However, the knowledge of PRMT5 non-histone substrates is still limited, as are the dynamic changes in methylation levels upon its inhibition. Here, we employed a newly established pipeline coupling SILAC with methyl-peptides immuno-enrichment to globally profile arginine methylation following PRMT5 inhibition by GSK591 and adopted the heavy-methyl SILAC as orthogonal validation method to reduce false discovery rate. Then, in vitro methylation assays on a set of PRMT5 targets provided novel mechanistic insights into its strict preference to methylate arginine sandwiched between two neighbouring glycines (GRG). In conclusion, we identified novel PRMT5 substrates, thus providing the first proof of concept of the in vivo efficacy of PRMT5 inhibitor that impacts on arginine methylation beyond histones.
2019-04-10 | PXD009070 | Pride
Project description:Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues in histones H3 and H4, marks generally associated with transcriptional repression. However, we found that PRMT5 inhibition (or depletion) led to more genes being down-regulated than up-regulated, indicating that PRMT5 can also act as a transcriptional activator. Indeed, the global level of histone H3K27me3 increases in PRMT5 deficient cells. Although PRMT5 does not directly affect PRC2 enzymatic activity, methylation of histone H3 by PRMT5 abrogates its subsequent methylation by PRC2. Treating AML cells with an EZH2 inhibitor partially restored the expression of approximately 50% of the genes that are initially down-regulated by PRMT5 inhibition, suggesting that the increased H3K27me3 contributes to the transcription repression of these genes. Interestingly, the growth inhibitory effect of PRMT5 inhibition was also partially rescued by combined treatment with EZH2 inhibitor in several leukemia cell lines. Thus, PRMT5-mediated crosstalk between histone marks contributes to its functional effects.
2021-05-30 | GSE142764 | GEO
Project description:Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues in histones H3 and H4, marks generally associated with transcriptional repression. However, we found that PRMT5 inhibition (or depletion) led to more genes being down-regulated than up-regulated, indicating that PRMT5 can also act as a transcriptional activator. Indeed, the global level of histone H3K27me3 increases in PRMT5 deficient cells. Although PRMT5 does not directly affect PRC2 enzymatic activity, methylation of histone H3 by PRMT5 abrogates its subsequent methylation by PRC2. Treating AML cells with an EZH2 inhibitor partially restored the expression of approximately 50% of the genes that are initially down-regulated by PRMT5 inhibition, suggesting that the increased H3K27me3 contributes to the transcription repression of these genes. Interestingly, the growth inhibitory effect of PRMT5 inhibition was also partially rescued by combined treatment with EZH2 inhibitor in several leukemia cell lines. Thus, PRMT5-mediated crosstalk between histone marks contributes to its functional effects.
2021-05-30 | GSE132407 | 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:Symmetrical dimethylation on arginine-3 of histone H4 (H4R3me2s) has been reported to occur at several repressed genes, but its specific regulation and genomic distribution remained unclear. Here, we show that the type-II protein arginine methyltransferase PRMT5 controls H4R3me2s in mouse embryonic fibroblasts (MEFs). In these differentiated cells, we find that the genome-wide pattern of H4R3me2s is highly similar to that in embryonic stem cells. In both the cell types, H4R3me2s peaks are detected predominantly at G + C-rich regions. Promoters are consistently marked by H4R3me2s, independently of transcriptional activity. Remarkably, H4R3me2s is mono-allelic at imprinting control regions (ICRs), at which it marks the same parental allele as H3K9me3, H4K20me3 and DNA methylation. These repressive chromatin modifications are regulated independently, however, since PRMT5-depletion in MEFs resulted in loss of H4R3me2s, without affecting H3K9me3, H4K20me3 or DNA methylation. Conversely, depletion of ESET (KMT1E) or SUV420H1/H2 (KMT5B/C) affected H3K9me3 and H4K20me3, respectively, without altering H4R3me2s at ICRs. Combined, our data indicate that PRMT5-mediated H4R3me2s uniquely marks the mammalian genome, mostly at G + C-rich regions, and independently from transcriptional activity or chromatin repression. Furthermore, comparative bioinformatics analyses suggest a putative role of PRMT5-mediated H4R3me2s in chromatin configuration in the nucleus. High throughput sequencing data from H4R3me2s native ChIP samples from mouse embryonic stem cells and fibroblasts were generated using Illumina Hi-seq 2000.
2013-10-04 | E-GEOD-37604 | biostudies-arrayexpress
Project description:Arginine methyltransferases critically regulate cellular homeostasis by modulating the functional outcome of their substrates. The protein arginine methyltransferase 5 (PRMT5) is an enzyme involved in growth and survival pathways promoting tumorigenesis. However, little is known about the biologic function of PRMT5 and its therapeutic potential in multiple myeloma (MM). In the present study, we identified and validated PRMT5 as a new therapeutic target in MM. PRMT5 is overexpressed in patient MM cells and associated with decreased progression free survival and overall survival. Either genetic knockdown or pharmacological inhibition of PRMT5 with the inhibitor EPZ015666 significantly inhibited growth of both cell lines and patient MM cells. Furthermore, PRMT5 inhibition abrogated NF-kB signaling. Interestingly, mass spectrometry identified a tripartite motif-containing protein 21 TRIM-21 as a new PRMT5-partner, and we delineated a TRIM21-dependent mechanism of NF-kB inhibition. Importantly, oral administration of EPZ015666 significantly decreased MM growth in a humanized murine model of MM. These data both demonstrate the oncogenic role and prognostic relevance of PRMT5 in MM pathogenesis, and provide the rationale for novel therapies targeting PRMT5 to improve patient outcome.
2017-09-19 | GSE103966 | GEO