Disordered N-Terminal DNMT3A Domain Is Required for Mouse Postnatal Development
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ABSTRACT:
PROVIDER: PRJNA689766 | ENA |
REPOSITORIES: ENA
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Project description:DNA methyltransferase 3a (DNMT3A) plays a crucial role in multiple biological processes during mouse development. We report that the longer isoform DNMT3A1, but not the shorter DNMT3A2, is essential for mouse postnatal development. DNMT3A1 binds to and regulates bivalent developmental genes in the brain. The disordered N-terminal domain is required for DNMT3A1-regulated development, DNA methylation and gene expression in the nervous system. A potential ubiquitin-interacting motif (UIM) in the N-terminus may bind to histone H2AK119 ubiquitination, mediating the recruitment of DNMT3A1 to its targets. These data reveal the N-terminus as a necessary regulatory domain for DNMT3A1 chromatin occupancy and functions.
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Project description:DROSHA serves as a gatekeeper of the microRNA (miRNA) pathway by processing primary transcripts (pri-miRNAs). While the functions of structured domains of DROSHA have been well-documented, the contribution of N-terminal proline-rich disordered domain (PRD) remains elusive. Here we show that the PRD promotes the processing of miRNA hairpins located within introns. We identified a DROSHA isoform (p140) lacking the PRD, which is produced by proteolytic cleavage. Small RNA sequencing revealed that p140 is significantly impaired in the maturation of intronic miRNAs. Consistently, our minigene constructs demonstrated that PRD enhances the processing of intronic hairpins, but not those in exons. Splice site mutations did not affect the PRD’s enhancing effect on intronic constructs, suggesting that the PRD acts independently of splicing reaction by interacting with sequences residing within introns. The N-terminal regions from zebrafish and Xenopus DROSHA can replace the human counterpart, indicating functional conservation despite poor sequence alignment. Moreover, we found that rapidly evolving intronic miRNAs are generally more dependent on PRD than conserved ones, suggesting a role of PRD in miRNA evolution. Our study reveals a new layer of miRNA regulation mediated by a low-complexity disordered domain that senses the genomic contexts of miRNA loci.
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Project description:DNA methyltransferases (DNMTs) deposit repressive DNA methylation, which regulates gene expression and is essential for mammalian development. Histone post-translational modifications can recruit DNMTs to DNA. The PWWP domains of DNMT3A and DNMT3B are posited to interact with histone 3 lysine 36 trimethylation (H3K36me3); however, the functionality of this interaction for DNMT3A remains untested in vivo. Here we present a mouse model carrying a D329A point mutation in the DNMT3A PWWP domain. The mutation causes dominant postnatal growth retardation. At the molecular level, it results in aberrant progressive acquisition of DNA methylation across domains marked by bivalent chromatin, resulting in de-repression of important developmental regulatory genes in adult hypothalamus. Evaluation of non-CpG methylation further demonstrates the altered recruitment and activity of mutant DNMT3A at bivalent domains. This work provides key molecular insights into analogous growth phenotypes observed in humans with congenital mutations in the DNMT3A PWWP domain.
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Project description:Human periostin is a 78-91 kDa alternatively spliced protein belonging to the group of matricellular proteins. The protein has been implicated in extracellular matrix remodeling, tumor development, and metastasis, inflammatory diseases like atopic dermatitis, psoriasis, and asthma. The C-terminal may be alternatively spliced, but the role of the ten variants is not understood. Here we investigate the structure of the C-terminal domain containing the protein sequence encoded by the fourall exons and its interactome. Structural analysis using SAXS, CD spectroscopy, and limited proteolysis suggested that the C-terminal domain was disordered. In addition, the motif responsible for heparin-binding was mapped to an arginine-rich sequence in the conserved very C-terminal part of periostin. Co-immunoprecipitationPull-down confirmed three known interaction partners bound to the C-terminal domain of periostin and identified an additional 140 novel potential interaction partners. Nine of these have been implicated in atopic dermatitis. Based on our findings, we suggest that the C-terminal domain anchor periostin to cell surfaces and facilitates interactions between connective tissue components or other cells. We propose that the C-terminal domain is a central part of the suggested function as a multifunctional modulator of extracellular matrix stability and wound healing.
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Project description:Transcriptional profiling of mouse postnatal SVZ NSCs comparing WT NSCs with KO NSCs under proliferating/undifferentiated states as well as differentiating conditions. Goal was to determine Dnmt3a-dependent gene expression changes in postnatal SVZ NSCs
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Project description:This SuperSeries is composed of the following subset Series: GSE22473: Murine postnatal subventricular zone (SVZ) neural stem cells (NSCs): Wild-type (WT) vs. Dnmt3a-null (KO) GSE22474: Genome-wide location analysis of Dnmt3a-mediated epigenetic regulation in murine postnatal subventricular zone (SVZ) neural stem cells (NSCs) [Agilent] GSE22475: Genome-wide location analysis of Dnmt3a-mediated epigenetic regulation in murine postnatal subventricular zone (SVZ) neural stem cells (NSCs) [NimbleGen] Refer to individual Series
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Project description:DNA methylation at proximal promoters facilitates lineage restriction by silencing cell-type specific genes. However, euchromatic DNA methylation frequently occurs in regions outside promoters. The functions of such non-proximal promoter DNA methylation are unclear. Here we show that the de novo DNA methyltransferase Dnmt3a is expressed in postnatal neural stem cells (NSCs) and is required for neurogenesis. Genome-wide analysis of postnatal NSCs indicates that Dnmt3a occupies and methylates intergenic regions and gene bodies flanking proximal promoters of a large cohort of transcriptionally permissive genes, many of which encode regulators of neurogenesis. Surprisingly, Dnmt3a-dependent non-proximal promoter methylation promotes expression of these neurogenic genes by functionally antagonizing Polycomb repression. Thus, non-promoter DNA methylation by Dnmt3a may be utilized for maintaining active chromatin states of genes critical for development.
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