(2018). Diverse genetic-driven immune landscapes dictate tumor progression through distinct mechanisms. Nature medicine,
(2017). PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK–ERK signaling. Nature genetics,
(2017). A circular twist on microRNA regulation. Cell research,
(2016). Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations. Cell,
(2015). The Where and the How of PRMT5. Current molecular biology reports,
(2015). MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis. Nature,
(2015). Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growth. Journal of clinical investigation,
(2014). NUCKS Is a Positive Transcriptional Regulator of Insulin Signaling. Cell reports,
(2013). Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery. Genes & development,
The tight control of gene expression at the level of both transcription and post-transcriptional RNA processing is essential for mammalian development. We here investigate the role of protein arginine methyltransferase 5 (PRMT5), a putative splicing regulator and transcriptional cofactor, in mammalian development. We demonstrate that selective deletion of PRMT5 in neural stem/progenitor cells (NPCs) leads to postnatal death in mice. At the molecular level, the absence of PRMT5 results in reduced methylation of Sm proteins, aberrant constitutive splicing, and the alternative splicing of specific mRNAs with weak 5′ donor sites. Intriguingly, the products of these mRNAs are, among others, several proteins regulating cell cycle progression. We identify Mdm4 as one of these key mRNAs that senses the defects in the spliceosomal machinery and transduces the signal to activate the p53 response, providing a mechanistic explanation of the phenotype observed in vivo. Our data demonstrate that PRMT5 is a master regulator of splicing in mammals and uncover a new role for the Mdm4 pre-mRNA, which could be exploited for anti-cancer therapy..
De Marco, A.
(2012). Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance. Nature structural & molecular biology,
(2012). p53-Independent regulation of p21Waf1/Cip1 expression and senescence by PRMT6. Nucleic acids research,
(2012). Hairless promotes PPARγ expression and is required for white adipogenesis. Embo reports,
Adipose tissue is the largest compartment in the mammalian body for storing energy as fat, providing an important reservoir of fuel for maintaining whole body energy homeostasis. Herein, we identify the transcriptional cofactor hairless (HR) to be required for white adipogenesis. Moreover, forced expression of HR in non‐adipogenic precursor cells induces adipogenic gene expression and enhances adipocyte formation under permissive conditions. HR exerts its proadipogenic effects by regulating the expression of PPARγ, one of the central adipogenic transcription factors. In conclusion, our data provide a new mechanism required for white adipogenesis..
(2010). Arginine/lysine–methyl/methyl switches: biochemical role of histone arginine methylation in transcriptional regulation. Epigenomics,
Post-translational modifications (PTMs) are commonly used to modify protein function. Modifications such as phosphorylation, acetylation and methylation can influence the conformation of the modified protein and its interaction with other proteins or DNA. In the case of histones, PTMs on specific residues can influence chromatin structure and function by modifying the biochemical properties of key amino acids. Histone methylation events, especially on arginine- and lysine-residues, are among the best-characterized PTMs, and many of these modifications have been linked to downstream effects. The addition of a methyl group to either residue results in a slight increase in hydrophobicity, in the loss of a potential hydrogen-bond donor site and, in the alteration of the protein interaction surface. Thus far, a number of protein domains have been demonstrated to directly bind to methylated lysine residues. However, the biochemical mechanisms linking histone arginine methylation to downstream biological outputs remain poorly characterized. This review will focus on the role of histone arginine methylation in transcriptional regulation and on the crosstalk between arginine methylation and other PTMs. We will discuss the mechanisms by which differentially methylated arginines on histones modulate transcriptional outcomes and contribute to the complexity of the ‘histone code’..