Arginine methyltransferase CARM1/PRMT4 regulates endochondral ossification
ABSTRACT Chondrogenesis and subsequent endochondral ossification are processes tightly regulated by the transcription factor Sox9 (SRY-related high mobility group-Box gene 9), but molecular mechanisms underlying this activity remain unclear. Here we report that coactivator-associated arginine methyltransferase 1 (CARM1) regulates chondrocyte proliferation via arginine methylation of Sox9.
CARM1-null mice display delayed endochondral ossification and decreased chondrocyte proliferation. Conversely, cartilage development of CARM1 transgenic mice was accelerated. CARM1 specifically methylates Sox9 at its HMG domain in vivo and in vitro. Arg-methylation of Sox9 by CARM1 disrupts interaction of Sox9 with beta-catenin, regulating Cyclin D1 expression and cell cycle progression of chondrocytes.
These results establish a role for CARM1 as an important regulator of chondrocyte proliferation during embryogenesis.
Full-textDOI: · Available from: Martin Lotz, Aug 12, 2015
Conference Paper: Novel SiC-trench-MOSFET with reduced oxide electric field[Show abstract] [Hide abstract]
ABSTRACT: It has been shown theoretically that the specific on-resistance of the drift region of SiC metal oxide semiconductor field effect transistor (MOSFET) is about 200 times lower than that of a Si MOSFET with the same breakdown voltage (Bhatnagar and Balaiga, 1993). However, the blocking performance of the trench MOSFET (TMOSFET) is limited by the breakdown of the gate dielectric and not by avalanche breakdown in the SiC (Agarwal et al., 1996). Our analysis indicates that this is because the electric field in the SiO<sub>2</sub> gate dielectric exceeds the dielectric breakdown field strength when high voltages are being blocked by the MOSFET well before the electric field in the SiC is high enough to cause avalanche breakdown in the semiconductor. This paper will introduce, for the first time, a P-type polysilicon filled trench (P-trench) in the TMOSFET that is deeper than the trench gate. The high electric field stress in the oxide is moved to the corner of the P-trench. Hence, the electric field problem can be solved without the need to replace the SiO<sub>2</sub> with high dielectric constant gate insulators as suggested by others (Sridevan and Baliga, 1997).Solid-State and Integrated Circuits Technology, 2004. Proceedings. 7th International Conference on; 11/2004
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ABSTRACT: Arginine methylation is a common posttranslational modification (PTM). This type of PTM occurs on both nuclear and cytoplasmic proteins, and is particularly abundant on shuttling proteins. In this review, we will focus on one aspect of this PTM: the diverse roles that arginine methylation of the core histone tails play in regulating chromatin function. A family of nine protein arginine methyltransferases (PRMTs) catalyze methylation reactions, and a subset target histones. Importantly, arginine methylation of histone tails can promote or prevent the docking of key transcriptional effector molecules, thus playing a central role in the orchestration of the histone code.FEBS letters 11/2010; 585(13):2024-31. DOI:10.1016/j.febslet.2010.11.010 · 3.34 Impact Factor
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ABSTRACT: Spinal muscular atrophy is an autosomal-recessive neuromuscular disease caused by disruption of the survival of motor neuron (SMN) gene, which promotes cytoplasmic assembly of the splicing core machinery. It remains unclear how a deficiency in SMN results in a disorder leading to selective degeneration of lower motor neurons. We report here that SMN interacts with RNA-binding protein HuD in neurites of motorneuron-derived MN-1 cells. This interaction is mediated through the Tudor domain of SMN and, importantly, naturally occurring Tudor mutations found in patients with severe spinal muscular atrophy (SMA) completely abrogate the interaction, underscoring its relevance to the disease process. We also characterized a regulatory pathway involving coactivator-associated arginine methyltransferase 1 (CARM1) and HuD. Specifically, we show that CARM1 expression is rapidly downregulated, at the protein level, following induction of differentiation through retinoid and neurotrophic signaling. Using purified proteins, we demonstrate that methylation of HuD by CARM1 reduces its interaction with the p21(cip1/waf1) mRNA, showing that CARM1 can directly influence RNA-binding activity. We further demonstrate that this CARM1-dependent regulatory switch mainly controls the activity of HuD in promoting cell-cycle exit, whereas the interaction between HuD and SMN is required for proper recruitment of HuD and its mRNA targets in neuronal RNA granules. Finally, we were able to rescue SMA-like defects in a hypomorphic Smn knockdown MN-1 cell line through overexpression of HuD. Together, these findings extend our understanding of specific role(s) of SMN in motor neurons and provide crucial insights into potential new avenues for SMA therapeutic strategies.Human Molecular Genetics 11/2010; 20(3):553-79. DOI:10.1093/hmg/ddq500 · 6.68 Impact Factor