ARGLU1 is a Transcriptional Coactivator and Splicing Regulator Important for Stress Hormone Signaling and Development

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2019 Jan 31

PMID 30698747

Citations 12

Authors

Lilia Magomedova

Jens Tiefenbach

Emma Zilberman

Florian Le Billan

Veronique Voisin

Michael Saikali

Vincent Boivin

Melanie Robitaille

Serge Gueroussov

Manuel Irimia

Debashish Ray

Rucha Patel

Changjiang Xu

Pancharatnam Jeyasuria

Gary D Bader

Timothy R Hughes

Quaid D Morris

Michelle S Scott

Henry Krause

Stephane Angers

Benjamin J Blencowe

Carolyn L Cummins

Affiliations

Soon will be listed here.

Abstract

Stress hormones bind and activate the glucocorticoid receptor (GR) in many tissues including the brain. We identified arginine and glutamate rich 1 (ARGLU1) in a screen for new modulators of glucocorticoid signaling in the CNS. Biochemical studies show that the glutamate rich C-terminus of ARGLU1 coactivates multiple nuclear receptors including the glucocorticoid receptor (GR) and the arginine rich N-terminus interacts with splicing factors and binds to RNA. RNA-seq of neural cells depleted of ARGLU1 revealed significant changes in the expression and alternative splicing of distinct genes involved in neurogenesis. Loss of ARGLU1 is embryonic lethal in mice, and knockdown in zebrafish causes neurodevelopmental and heart defects. Treatment with dexamethasone, a GR activator, also induces changes in the pattern of alternatively spliced genes, many of which were lost when ARGLU1 was absent. Importantly, the genes found to be alternatively spliced in response to glucocorticoid treatment were distinct from those under transcriptional control by GR, suggesting an additional mechanism of glucocorticoid action is present in neural cells. Our results thus show that ARGLU1 is a novel factor for embryonic development that modulates basal transcription and alternative splicing in neural cells with consequences for glucocorticoid signaling.

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References

Auboeuf D, Batsche E, Dutertre M, Muchardt C, OMalley B . Coregulators: transducing signal from transcription to alternative splicing. Trends Endocrinol Metab. 2007; 18(3):122-9. DOI: 10.1016/j.tem.2007.02.003. View

Bhat-Nakshatri P, Song E, Collins N, Uversky V, Dunker A, OMalley B . Interplay between estrogen receptor and AKT in estradiol-induced alternative splicing. BMC Med Genomics. 2013; 6:21. PMC: 3687557. DOI: 10.1186/1755-8794-6-21. View

Iwasaki T, Chin W, Ko L . Identification and characterization of RRM-containing coactivator activator (CoAA) as TRBP-interacting protein, and its splice variant as a coactivator modulator (CoAM). J Biol Chem. 2001; 276(36):33375-83. DOI: 10.1074/jbc.M101517200. View

Kadmiel M, Cidlowski J . Glucocorticoid receptor signaling in health and disease. Trends Pharmacol Sci. 2013; 34(9):518-30. PMC: 3951203. DOI: 10.1016/j.tips.2013.07.003. View

Zhang C, Dowd D, Staal A, Gu C, Lian J, van Wijnen A . Nuclear coactivator-62 kDa/Ski-interacting protein is a nuclear matrix-associated coactivator that may couple vitamin D receptor-mediated transcription and RNA splicing. J Biol Chem. 2003; 278(37):35325-36. DOI: 10.1074/jbc.M305191200. View

Calnan B, Biancalana S, Hudson D, Frankel A . Analysis of arginine-rich peptides from the HIV Tat protein reveals unusual features of RNA-protein recognition. Genes Dev. 1991; 5(2):201-10. DOI: 10.1101/gad.5.2.201. View

Raj B, OHanlon D, Vessey J, Pan Q, Ray D, Buckley N . Cross-regulation between an alternative splicing activator and a transcription repressor controls neurogenesis. Mol Cell. 2011; 43(5):843-50. DOI: 10.1016/j.molcel.2011.08.014. View

Martinez-Contreras R, Cloutier P, Shkreta L, Fisette J, Revil T, Chabot B . hnRNP proteins and splicing control. Adv Exp Med Biol. 2008; 623:123-47. DOI: 10.1007/978-0-387-77374-2_8. View

Spencer T, Jenster G, Burcin M, Allis C, Zhou J, Mizzen C . Steroid receptor coactivator-1 is a histone acetyltransferase. Nature. 1997; 389(6647):194-8. DOI: 10.1038/38304. View

10.

L Bookout A, Cummins C, Mangelsdorf D, Pesola J, Kramer M . High-throughput real-time quantitative reverse transcription PCR. Curr Protoc Mol Biol. 2008; Chapter 15:Unit 15.8. DOI: 10.1002/0471142727.mb1508s73. View

11.

Pan Q, Shai O, Lee L, Frey B, Blencowe B . Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet. 2008; 40(12):1413-5. DOI: 10.1038/ng.259. View

12.

MacDonald P, Baudino T, Tokumaru H, Dowd D, Zhang C . Vitamin D receptor and nuclear receptor coactivators: crucial interactions in vitamin D-mediated transcription. Steroids. 2001; 66(3-5):171-6. DOI: 10.1016/s0039-128x(00)00200-2. View

13.

Webby C, Wolf A, Gromak N, Dreger M, Kramer H, Kessler B . Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing. Science. 2009; 325(5936):90-3. DOI: 10.1126/science.1175865. View

14.

Chen H, Lin R, Schiltz R, Chakravarti D, Nash A, Nagy L . Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell. 1997; 90(3):569-80. DOI: 10.1016/s0092-8674(00)80516-4. View

15.

Sun J, Blair A, Aiyar S, Li R . Cofactor of BRCA1 modulates androgen-dependent transcription and alternative splicing. J Steroid Biochem Mol Biol. 2007; 107(3-5):131-9. PMC: 2701476. DOI: 10.1016/j.jsbmb.2007.05.031. View

16.

Fitzsimons C, van Hooijdonk L, Schouten M, Zalachoras I, Brinks V, Zheng T . Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior. Mol Psychiatry. 2012; 18(9):993-1005. DOI: 10.1038/mp.2012.123. View

17.

Vizcaino J, Cote R, Csordas A, Dianes J, Fabregat A, Foster J . The PRoteomics IDEntifications (PRIDE) database and associated tools: status in 2013. Nucleic Acids Res. 2012; 41(Database issue):D1063-9. PMC: 3531176. DOI: 10.1093/nar/gks1262. View

18.

Ray D, Ha K, Nie K, Zheng H, Hughes T, Morris Q . RNAcompete methodology and application to determine sequence preferences of unconventional RNA-binding proteins. Methods. 2016; 118-119():3-15. PMC: 5411283. DOI: 10.1016/j.ymeth.2016.12.003. View

19.

Makishima M, Okamoto A, REPA J, Tu H, Learned R, Luk A . Identification of a nuclear receptor for bile acids. Science. 1999; 284(5418):1362-5. DOI: 10.1126/science.284.5418.1362. View

20.

Boucher L, Ouzounis C, Enright A, Blencowe B . A genome-wide survey of RS domain proteins. RNA. 2002; 7(12):1693-701. PMC: 1370209. View