Direct methylation of FXR by Set7/9, a lysine methyltransferase, regulates the expression of FXR target genes.

American Journal of Physiology. Gastrointestinal and Liver Physiology
Natarajan BalasubramaniyanFrederick J Suchy

Abstract

The farnesoid X receptor (FXR) is a ligand (bile acid)-dependent nuclear receptor that regulates target genes involved in every aspect of bile acid homeostasis. Upon binding of ligand, FXR recruits an array of coactivators and associated proteins, some of which have intrinsic enzymatic activity that modify histones or even components of the transcriptional complex. In this study, we show chromatin occupancy by the Set7/9 methyltransferase at the FXR response element (FXRE) and direct methylation of FXR in vivo and in vitro at lysine 206. siRNA depletion of Set7/9 in the Huh-7 liver cell line decreased endogenous mRNAs of the FXR target genes, the short heterodimer partner (SHP) and bile salt export pump (BSEP). Mutation of the methylation site at K206 of FXR to an arginine prevented methylation by Set7/9. A pan-methyllysine antibody recognized the wild-type FXR but not the K206R mutant form. An electromobility shift assay showed that methylation by Set7/9 enhanced binding of FXR/retinoic X receptor-α to the FXRE. Interaction between hinge domain of FXR (containing K206) and Set7/9 was confirmed by coimmunoprecipitation, GST pull down, and mammalian two-hybrid experiments. Set7/9 overexpression in Huh-7 cells significantly enhan...Continue Reading

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Citations

Oct 24, 2013·Trends in Biochemical Sciences·Hans-Martin HerzAli Shilatifard
Dec 24, 2013·Journal of Molecular Endocrinology·Raffaella Maria Gadaleta, Luca Magnani
Mar 27, 2015·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Frederick J Suchy, Meenakshisundaram Ananthanarayanan
Aug 1, 2015·Cellular and Molecular Life Sciences : CMLS·Xi ZhangXiaobing Shi
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Jan 18, 2018·The Journal of Experimental Medicine·Hagit ShapiroEran Elinav
Apr 3, 2013·The Journal of Biological Chemistry·Natarajan BalasubramaniyanFrederick J Suchy
Jul 18, 2018·Signal Transduction and Targeted Therapy·Inês de Albuquerque Almeida Batista, Luisa Alejandra Helguero
Nov 22, 2019·Biochimica Et Biophysica Acta. Molecular Cell Research·Arun MaheshArunkumar Dhayalan
Oct 24, 2020·International Journal of Molecular Sciences·Anna Maria CzarneckaMagdalena Zielińska
Aug 14, 2020·Physiological Reviews·Alessia PerinoKristina Schoonjans
Mar 28, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Katrin Panzitt, Martin Wagner
May 7, 2021·Endocrine Reviews·Lucie MalbeteauMuriel Le Romancer

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