title: A novel MeCP2 acetylation site regulates interaction with ATRX and HDAC1.
abstract: Methyl-CpG-binding protein-2 (MeCP2) regulates gene expression by recruiting SWI/SNF DNA helicase/ATPase (ATRX) and Histone Deacetylase-1 (HDAC1) to methylated gene regions and modulates heterochromatin association by interacting with Heterochromatin protein-1. As MeCP2 contributes to tumor suppressor gene silencing and its mutation causes Rett Syndrome, we investigated how novel post-translational-modification contributes to its function. Herein we report that upon pharmacological inhibition of SIRT1 in RKO colon and MCF-7 breast cancer cells, endogenous MeCP2 is acetylated at sites critical for binding to DNA and transcriptional regulators. We created an acetylation mimetic mutation in MeCP2 and found it to possess decreased binding to ATRX and HDAC1. Conditions inducing MeCP2 acetylation do not alter its promoter occupancy at a subset of target genes analyzed, but do cause decreased binding to ATRX and HDAC1. We also report here that a specific inhibitor of SIRT1, IV, can be used to selectively decrease H3K27me3 repressive marks on a subset of repressed target gene promoters analyzed. Lastly, we show that RKO cells over-expressing MeCP2 mutant show reduced proliferation compared to those over-expressing MeCP2-wildtype. Our study demonstrates the importance of acetylated lysine residues and suggests their key role in regulating MeCP2 function and its ability to bind transcriptional regulators.
authors.affiliation: Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors.forename: Somnath
authors.initials: S
authors.lastname: Pandey
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Simmons
authors.affiliation: Molecular and Cellular Physiology, Shreveport, LA, USA ; LSU Health Sciences Center School of Medicine, Shreveport, LA, USA.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Malyarchuk
authors.affiliation: Molecular and Cellular Physiology, Shreveport, LA, USA ; LSU Health Sciences Center School of Medicine, Shreveport, LA, USA.
authors.forename: Tara N
authors.initials: TN
authors.lastname: Calhoun
authors.affiliation: Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Pruitt
keywords: ATRX; HDAC1; MeCP2; SIRT1; epigenetics