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.

Brain phosphorylation of MeCP2 at serine 164 is developmentally regulated and globally alters its chromatin association

“…K171 has been recently proved to be acetylated 17 , whereas the ID has been demonstrated as a major site of poly(ADP-rybosyl)ation 18 . Both these PTMs highly impact on MeCP2 functions: K171 acetylation modulates the interaction of MeCP2 with ATRX and HDAC1, while (ADP-rybosyl)ation reduces the capability of MeCP2 to cluster heterochromatin 17 18 . By analyzing evolutional conservation, we noticed that S164 and S166 have been maintained from X. laevis to humans ( Fig.…”

HDAC1 promoted migration and invasion binding with TCF12 by promoting EMT progress in gallbladder cancer

“…Histone deacetylases (HDACs) remove acetyl groups from histones, resulting in chromatin compaction and decreased accessibility to DNA for interacting molecules such as transcription factors, resulting in compaction of chromatin structure and transcriptional repression. HDACs operate by direct association with DNA-binding factors and by incorporation into large multifunctional repressor complexes such as Sin3, NuRD, and PRC2 [12]. In addition to functions in chromatin remodeling, HDACs deacetylate certain transcription factors, such as P53 [13], resulting in their decreased activity.…”

Identification of Novel MeCP2 Cancer-Associated Target Genes and Post-Translational Modifications

“…We previously reported that MeCP2 undergoes acetylation on Lys-171 in both MCF7 and RKO cells. We further demonstrated that a K171 acetylation mimetic did not perturb binding to select gene targets, but it diminished interaction of MeCP2 with binding partners such as ATRX and HDAC1 in colorectal cancer cells (44). In vivo and in vitro studies have demonstrated the importance of MeCP2 post-translational regulation (45,(104)(105)(106)(107)), yet little has been done to comprehensively map novel MeCP2 PTMs.…”