SIRT1-mediated deacetylation of MeCP2 contributes to BDNF expression

Abstract

Methyl-CpG binding protein 2 (MeCP2) binds methylated cytosines at CpG sites on DNA and it is thought to function as a critical epigenetic regulator. Mutations in the MeCP2 gene have been associated to Rett syndrome, a human neurodevelopmental disorder. Here we show that MeCP2 is acetylated by p300 and that SIRT1 mediates its deacetylation. SIRT1, the mammalian homologue of Sir2 in yeast, is a nicotinamide-adenine dinucleotide (NAD⁺)-dependent histone deacetylase that belongs to the family of HDAC class III sirtuins. Importantly, SIRT1 has been shown to play a critical role in synaptic plasticity and memory formation. This study reveals a functional interplay between two critical epigenetic regulators, MeCP2 and SIRT1, which controls MeCP2 binding activity to the brain-derived neurotrophic factor (BDNF) promoter in a specific region of the brain.

Keywords: :

• MeCP2
• Rett Syndrome
• SIRT1
• acetylation
• sirtuins

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We are grateful to Li-Huei Tsai and Janine LaSalle for discussions, help and critical reading of the manuscript. We thank all the members of the Sassone-Corsi laboratory for helpful discussions. This work was supported by the National Institute of Health and Sirtris-GSK. L.Z. was in part supported by the American-Italian Cancer Foundation, New York.