Journal Article

MeCP2 links heterochromatin condensates and neurodevelopmental disease

Coffey, Eliot L., LeRoy, Gary, Henninger, Jonathan E., Svoboda, Devon S., Young, Richard A., Hannett, Nancy M., Lee, Tong Ihn, Dall’Agnese, Alessandra, Tang, Xin, Platt, Jesse M., Li, Charles H., Zamudio, Alicia V., Lungjangwa, Tenzin, Afeyan, Lena K., Oksuz, Ozgur, Wogram, Emile, Schuijers, Jurian, Jaenisch, Rudolf, Liu, X. Shawn, Markoulaki, Styliani

2020

Overview

Methyl CpG binding protein 2 (MeCP2) is a key component of constitutive heterochromatin, which is crucial for chromosome maintenance and transcriptional silencing 1 – 3 . Mutations in the MECP2 gene cause the progressive neurodevelopmental disorder Rett syndrome 3 – 5 , which is associated with severe mental disability and autism-like symptoms that affect girls during early childhood. Although previously thought to be a dense and relatively static structure 1 , 2 , heterochromatin is now understood to exhibit properties consistent with a liquid-like condensate 6 , 7 . Here we show that MeCP2 is a dynamic component of heterochromatin condensates in cells, and is stimulated by DNA to form liquid-like condensates. MeCP2 contains several domains that contribute to the formation of condensates, and mutations in MECP2 that lead to Rett syndrome disrupt the ability of MeCP2 to form condensates. Condensates formed by MeCP2 selectively incorporate and concentrate heterochromatin cofactors rather than components of euchromatic transcriptionally active condensates. We propose that MeCP2 enhances the separation of heterochromatin and euchromatin through its condensate partitioning properties, and that disruption of condensates may be a common consequence of mutations in MeCP2 that cause Rett syndrome. The chromatin protein MeCP2 is a component of dynamic, liquid-like heterochromatin condensates, and the ability of MeCP2 to form condensates is disrupted by mutations in the MECP2 gene that occur in the neurodevelopmental disorder Rett syndrome.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 14/63 / 42/100 / 42/35 / 631/208/176 / 631/208/366 / 631/337/386 / 631/337/572 / 631/57/2269 / 64/60 / Adaptive Immunity / Animals / Autism / Child development deviations / Children / Chromatin / Chromosomes / Cofactors / Condensates / CpG islands / Deoxyribonucleic acid / Development and progression / Developmental disabilities / DNA / Euchromatin / Female / Genetic aspects / Health aspects / Heterochromatin / Heterochromatin - metabolism / Humanities and Social Sciences / Immunity, Innate / Intellectual Disability - genetics / Intellectual Disability - pathology / MeCP2 protein / Methyl-CpG binding protein / Methyl-CpG-Binding Protein 2 - genetics / Methyl-CpG-Binding Protein 2 - metabolism / Mice / multidisciplinary / Mutation / Neurodevelopmental disorders / Neurons - metabolism / Neurons - pathology / Phenotype / Physiological aspects / Proteins / Rett syndrome / Rett Syndrome - genetics / Science / Science (multidisciplinary) / Signs and symptoms / Transcription