Rett syndrome-causing mutations compromise MeCP2-mediated liquid–liquid phase separation of chromatin

Wang, Liang; Hu, Mingming; Zuo, Mei-Qing; Zhao, Ji‐Cheng; Wu, Di; Huang, Li; Wen, Yongxin; Li, Yunfan; Chen, Ping; Bao, Xinhua; Dong, Meng‐Qiu; Li, Guohong; Li, Pilong

doi:10.1038/s41422-020-0288-7

Cited by 86 publications

(100 citation statements)

References 59 publications

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“…More interestingly, this ability of MeCP2 in driving LLPS is commonly compromised in the presence of mutations found in Rett syndrome patients both inside and outside MBD domain. A recent report published during revision of this study also revealed the impairment of MeCP2 phase separation by Rett mutations 14 . These findings suggest a potential role of MeCP2 in driving the formation of chromatin compartmentation necessary for normal neuronal function, providing a new angle to understand the mechanism underlying Rett syndrome.…”

supporting

confidence: 62%

Rett mutations attenuate phase separation of MeCP2

Fan

Zhang

et al. 2020

Cell Discov

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Dear Editor, Methyl-CpG-binding protein 2 (MeCP2) is a ubiquitously expressed nuclear protein originally identified as a methylated DNA binding protein, which is particularly abundant in mature neurons 1,2. Deficiency or excess of MeCP2 causes severe neurological problems. Mutations in MeCP2 account for 95% of the dominant X-linked neurological disorder Rett syndrome 3. MeCP2 have two key functional domains: the methyl-DNA binding domain (MBD) and the transcriptional repressor domain (TRD). Almost all of missense Rett mutations are clustered in these two domains, such as R133C, F155S, T158M in MBD, and R306H in TRD 4,5. The mechanism of the mutations leading to Rett syndrome is still not well understood. Here, we reveal that MeCP2 can drive the liquid-liquid phase separation (LLPS) in complex with DNA. Interestingly, this ability is compromised in the presence of mutations found in Rett syndrome patients, suggesting a potential common mechanism by disrupting LLPS of MeCP2 droplets underlying Rett syndrome. MeCP2 forms sharp condensed foci which highly overlap with DNA dense compartments in neuronal nuclei 6,7. Recently, LLPS has been recognized as an important mechanism to condensate molecules to form membraneless compartments within a cell 8. As both the MBD and TRD of MeCP2 bind to DNA 9 , we hypothesized that the sharp puncta of MeCP2 in the nuclei were phase separated liquid droplets mediated by multivalent interactions between MeCP2 and DNA. To test this hypothesis, we purified full-length recombinant His-MBP-MeCP2 (mouse MeCP2-e2 if not specified) and released

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supporting

confidence: 62%

Rett mutations attenuate phase separation of MeCP2

Fan

Zhang

et al. 2020

Cell Discov

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“…A more detailed follow up, carried out by Nikitina et al, highlighted the role of residues 295–486 for chromatin interaction ( Nikitina et al, 2007b ), and showed that R294X failed to produce the nucleosome–nucleosome interactions ( Nikitina et al, 2007a ) that are observed with the native form of the protein. Disruption of the inter-nucleosome interactions may play an important role in the intrinsic ability of MeCP2 to organize chromatin into chromocenters ( Brero et al, 2005 ; Agarwal et al, 2011 ; Ausio, 2016 ; Wang et al, 2020 ). The RTT nonsense mutations, R168X, R255X, R270X, and R294X, which together account for about 90% of all nonsense mutations ( Krishnaraj et al, 2017 ) were recently shown to disrupt the ability of MeCP2 to cluster heterochromatin ( Li et al, 2020 ) in a way that progressively decreased with the proximity of the MeCP2 truncation to the C-terminus ( Wang et al, 2020 ).…”

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confidence: 99%

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

2021

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Mutations in methyl CpG binding protein 2 (MeCP2) are the major cause of Rett syndrome (RTT), a rare neurodevelopmental disorder with a notable period of developmental regression following apparently normal initial development. Such MeCP2 alterations often result in changes to DNA binding and chromatin clustering ability, and in the stability of this protein. Among other functions, MeCP2 binds to methylated genomic DNA, which represents an important epigenetic mark with broad physiological implications, including neuronal development. In this review, we will summarize the genetic foundations behind RTT, and the variable degrees of protein stability exhibited by MeCP2 and its mutated versions. Also, past and emerging relationships that MeCP2 has with mRNA splicing, miRNA processing, and other non-coding RNAs (ncRNA) will be explored, and we suggest that these molecules could be missing links in understanding the epigenetic consequences incurred from genetic ablation of this important chromatin modifier. Importantly, although MeCP2 is highly expressed in the brain, where it has been most extensively studied, the role of this protein and its alterations in other tissues cannot be ignored and will also be discussed. Finally, the additional complexity to RTT pathology introduced by structural and functional implications of the two MeCP2 isoforms (MeCP2-E1 and MeCP2-E2) will be described. Epigenetic therapeutics are gaining clinical popularity, yet treatment for Rett syndrome is more complicated than would be anticipated for a purely epigenetic disorder, which should be taken into account in future clinical contexts.

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“…Of interest, MeCP2 competes with linker histone H1 and forms distinct heterochromatin condensates that coexist but do not mix (Fig. 1b ) 57 . The LLPS of nucleosome arrays likely acts on a shorter length scale within chromosomes.…”

Section: Llps In Heterochromatin and Genome Organizationmentioning

confidence: 99%

Biomolecular condensates as arbiters of biochemical reactions inside the nucleus

Laflamme

Mekhail

2020

Commun Biol

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Liquid-liquid phase separation (LLPS) has emerged as a central player in the assembly of membraneless compartments termed biomolecular condensates. These compartments are dynamic structures that can condense or dissolve under specific conditions to regulate molecular functions. Such properties allow biomolecular condensates to rapidly respond to changing endogenous or environmental conditions. Here, we review emerging roles for LLPS within the nuclear space, with a specific emphasis on genome organization, expression and repair. Our review highlights the emerging notion that biomolecular condensates regulate the sequential engagement of molecules in multistep biological processes.

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Rett syndrome-causing mutations compromise MeCP2-mediated liquid–liquid phase separation of chromatin

Cited by 86 publications

References 59 publications

Rett mutations attenuate phase separation of MeCP2

Rett mutations attenuate phase separation of MeCP2

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

Biomolecular condensates as arbiters of biochemical reactions inside the nucleus

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