MeCP2-induced heterochromatin organization is driven by oligomerization-based liquid–liquid phase separation and restricted by DNA methylation
Heterochromatin is the highly compacted form of chromatin with various condensation levels hallmarked by high DNA methylation. MeCP2 is mostly known as a DNA methylation reader but has also been reported as a heterochromatin organizer. Here, we combine liquid–liquid phase separation (LLPS) analysis...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Nucleus |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/19491034.2021.2024691 |
| _version_ | 1818984829962682368 |
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| author | Hui Zhang Hector Romero Annika Schmidt Katalina Gagova Weihua Qin Bianca Bertulat Anne Lehmkuhl Manuela Milden Malte Eck Tobias Meckel Heinrich Leonhardt M. Cristina Cardoso |
| author_facet | Hui Zhang Hector Romero Annika Schmidt Katalina Gagova Weihua Qin Bianca Bertulat Anne Lehmkuhl Manuela Milden Malte Eck Tobias Meckel Heinrich Leonhardt M. Cristina Cardoso |
| author_sort | Hui Zhang |
| collection | DOAJ |
| description | Heterochromatin is the highly compacted form of chromatin with various condensation levels hallmarked by high DNA methylation. MeCP2 is mostly known as a DNA methylation reader but has also been reported as a heterochromatin organizer. Here, we combine liquid–liquid phase separation (LLPS) analysis and single-molecule tracking with quantification of local MeCP2 concentrations in vitro and in vivo to explore the mechanism of MeCP2-driven heterochromatin organization and dynamics. We show that MeCP2 alone forms liquid-like spherical droplets via multivalent electrostatic interactions and with isotropic mobility. Crowded environments and DNA promote MeCP2 LLPS and slow down MeCP2 mobility. DNA methylation, however, restricts the growth of heterochromatin compartments correlating with immobilization of MeCP2. Furthermore, MeCP2 self-interaction is required for LLPS and is disrupted by Rett syndrome mutations. In summary, we are able to model the heterochromatin compartmentalization as well as MeCP2 concentration and heterogeneous motion in the minimal in vitro system. |
| first_indexed | 2024-12-20T18:25:14Z |
| format | Article |
| id | doaj.art-f32134fb8d744d22b07daf1e94f6c84b |
| institution | Directory Open Access Journal |
| issn | 1949-1034 1949-1042 |
| language | English |
| last_indexed | 2024-12-20T18:25:14Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Nucleus |
| spelling | doaj.art-f32134fb8d744d22b07daf1e94f6c84b2022-12-21T19:30:11ZengTaylor & Francis GroupNucleus1949-10341949-10422022-12-0113113410.1080/19491034.2021.20246912024691MeCP2-induced heterochromatin organization is driven by oligomerization-based liquid–liquid phase separation and restricted by DNA methylationHui Zhang0Hector Romero1Annika Schmidt2Katalina Gagova3Weihua Qin4Bianca Bertulat5Anne Lehmkuhl6Manuela Milden7Malte Eck8Tobias Meckel9Heinrich Leonhardt10M. Cristina Cardoso11Technical University of DarmstadtTechnical University of DarmstadtTechnical University of DarmstadtTechnical University of DarmstadtLudwig Maximilians University MunichTechnical University of DarmstadtTechnical University of DarmstadtTechnical University of DarmstadtTechnical University of DarmstadtTechnical University of DarmstadtLudwig Maximilians University MunichTechnical University of DarmstadtHeterochromatin is the highly compacted form of chromatin with various condensation levels hallmarked by high DNA methylation. MeCP2 is mostly known as a DNA methylation reader but has also been reported as a heterochromatin organizer. Here, we combine liquid–liquid phase separation (LLPS) analysis and single-molecule tracking with quantification of local MeCP2 concentrations in vitro and in vivo to explore the mechanism of MeCP2-driven heterochromatin organization and dynamics. We show that MeCP2 alone forms liquid-like spherical droplets via multivalent electrostatic interactions and with isotropic mobility. Crowded environments and DNA promote MeCP2 LLPS and slow down MeCP2 mobility. DNA methylation, however, restricts the growth of heterochromatin compartments correlating with immobilization of MeCP2. Furthermore, MeCP2 self-interaction is required for LLPS and is disrupted by Rett syndrome mutations. In summary, we are able to model the heterochromatin compartmentalization as well as MeCP2 concentration and heterogeneous motion in the minimal in vitro system.http://dx.doi.org/10.1080/19491034.2021.2024691dna methylationheterochromatinliquid-liquid phase separationmecp2protein–protein interactionrett syndromesingle molecule tracking |
| spellingShingle | Hui Zhang Hector Romero Annika Schmidt Katalina Gagova Weihua Qin Bianca Bertulat Anne Lehmkuhl Manuela Milden Malte Eck Tobias Meckel Heinrich Leonhardt M. Cristina Cardoso MeCP2-induced heterochromatin organization is driven by oligomerization-based liquid–liquid phase separation and restricted by DNA methylation Nucleus dna methylation heterochromatin liquid-liquid phase separation mecp2 protein–protein interaction rett syndrome single molecule tracking |
| title | MeCP2-induced heterochromatin organization is driven by oligomerization-based liquid–liquid phase separation and restricted by DNA methylation |
| title_full | MeCP2-induced heterochromatin organization is driven by oligomerization-based liquid–liquid phase separation and restricted by DNA methylation |
| title_fullStr | MeCP2-induced heterochromatin organization is driven by oligomerization-based liquid–liquid phase separation and restricted by DNA methylation |
| title_full_unstemmed | MeCP2-induced heterochromatin organization is driven by oligomerization-based liquid–liquid phase separation and restricted by DNA methylation |
| title_short | MeCP2-induced heterochromatin organization is driven by oligomerization-based liquid–liquid phase separation and restricted by DNA methylation |
| title_sort | mecp2 induced heterochromatin organization is driven by oligomerization based liquid liquid phase separation and restricted by dna methylation |
| topic | dna methylation heterochromatin liquid-liquid phase separation mecp2 protein–protein interaction rett syndrome single molecule tracking |
| url | http://dx.doi.org/10.1080/19491034.2021.2024691 |
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