How heterochromatin composition impacts architecture

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In different tissues, the same genetic information is present in the cell nucleus but its expression and organization differs. This is largely controlled not at the level of the DNA sequence per se but at the epigenetic level. This epigenetic regulation depends on several factors, including DNA methylation and interaction with nuclear proteins. One important regulatory mechanism is the organization of DNA into actively transcribed euchromatin and condensed, mostly ‘silent’ heterochromatin. The structure, composition, and formation of heterochromatin are not fully understood, but they are known to differ between tissues, and this likely contributes to and reflects the different proteomes found in different cell types. An important aspect of heterochromatin organization is the large-scale clustering that leads to the formation of so-called chromocenters. The protein MeCP2 interacts with methylated DNA and is known to be involved in chromocenter formation, but its role is not fully understood. Mutations in this X chromosome-linked gene are important to human health, as they are associated with in utero lethal (males) or neurological (females) phenotypes. The molecular mechanism behind this pathology is not well understood. Our project brings together researchers with strong track records in cell biology, epigenetics, microscopy, proteomics, and structural biology. Using our combined expertise and infrastructure, we will investigate the structure and molecular composition of heterochromatin from different cell and tissue types, with particular attention to the structure and interactions of different MeCP2 mutants from the subcellular to the molecular scale. We will achieve this through the synergistic use of a range of techniques, including (fluorescence) microscopy and image analysis, protein biochemistry, mass spectrometry-based proteomics, and conformation-sensitive mass spectrometry.