Methyl CpG-binding Proteins Induce Large-scale Chromatin Reorganization During Terminal Differentiation

Pericentric heterochromatin plays an important role in epigenetic gene regulation. In particular, the localization of genes in close physical proximity to heterochromatin has been shown to cause heritable silencing. This chromatin is characterized by high level of DNA methylation. The latter represents another type of epigenetic modulator involved in establishing cell type specific transcriptional profiles that, if not set properly, impedes normal development and can induce malignant transformation. Located on the X chromosome, the MeCP2 gene encodes a protein that binds specifically to methylated DNA and is mutated in the second most frequent mental retardation disease in girls, the Rett syndrome. Now, researchers from the MDC and the Ludwig Maximilians University in Munich have shown that MeCP2 can induce a large-scale reorganization of pericentric heterochromatin during terminal differentiation, thus connecting two levels of epigenetic control: DNA methylation and nuclear organization (Journal of Cell Biology 2005, vol. 169 (5), pp. 733-743, doi:10.1083/jcb.200502062).

The study by Dr. Alessandro Brero (laboratory of M. Cristina Cardoso) and colleagues reveals that pericentric heterochromatin aggregates during myogenic differentiation. This clustering leads to the formation of large chromocenters and correlates with increased levels of the methyl CpG binding protein MeCP2 and pericentric DNA methylation. Ectopic expression of fluorescently tagged MeCP2 mimicks this effect, causing a dose dependent clustering of chromocenters in the absence of differentiation. The scientists found that MeCP2 induced rearrangement of heterochromatin occurred throughout interphase, did not depend on the H3K9 histone methylation pathway, and required the methyl CpG binding domain (MBD) only. Similar to MeCP2, another methyl CpG binding protein MBD2, also increased during myogenic differentiation and could induce clustering of pericentric regions, arguing for functional redundancy. Thus, the study results suggest that MeCP2 and MBD2 mediated chromatin reorganization represent a molecular link between nuclear genome topology and the epigenetic maintenance of cellular differentiation.


Pamela Cohen
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