DNA methylation reader MECP2: cell type- and differentiation stage-specific protein distribution

Abstract

BackgroundMethyl-CpG binding protein 2 (MECP2) is a protein that specifically binds methylated DNA, thus regulating transcription and chromatin organization. Mutations in the gene have been identified as the principal cause of Rett syndrome, a severe neurological disorder. Although the role of MECP2 has been extensively studied in nervous tissues, still very little is known about its function and cell type specific distribution in other tissues.ResultsUsing immunostaining on tissue cryosections, we characterized the distribution of MECP2 in 60 cell types of 16 mouse neuronal and non-neuronal tissues. We show that MECP2 is expressed at a very high level in all retinal neurons except rod photoreceptors. The onset of its expression during retina development coincides with massive synapse formation. In contrast to astroglia, retinal microglial cells lack MECP2, similar to microglia in the brain, cerebellum, and spinal cord. MECP2 is also present in almost all non-neural cell types, with the exception of intestinal epithelial cells, erythropoietic cells, and hair matrix keratinocytes. Our study demonstrates the role of MECP2 as a marker of the differentiated state in all studied cells other than oocytes and spermatogenic cells. MECP2-deficient male (Mecp2-/y ) mice show no apparent defects in the morphology and development of the retina. The nuclear architecture of retinal neurons is also unaffected as the degree of chromocenter fusion and the distribution of major histone modifications do not differ between Mecp2-/y and Mecp2 wt mice. Surprisingly, the absence of MECP2 is not compensated by other methyl-CpG binding proteins. On the contrary, their mRNA levels were downregulated in Mecp2-/y mice.ConclusionsMECP2 is almost universally expressed in all studied cell types with few exceptions, including microglia. MECP2 deficiency does not change the nuclear architecture and epigenetic landscape of retinal cells despite the missing compensatory expression of other methyl-CpG binding proteins. Furthermore, retinal development and morphology are also preserved in Mecp2-null mice. Our study reveals the significance of MECP2 function in cell differentiation and sets the basis for future investigations in this direction.

A High-Resolution Imaging Approach to Investigate Chromatin Architecture in Complex Tissues

“…Our general observation is that MeCP2 expression scales with nuclear size, and cerebellar granule cells express the lowest amount of MeCP2 of the cell types examined in this study (data not shown). The lack of changes in H4K20me3 distribution in cerebellar granule cells agrees with results from a previous study that did not find differences in histone modifications in Mecp2 -null retinal neurons (Song et al, 2014). These results stress the importance of cell sorting or in situ approaches when studying gene expression in the brain.…”

Expression of Phospho-MeCP2s in the Developing Rat Brain and Function of Postnatal MeCP2 in Cerebellar Neural Cell Development

“…Moreover, MeCP2 was observed in a few astrocytes (Fig. 6A, B), consistent with previous findings [11,28]. Interestingly, pS80 MeCP2, pS421 MeCP2, and pS292 MeCP2 were also detected in astrocytes, although doublelabeled cells were extremely few (Fig.…”

Clinical and biological progress over 50 years in Rett syndrome

“…50,51 Deletion of Mecp2 from glia in mice has relatively minor phenotypic consequences but a restoration of MeCP2 to astrocytes in an otherwise MeCP2-deficient nervous system results in a partial amelioration of phenotypes including a normalisation of breathing patterns, motor activities and anxiety. 48 As also indicated in primary culture experiments, 52 MeCP2 in glial cells may contributing to certain non-cell autonomous functions such as supporting normal dendritic morphology through the release of trophic factors within the nervous system.…”