Latest MECP2 News from the Mandel Lab
Housed in the nucleus of every cell in the body is 6 feet of DNA. The nucleus is so small that 10,000 of them with a combined total of 11 miles of DNA would fit on the tip of a needle. The video below explains how the unimaginable feat of coiling this amount of DNA is accomplished.
Today the journal, Cell, published research from the lab of Gail Mandel showing that the Rett protein, MeCP2, plays a role in how DNA is packaged into the nucleus. This research was funded, in part, by RSRT through the MECP2 Consortium. Using a technology called array tomography the Mandel lab found that in cells that are missing MeCP2 the DNA is more tightly compacted.
Increased compaction “hides” genes from the cellular machinery needed for protein production. So genes that are compacted are less likely to be producing protein.
Imagine DNA as a slinky with genes along the coils. In a compressed state it is difficult for these genes to be accessed by the necessary molecules that facilitate protein production. However, when the slinky is stretched out the genes become very accessible for protein production.
The scientists also found that the degree of DNA compaction was correlated to the degree of MeCP2 requirement in a given cell type. For example, cells that typically require large amounts of MeCP2 (eg. Purkinje cells) will suffer a greater change in compaction when MeCP2 is missing than cells who normally have a smaller requirement of MeCP2 (eg. astrocytes).
The video below shows normal nuclear compaction in Purkinje cells of female mice on the left and Rett mutant mice on the right.
The person responsible for this work, Mike Linhoff of the Mandel lab, describes the video, “The white shows DNA, while the green shows DNA sequences where MeCP2 binds. Red shows a particular protein modification that promotes DNA compaction. In the absence of MeCP2 this compacting modification invades the DNA sequences where MeCP2 usually binds.”
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The clinical relevance of the work is to point towards cures that will take into account neuronal-specific effects of MeCP2 loss. Once such strategy, which RSRT is already pursuing, is to reactivate the silent MECP2 on the inactive X. Other strategies might include identifying factors that can titrate gene therapy levels of MeCP2 in different neuronal types, or identifying a druggable common downstream consequence that occurs in all neuronal types.
– Gail Mandel