Molecular mechanisms: Rett changes gene expression in glia

MeCP2, a regulator of gene expression that is mutated in Rett syndrome, may regulate a different set of genes in brain cells called astrocytes than in neurons, according to a study published 25 January in Molecular Autism¹.

Astrocytes are part of the glia family of cells, which includes all non-neuronal cells in the brain. Astrocytes support neurons and stabilize the junctions between them. Studies in the past few years have shown that astrocytes and other glia also contribute to important brain functions, such as learning and memory.

Researchers have linked glia to Rett syndrome, a developmental disorder that resembles autism. A 2011 study found that expressing MeCP2 only in the astrocytes of MeCP2-deficient mice alleviates symptoms of Rett syndrome and corrects abnormalities in neuronal shape². Giving the mice a bone marrow transplant has a similar effect, perhaps by introducing functional microglia, the immune cells of the brain.

Despite the fact that glia may play a significant role in Rett syndrome, however, most studies of the syndrome have focused only on neurons. MeCP2 both boosts and dampens the expression of literally thousands of genes. It also binds at multiple sites across the genome. Narrowing down which of MeCP2’s targets contribute to Rett syndrome remains a challenge.

In the new study, researchers looked specifically at MeCP2’s targets in astrocytes. They found that 118 genes are expressed at significantly higher or lower levels in astrocytes that lack MeCP2 than in typical astrocytes.

Only 4 of these genes overlap with the 2,582 genes that show altered expression in neurons lacking MeCP2³. This suggests that MeCP2 may have different targets in astrocytes than in neurons, the researchers say.

To learn whether the gene expression changes could be related to MeCP2, the researchers sequenced all of the DNA that MeCP2 binds to in astrocytes. They then looked at MeCP2’s binding sites near the beginnings and ends of genes — which are known to contain regulatory regions for gene expression — and within the gene sequences themselves.

Of the 1,973 regions that show the highest binding to MeCP2, 19 overlap with genes that have altered expression in astrocytes lacking MeCP2, they found.

For example, MeCP2 binds to an area within the coding region of the gene SLC38A1, and in MeCP2’s absence, SLC38A1 expression drops. SLC38A1 is involved in regenerating levels of the chemical messenger glutamate, which sends activating signals in the brain.

References:

1: Yasui D.H. et al. Mol. Autism 4, 3 (2013) PubMed

2: Lioy D.T. et al. Nature 475, 497-500 (2011) PubMed

3:Chahrour M. et al. Science 320, 1224-1229 (2008) PubMed