Abstract
MeCP2 is a critical epigenetic regulator in brain and its abnormal expression or compromised function leads to a spectrum of neurological disorders including Rett Syndrome and autism. Altered expression of the two MeCP2 isoforms, MeCP2E1 and MeCP2E2 has been implicated in neurological complications. However, expression, regulation and functions of the two isoforms are largely uncharacterized. Previously, we showed the role of MeCP2E1 in neuronal maturation and reported MeCP2E1 as the major protein isoform in the adult mouse brain, embryonic neurons and astrocytes. Recently, we showed that DNA methylation at the regulatory elements (REs) within the Mecp2 promoter and intron 1 impact the expression of Mecp2 isoforms in differentiating neural stem cells. This current study is aimed for a comparative analysis of temporal, regional and cell type-specific expression of MeCP2 isoforms in the developing and adult mouse brain. MeCP2E2 displayed a later expression onset than MeCP2E1 during mouse brain development. In the adult female and male brain hippocampus, both MeCP2 isoforms were detected in neurons, astrocytes and oligodendrocytes. Furthermore, MeCP2E1 expression was relatively uniform in different brain regions (olfactory bulb, striatum, cortex, hippocampus, thalamus, brainstem and cerebellum), whereas MeCP2E2 showed differential enrichment in these brain regions. Both MeCP2 isoforms showed relatively similar distribution in these brain regions, except for cerebellum. Lastly, a preferential correlation was observed between DNA methylation at specific CpG dinucleotides within the REs and Mecp2 isoform-specific expression in these brain regions. Taken together, we show that MeCP2 isoforms display differential expression patterns during brain development and in adult mouse brain regions. DNA methylation patterns at the Mecp2 REs may impact this differential expression of Mecp2/MeCP2 isoforms in brain regions. Our results significantly contribute towards characterizing the expression profiles of Mecp2/MeCP2 isoforms and thereby provide insights on the potential role of MeCP2 isoforms in the developing and adult brain.
Highlights
Mutation or altered expression of the X-linked Methyl CpG Binding Protein 2 (MECP2) gene leads to a wide spectrum of neurodevelopmental disorders including autism spectrum disorders and Rett Syndrome [1,2,3]
We present a comparative analysis of MeCP2 isoforms during mouse brain development and in the adult mouse brain
We show that MeCP2E1 and MeCP2E2 are expressed in neurons, astrocytes and oligodendrocytes in the brain hippocampus of both male and female brains
Summary
Mutation or altered expression of the X-linked Methyl CpG Binding Protein 2 (MECP2) gene leads to a wide spectrum of neurodevelopmental disorders including autism spectrum disorders and Rett Syndrome [1,2,3]. Recent studies have shown that MeCP2 binds to 5-hydroxymethylcytosine (5 hmC), presumably associated with transcriptional activators [11,12]. While 5 mC is a hallmark of inactive genes [9], 5 hmC is generally associated with active genes [11]. It is unclear how, as a single protein MeCP2 provides so many different nuclear functions. One possible explanation could be the existence of redundant and non-redundant functions between the two MeCP2 isoforms
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