Early postnatal DNA methylation dynamics define neuronal subtypes and are disrupted by MECP2 loss

Area of Science:

• Epigenetics
• Neuroscience
• Developmental Biology

Background:

• DNA methylation is crucial for mammalian tissue development.
• Noncanonical methylation (mCH) is abundant in developing neurons, but its role is unclear.
• Disruption of MECP2, an mCH reader, causes Rett syndrome.

Purpose of the Study:

• To create the first large-scale single-cell methylation atlas of the early postnatal mouse brain.
• To understand the role of mCH in neuronal subtype specification.
• To investigate mCH disruptions in a mouse model of Rett syndrome.

Main Methods:

• Generated a single-cell methylation atlas of the early postnatal mouse brain.
• Analyzed subtype-specific methylation changes during neuronal development.
• Applied single-cell methylation analysis to a Rett syndrome mouse model.

Main Results:

• Identified rapid maturation of the noncanonical methylome (mCH) in neuronal subtypes between postnatal weeks 1 and 2.
• Found mCH changes are concentrated in genes for synaptic partner establishment and membrane potential regulation.
• Observed that in Rett syndrome models, mCH accumulation is globally disrupted, particularly in GABAergic interneurons.

Conclusions:

• Defined methylation dynamics facilitating neuronal subtype specification.
• Resolved subtype-specific, global disruptions of noncanonical methylation in Rett syndrome.
• Highlighted the importance of mCH in neurodevelopment and its dysregulation in Rett syndrome.