Epigenetic architecture of the developing brain

This chapter reviews the evolution of DNA methylation programs during brain development, focusing on how DNA methylation patterns define cell identity and regulate gene expression. It traces early hypotheses about tissue-specific DNA methylation and highlights limitations of bulk tissue analysis. Advances in genome-wide mapping, cell sorting, and single-cell sequencing have clarified the roles of CG and non-CG methylation in neuronal and glial differentiation. The chapter details how enhancer and gene body methylation correlate with transcriptional activity and how transcription factors, like Early Growth Response 1, recruit demethylation machinery during development. It also discusses the emergence of non-CG methylation in neurons, its association with gene repression, and its potential role in neurodevelopmental disorders. Differentially methylated regions and methylation-sensitive genetic variants are increasingly linked to neurodevelopmental disease risk, such as autism and schizophrenia, highlighting the relevance of epigenetic mapping for understanding brain pathology. Finally, integrated methylome and chromatin accessibility data are used to classify neuronal subtypes and link methylation states to 3D genome architecture.