Summary: Researchers have produced a comprehensive map of DNA methylation across nearly 1,000 human brains, spanning development from six weeks after conception through old age. The study reveals pronounced epigenetic changes before birth that direct formation of the cerebral cortex—the brain region central to thought, memory, perception, and behavior—and highlights links between these changes and neurodevelopmental conditions.
The work shows that gene-associated chemical tags, known as DNA methylation, are especially dynamic during prenatal development. Genes previously associated with autism and schizophrenia display particularly active methylation changes in early life, suggesting that disrupted epigenetic programming during prenatal periods may contribute to the origins of these conditions. Together, these findings emphasize the importance of epigenetic regulation in brain development and provide a resource for future research into mental health and neurodevelopmental disorders.
Key Facts
- DNA Methylation Shifts: Major epigenetic transitions occur predominantly before birth, guiding cortical development.
- Cell-Type Specificity: Neurons exhibit distinct DNA methylation patterns early in development that differ from other brain cell types.
- Neurodevelopmental Links: Genes implicated in autism and schizophrenia undergo especially dynamic methylation changes during prenatal and early postnatal periods.
Source: University of Exeter
Researchers at the University of Exeter have assembled a high-resolution temporal map of DNA methylation throughout human brain development and aging, providing new insight into how epigenetic processes shape the cortex and how their disruption might relate to disorders such as autism and schizophrenia.
The team examined epigenetic modifications—chemical marks on DNA that influence whether genes are turned on or off—across a large collection of donated human brain tissue. These marks play a central role in guiding cells to adopt specialized identities and establishing the cellular architecture required for brain function.
One epigenetic mechanism studied in depth was DNA methylation. The researchers measured genome-wide methylation patterns in almost 1,000 human cortex samples, covering donors from 6 post-conception weeks to 108 years of age. This extensive age range allowed the team to chart how methylation changes evolve across prenatal development, through infancy and childhood, and into old age.
Focusing on the cortex—a region responsible for higher-order cognitive functions—the study found that the most dramatic methylation shifts occur before birth. These prenatal changes correspond to activation of biological pathways needed to assemble the cortex, including those involved in neuronal differentiation and circuit formation.
Using cell-type separation techniques, the researchers identified methylation patterns specific to neurons. Neuronal nuclei began to show unique methylation signatures early in development, distinct from glial and other non-neuronal cells. These cell-specific trajectories underscore how epigenetic programming contributes to the emergence of diverse brain cell types.
Notably, sites of methylation that changed dynamically during development were enriched near genes previously linked to autism and schizophrenia. This enrichment suggests that epigenetic modulation of these genes is an integral part of normal brain development and that perturbations in these processes may play a role in the pathogenesis of neurodevelopmental disorders.
Alice Franklin, the study’s first author, commented that mapping chemical changes to DNA across the human lifespan has revealed important clues about when and how neurodevelopmental conditions may originate. She emphasized that many of the relevant epigenetic events occur very early, during prenatal development.
Professor Jonathan Mill, who led the research, noted that the work clarifies biological processes guiding brain development and how these processes differ across cell types. Over time, he suggests, these insights could help researchers better understand the mechanisms underlying neurodevelopmental conditions and identify more targeted avenues for investigation.
Funding: This research was supported by the Simons Foundation Autism Research Initiative, the Medical Research Council, and the European Union’s Horizon Programme, with additional backing from Wellcome and the NIHR Exeter Biomedical Research Centre.
About this genetics, Autism, and schizophrenia research news
Author: Louise Vennells
Source: University of Exeter
Contact: Louise Vennells – University of Exeter
Image: The image is credited to Neuroscience News
Original Research: Open access. “Cell-type-specific DNA methylation dynamics in the prenatal and postnatal human cortex” by Alice Franklin et al., published in Cell Genomics. The study presents genome-wide DNA methylation profiling across human cortex samples spanning early prenatal development to advanced age.
Abstract
Cell-type-specific DNA methylation dynamics in the prenatal and postnatal human cortex
The human cortex experiences extensive epigenomic remodeling across development, yet the precise timing and cell-type specificity of DNA methylation changes have not been fully defined. In this study, researchers profiled genome-wide DNA methylation in human cortex tissue from donors aged 6 post-conception weeks to 108 years. They observed widespread, developmentally regulated methylation changes, with pronounced shifts during early and mid-gestation that contrast with age-related modifications occurring postnatally.
By applying fluorescence-activated nuclei sorting to isolate SATB2-positive neuronal nuclei, the team characterized cell-type-specific methylation trajectories in the developing cortex. Developmentally dynamic methylation sites were significantly enriched near genes implicated in autism and schizophrenia, supporting a role for epigenetic regulation in neurodevelopmental phenotypes. These results emphasize the prenatal period as a critical window of epigenomic plasticity with important implications for understanding the genetic and epigenetic basis of neurodevelopmental conditions.