Cell-type-specific DNA methylation dynamics in the prenatal and postnatal human cortex

Franklin, Alice, Davies, Jonathan P., Clifton, Nicholas E., Blake, Georgina E.T., Bamford, Rosemary, Walker, Emma M., Chioza, Barry, Frith, Martyn, Burrage, Joe, Owens, Nick, Prabhakar, Shyam, Dempster, Emma, Hannon, Eilis, Mill, Jonathan, Riglin, Lucy, Richards, Alex and O’Donovan, Mick ORCID: https://orcid.org/0000-0001-7073-2379 2025. Cell-type-specific DNA methylation dynamics in the prenatal and postnatal human cortex. Cell Genomics 5 (12) , 101010. 10.1016/j.xgen.2025.101010

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Abstract

The human cortex undergoes extensive epigenetic remodeling during development, although the precise temporal and cell-type-specific dynamics of DNA methylation remain incompletely understood. In this study, we profiled genome-wide DNA methylation across human cortex tissue from donors aged 6 post-conception weeks to 108 years of age. We observed widespread, developmentally regulated changes in DNA methylation, with pronounced shifts occurring during early- and mid-gestation that were distinct from age-associated modifications in the postnatal cortex. Using fluorescence-activated nuclei sorting, we optimized a protocol for the isolation of SATB2-positive neuronal nuclei, enabling the identification of cell-type-specific DNA methylation trajectories in the developing cortex. Developmentally dynamic DNA methylation sites were significantly enriched near genes implicated in autism and schizophrenia, supporting a role for epigenetic dysregulation in neurodevelopmental conditions. Our findings underscore the prenatal period as a critical window of epigenomic plasticity in the brain with important implications for understanding the genetic basis of neurodevelopmental phenotypes.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Cell Press
ISSN:	2666-979X
Date of First Compliant Deposit:	26 February 2026
Date of Acceptance:	27 August 2025
Last Modified:	26 Feb 2026 13:14
URI:	https://orca.cardiff.ac.uk/id/eprint/185334

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