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

Franklin, A.; Davies, J.; Clifton, N.; Blake, G.; Bamford, R.; Walker, E.; Chioza, B.; Frith, M.; Burrage, J.; Owens, N.; Prabhakar, S.; Dempster, E.; Hannon, E.; Mill, J.

doi:10.1101/2025.02.21.639467

bioRxiv · 10.1101/2025.02.21.639467

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

Franklin, A.·Davies, J.·Clifton, N.·Blake, G.·Bamford, R.·Walker, E.·Chioza, B.·Frith, M.·Burrage, J.·Owens, N.·Prabhakar, S.·Dempster, E.·Hannon, E.·Mill, J.

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Abstract

The human cortex undergoes extensive epigenetic remodelling 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 (pcw) 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 (FANS), we optimized a protocol for the isolation of SATB2-positive neuronal nuclei, enabling the identification of cell-type-specific DNA methylation trajectories in developing neuronal and non-neuronal populations. Developmentally dynamic DNA methylation sites were significantly enriched near genes implicated in autism and schizophrenia, supporting a role for epigenetic dysregulation in neurodevelopmental disorders. Our findings underscore the prenatal period as a critical window of epigenomic plasticity in the central nervous system with important implications for understanding the genetic basis of neurodevelopmental phenotypes.

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Franklin, A., Davies, J., Clifton, N., Blake, G., Bamford, R., Walker, E., Chioza, B., Frith, M., Burrage, J., Owens, N., Prabhakar, S., Dempster, E., Hannon, E., Mill, J.. 2025-02-21. Cell-type-specific DNA methylation dynamics in the prenatal and postnatal human cortex. https://doi.org/10.1101/2025.02.21.639467

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