Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons

Leonard C. Steg, Gemma L. Shireby, Jennifer Imm, Jonathan P. Davies, Alice Franklin, Robert Flynn, Seema C. Namboori, Akshay Bhinge, Aaron R. Jeffries, Joe Burrage, Grant W.A. Neilson, Emma M. Walker, Leo W. Perfect, Jack Price, Grainne McAlonan, Deepak P. Srivastava, Nicholas J. Bray, Emma L. Cope, Kimberley M. Jones, Nicholas D. AllenEhsan Pishva, Emma L. Dempster, Katie Lunnon, Jonathan Mill, Eilis Hannon

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and embryonic stem cells and their derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases.

Original languageEnglish
Article number98
Pages (from-to)98
Number of pages1
JournalMolecular brain
Issue number1
Publication statusPublished - 26 Jun 2021


  • DNA methylation
  • DNAm clock
  • Epigenetic clock
  • Fetal
  • Induced pluripotent stem cells
  • iPSC-derived neurons
  • Neurodevelopment
  • Neuronal precursor cells


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