4.4 Article

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

期刊

MOLECULAR BRAIN
卷 14, 期 1, 页码 -

出版社

BMC
DOI: 10.1186/s13041-021-00810-w

关键词

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

资金

  1. Simons Foundation (SFARI) [573312]
  2. Medical Research Council (MRC) [MR/R005176/1]
  3. Medical Research Council [G0700089, MR/L010674/2, N013255/1]
  4. Wellcome Trust [GR082557]
  5. Alzheimer's Research UK
  6. Alzheimer's Society in association
  7. Medical Research Council
  8. Alzheimer's Society
  9. BRACE (Bristol Research into Alzheimer's and Care of the Elderly)
  10. European Autism Interventions (EU-AIMS): the Innovative Medicines Initiative Joint Undertaking from the European Union's Seventh Framework Programme (FP7/2007-2013) [115300]
  11. Innovative Medicines Initiative joint undertaking [115439-2]
  12. EU-AIMS (European Autism Interventions)/EU AIMS-2-TRIALS, an Innovative Medicines Initiative Joint Undertaking [777394]
  13. National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King's College London
  14. MRC [MR/L010674/2] Funding Source: UKRI

向作者/读者索取更多资源

The use of fetal brain clock (FBC) allows for a more precise study of the epigenetic age of iPSCs and iPSC-neurons. Analysis of DNA methylation data from iPSCs, embryonic stem cells, and their derived neuronal precursor cells and neurons reveals that these cell types are characterized as having an early fetal age. Differentiation from iPSCs to neurons increases epigenetic age, but iPSC-neurons are still predicted as being fetal.
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.

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