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

Molecular Brain

Joe Burrage¹  Eilis Hannon¹  Akshay Bhinge¹  Gemma L. Shireby¹  Grant W. A. Neilson¹  Alice Franklin¹  Jennifer Imm¹  Aaron R. Jeffries¹  Emma L. Dempster¹  Jonathan Mill¹  Jonathan P. Davies¹  Leonard C. Steg¹  Robert Flynn¹  Seema C. Namboori¹  Katie Lunnon¹  Emma M. Walker¹  Ehsan Pishva²  Leo W. Perfect³  Jack Price³  Deepak P. Srivastava⁴  Grainne McAlonan⁵  Nicholas J. Bray⁶  Emma L. Cope⁷  Kimberley M. Jones⁷  Nicholas D. Allen⁷ 

[1] College of Medicine and Health, University of Exeter, RILD Building Level 3, Barrack Rd, Exeter, UK;College of Medicine and Health, University of Exeter, RILD Building Level 3, Barrack Rd, Exeter, UK;Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands;Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK;Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK;MRC Centre for Neurodevelopmental Disorders, King’s College London, London, UK;Department of Forensic and Neurodevelopmental Sciences, King’s College London, London, UK;MRC Centre for Neurodevelopmental Disorders, King’s College London, London, UK;Behavioural and Developmental Psychiatry, South London and Maudsley NHS Foundation Trust, London, UK;Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK;School of Biosciences, Cardiff University, Cardiff, UK;

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

DOI  :  10.1186/s13041-021-00810-w

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY