Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons
Abstract 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 pr...
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-06-01
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| Series: | Molecular Brain |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13041-021-00810-w |
| _version_ | 1818743113640837120 |
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| author | 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. Allen Ehsan Pishva Emma L. Dempster Katie Lunnon Jonathan Mill Eilis Hannon |
| author_facet | 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. Allen Ehsan Pishva Emma L. Dempster Katie Lunnon Jonathan Mill Eilis Hannon |
| author_sort | Leonard C. Steg |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-18T02:23:15Z |
| format | Article |
| id | doaj.art-18efbbb134be4d4aa4a20747dc35b350 |
| institution | Directory Open Access Journal |
| issn | 1756-6606 |
| language | English |
| last_indexed | 2024-12-18T02:23:15Z |
| publishDate | 2021-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Brain |
| spelling | doaj.art-18efbbb134be4d4aa4a20747dc35b3502022-12-21T21:24:06ZengBMCMolecular Brain1756-66062021-06-0114111110.1186/s13041-021-00810-wNovel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neuronsLeonard C. Steg0Gemma L. Shireby1Jennifer Imm2Jonathan P. Davies3Alice Franklin4Robert Flynn5Seema C. Namboori6Akshay Bhinge7Aaron R. Jeffries8Joe Burrage9Grant W. A. Neilson10Emma M. Walker11Leo W. Perfect12Jack Price13Grainne McAlonan14Deepak P. Srivastava15Nicholas J. Bray16Emma L. Cope17Kimberley M. Jones18Nicholas D. Allen19Ehsan Pishva20Emma L. Dempster21Katie Lunnon22Jonathan Mill23Eilis Hannon24College of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDepartment of Forensic and Neurodevelopmental Sciences, King’s College LondonDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonDivision of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff UniversitySchool of Biosciences, Cardiff UniversitySchool of Biosciences, Cardiff UniversitySchool of Biosciences, Cardiff UniversityCollege of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterCollege of Medicine and Health, University of ExeterAbstract 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.https://doi.org/10.1186/s13041-021-00810-wEpigenetic clockDNA methylationFetalNeurodevelopmentInduced pluripotent stem cellsiPSC-derived neurons |
| spellingShingle | 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. Allen Ehsan Pishva Emma L. Dempster Katie Lunnon Jonathan Mill Eilis Hannon Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons Molecular Brain Epigenetic clock DNA methylation Fetal Neurodevelopment Induced pluripotent stem cells iPSC-derived neurons |
| title | Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons |
| title_full | Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons |
| title_fullStr | Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons |
| title_full_unstemmed | Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons |
| title_short | Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons |
| title_sort | novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons |
| topic | Epigenetic clock DNA methylation Fetal Neurodevelopment Induced pluripotent stem cells iPSC-derived neurons |
| url | https://doi.org/10.1186/s13041-021-00810-w |
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