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

Area of Science:

• Neuroscience
• Epigenetics
• Stem Cell Biology

Background:

• Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are valuable models for central nervous system research.
• The suitability of these models for studying age-associated processes is uncertain, as pluripotency is limited to early development.
• Epigenetic clocks, based on DNA methylation, predict biological age but existing ones are not optimized for brain development.

Purpose of the Study:

• To develop and validate a bespoke epigenetic clock, the fetal brain clock (FBC), specifically for human prenatal brain samples.
• To investigate the epigenetic age of iPSCs and iPSC-neurons using the FBC.
• To assess the utility of iPSC-derived cells as models for age-related neurological conditions.

Main Methods:

• Development of the fetal brain clock (FBC) trained on human prenatal brain DNA methylation data.
• Validation of the FBC in two independent cohorts (194 samples) against established epigenetic clocks.
• Application of the FBC to DNA methylation data from iPSCs, embryonic stem cells, and their neuronal derivatives.

Main Results:

• The FBC demonstrated superior performance in fetal brain cohorts compared to existing epigenetic clocks.
• iPSCs and derived neuronal precursor cells/neurons were epigenetically characterized as having an early fetal age.
• Differentiation into iPSC-neurons increased epigenetic age, but these cells remained epigenetically fetal.

Conclusions:

• The findings underscore the limitations of current epigenetic clocks for specific research questions, particularly in brain development.
• iPSC-neurons exhibit an epigenetic age that may not accurately reflect age-related changes in the adult central nervous system.
• The study highlights a significant limitation of using iPSC-neurons for modeling age-related neurological diseases.