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bioRxiv · 10.1101/2024.08.29.610372

Epigenomic anomalies in induced pluripotent stem cells from Alzheimer disease cases

Flamier, A.·Katbe, A.·Serhani, D.·Hamam, R.·Hogan, R.·Tavares, E.·Heon, E.·Hanna, R.·Bernier, G.
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Abstract

Reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) resets the aging clock. However, primed iPSCs can retain cell-of-origin epigenomic marks, especially those linked to heterochromatin and lamina-associated regions. Here we show that iPSCs produced from dermal fibroblasts of late-onset sporadic Alzheimers disease (AD) cases retain epigenomic anomalies that supersede developmental defects and neurodegeneration. When compared to iPSCs from elderly controls, AD iPSCs show reduced BMI1 expression, lower H3K9me3 levels, and an altered DNA methylome. Gene Ontology analysis of differentially methylated DNA regions (DMRs) reveals terms linked to cell-cell adhesion and synapse, with the cognitive resilience-associated MEF2 family of transcription factors being the most enriched at DMRs. Upon noggin exposure, AD iPSCs show lesser efficient neural induction and forebrain specification, together with increased ZIC2, ZIC5 and WNT-related gene expression. Long-term AD neuronal cultures present a dedifferentiation and loss-of-cell identity phenotype. Despite these epigenomic anomalies, AD iPSCs generate cortical neurons in normal proportion and readily form cerebral organoids developing amyloid and Tau pathology. BMI1 overexpression in AD neurons mitigates amyloid and tau accumulation, heterochromatin fragmentation, and G4 DNA induction. These findings implicate reprogramming resistant epigenomic anomalies or uncharacterized genetic alterations working in trans on the epigenome in AD pathophysiology.

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Flamier, A., Katbe, A., Serhani, D., Hamam, R., Hogan, R., Tavares, E., Heon, E., Hanna, R., Bernier, G.. 2024-08-30. Epigenomic anomalies in induced pluripotent stem cells from Alzheimer disease cases. https://doi.org/10.1101/2024.08.29.610372

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