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Characterisation of DNA methylomic signatures of induced pluripotent stem cells during neuronal differentiation

ABSTRACT: In development, inducing pluripotency and differentiation into different cell types results in global epigenetic changes, although the extent this occurs in induced pluripotent stem cell (iPSC)-based neuronal models has not been extensively characterized. We have differentiated iPSCs (33Qn1 cell line) into cortical neurons and assessed their DNA methylation profile at different time points during differentiation and maturation to identify DNA methylomic trajectories of neuronal aging. Samples were collected at four different time points, these were at the iPSC, neuronal precursor (NPC) and two different terminally differentiated neuronal time points (day 37 and day 58). We have identified loci undergoing significant DNA methylation changes throughout differentiation, have created an epigenetic trajectory signature associated with differentiation/maturation and identified highly connected and influential loci using gene-gene interaction analysis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158089 | GEO | 2021/06/03

REPOSITORIES: GEO

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Project description:Rationale: Cardiac development is a complex process that results in the first integrated, multi-lineage embryonic tissue. Imperfect developmental progression leads to congenital heart disease, the most common birth defect with developmental corruption affecting more than 1% of all live births. Interrogation of individual genes has provided the backbone for cardiac developmental biology, yet a comprehensive transcriptome derived from natural cardiogenesis is required to establish an unbiased roadmap to gauge innate developmental milestones necessary for stem cell-based differentiation and in vitro disease modeling. Objective: Establish a contextual expression database of spatial-temporal cardiac structures, and validate a predictive tool to diagnose and predict cardiogenic outcomes from individual pluripotent stem cell lines. Methods and Results: Stage-specific cardiac structures were dissected from eight distinctive embryonic time points to produce a genome-wide expressome analysis across the spectrum of early to late cardiogenesis. Hierarchical clustering of the time course dataset demonstrated discrete gene expression profiles during natural embryonic development. In reference to the native cardiogenic expression roadmap, disruptive iPSC-derived cardiac expression profiles were revealed from pro-cardiogenic 3-factor (SOX2, OCT4, KLF4) compared to non-cardiogenic 4-factor (addition of c-MYC) reprogramming regimens upon stage-specific differentiation. Expression of cardiac-related genes from 3F-iPSC differentiated in vitro at day 0, 5, and 11 recapitulated expression of natural embryos at days 0, E7.5-E8.5, and E14.5-E18.5, respectively. In contrast, 4F-iPSC demonstrated variable gastrulation gene expression profiles beginning at day 5 of differentiation. Differential gene expression within the pluripotent ground state between the archetypical high cardiogenic potential of embryonic stem cells recapitulated in 3F-iPSC vs. the low cardiogenic potential of 4F-iPSC revealed 23 distinguishing candidate genes. Upon subsequent differentiation, cell line-specific gene expression differences were magnified to 399 genes at day 5 and 726 genes at day 11. A confirmed panel of 20 genes, differentially expressed between high and low cardiogenic cell lines, was transformed into a predictive score that was sufficient to correctly rank independent iPSC lines according to cardiogenic potential. Conclusions: Transcriptome analysis attuned to the embryonic developing heart provides a robust platform to probe coordinated cardiac specification and maturation from stem cell-based cardiogenesis model systems. Based on this genome-wide expressome roadmap, a panel of pre-cardiac genes was extracted that allowed differential prognosis of cardiogenic competency from individual reprogrammed cell lines at the pluripotent state. The overall experimental design includes 3 time points (Day0, Day5, Day11) and 3 different stem cell lines: R1 embryonic stem cells (ESCs), H9 induced pluripotent stem cells (H9-iPSCs) generated/reprogrammed by 3 transcription factors (called 3F-iPSCs), and 19BL induced pluripotent stem cells (19BL-iPSCs) generated/reprogrammed by 4 transcription factors (called 4F-iPSC). At each time point, each cell line has 3 biological replicates. In total, there are 27 samples. R1-embryonic stem cells (R1-ESCs): Day0 undifferentiated ESCs - 3 biological replicates, Differentiated for 5 days (Day5) - 3 biological replicates, Differentiated for 11 days (Day11) - 3 biological replicates. 3F-iPSC (H9 iPSCs): Day 0 undifferentiated - 3 biological replicates, Differentiated for 5 days (Day5) - 3 biological replicates, Differentiated for 11 days (Day11) - 3 biological replicates. 4F-iPSC (19BL-iPSCs): Day0 undifferentiated - 3 biological replicates, Differentiated for 5 days (Day5) - 3 biological replicates, Differentiated for 11 days (Day11) - 3 biological replicates.

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Characterisation of DNA methylomic signatures of induced pluripotent stem cells during neuronal differentiation

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