Integrative Meta-Analysis during Induced Pluripotent Stem Cell Reprogramming Reveals Conserved Networks and Chromatin Accessibility Signatures in Human and Mouse

Abstract

iPSC reprogramming involves dynamic changes in chromatin accessibility necessary for the conversion of somatic cells into induced pluripotent stem cells (iPSCs). IPSCs can be used to generate a wide range of cells to potentially replace damaged cells in a patient without the threat of immune rejection; however, efficiently reprogramming cells for medical applications remains a challenge, particularly in human cells. Here, we conducted a cross-species meta-analysis to identify conserved and species-specific differences in regulatory patterns during reprogramming. Chromatin accessibility and transcriptional data as fibroblasts transitioned to iPSCs were obtained from the publicly available Gene Expression Omnibus (GEO) database and integrated to generate time-resolved regulatory networks during cellular reprogramming. We observed consistent and conserved trends between the species in the chromatin accessibility signatures as cells transitioned from fibroblasts into iPSCs, indicating distal control of genes associated with pluripotency by master reprogramming regulators. Multi-omic integration showed key network changes across reprogramming states, revealing regulatory relationships between chromatin regulators, enhancers, transcription factors, and target genes that result in the silencing of the somatic transcription program and activation of the pluripotency gene regulatory network. This integrative analysis revealed distinct network changes between timepoints and leveraged multi-omics to gain novel insights into the regulatory mechanisms underlying reprogramming.