GSE171127
Comparative parallel meta-analysis of cells undergoing reprogramming to pluripotency and trophectoderm states
During early embryogenesis, totipotent cells undergo asymmetric cell divisions, resulting in two compartments in the early embryo: the inner cell mass (ICM) that gives rise to pluripotency cells and an outer layer of trophectoderm (TE). It is only at the 32-64- cell stage when a clear segregation between the two cell types can be observed.  This proposes a 'T'-like model where cells of each stage (2-16-cell stage) of the early embryo undergo a relatively similar changes in their transcriptome and epigenome before specification. Here, we sought to understand whether cells acquiring pluripotency or trophectoderm state, by reprogramming factors (OSKM vs GETM), share similar processes between themselves such as those of the early embryo.  To that end, we conducted a comparative parallel meta-analysis on cells undergoing reprogramming to induced pluripotent stem cells (iPSCs) and induced trophoblast stem cells (iTSCs) and examined their transcriptome (i.e. Bulk RNA-seq and SC-RNA-seq), methylome (i.e. RRBS), chromatin accessibility and activity (i.e. ATAC-seq and Chip-seq for H3K4me2 and H3K27ac) and genomic stability (CNVs) along the process. Our analysis revealed that, in contrast to cells of the pre-segregation embryo that mostly resemble each other in each stage, cells undergoing reprogramming to pluripotency and TSC states, exhibit unique and specific trajectories from the beginning of the process till the end, suggesting a 'V'-like behavior. Although similar processes such as somatic identity loss, proliferation, MET and metabolic shift occur in the two models, each of the processes mostly uses different sets of genes and regulatory elements to induce its own fate. We characterized each trajectory in details and illuminated key aspects that are either shared or distinguished between the two states. Using these analyses, we identified previously unknown markers for faithful reprogramming process and key factors that drastically inhibit both reprogramming processes. We show that this comparative parallel meta-analysis is a powerful tool to understand nuclear reprogramming and cellular plasticity at large. Overall design: we conducted a comparative parallel meta-analysis on cells undergoing reprogramming to induced pluripotent stem cells (iPSCs) and induced trophoblast stem cells (iTSCs) and examined their transcriptome (i.e. Bulk RNA-seq and SC-RNA-seq), methylome (i.e. RRBS), chromatin accessibility and activity (i.e. ATAC-seq and Chip-seq for H3K4me2 and H3K27ac) and genomic stability (CNVs) along the process