Decoding molecular markers and transcriptional circuitry of naive and primed states of human pluripotency

Pluripotent stem cells (PSCs) have been observed to occur in two distinct states — naive and primed. Both naive and primed state PSCs can give rise to tissues of all the three germ layers in vitro but differ in their potential to generate germline chimera in vivo. Understanding the molecular mechanisms that govern these two states of pluripotency in human can open a plethora of opportunities for studying early embryonic development and in biomedical applications. In this work, we use weighted gene co-expression network analysis (WGCNA) to identify the key molecular makers and their interactions that define the two distinct pluripotency states. Signed hybrid network was reconstructed from transcriptomic data (RNA-seq) of naive and primed state pluripotent samples. Our analysis revealed two sets of genes that are involved in the establishment and maintenance of naive and primed states. The naive state genes were found to be enriched for biological processes and pathways related to metabolic processes while primed state genes were associated with system development. We further filtered these lists to identify the intra-modular hubs and the hub transcription factors (TFs) for each group. Validation of the identified TFs was carried out using independent microarray datasets and we finally present a list of 52 and 33 TFs as the set of core TFs that are responsible for the induction and maintenance of naive and primed states of pluripotency in human, respectively. Among these, the TFs ZNF275, ZNF232, SP4, and MSANTD3 could be of interest as they were not reported in previous studies.