The divergent role of two PRDM1 isoforms during human naïve pluripotency reprogramming [CUT&Tag]

Induced pluripotent stem cells (iPSCs) technology offers great promise for scientific research and clinical applications. iPSCs can be generated from various cell types through different strategies. Two different pluripotent states, naive and primed, can be captured in vitro, corresponding to the pre- and post-implantation stages of in vivo development, respectively, with naive pluripotency being considered to possess better developmental potential. We can obtain naïve iPSCs and primed iPSCs through somatic cell reprogramming. Despite well-characterized transcriptional and epigenetic changes, the dynamic of the chromatin landscape during naïve and primed iPSC reprogramming is poorly understood, especially in humans. In this study, we applied ATAC-seq and RNA-seq to delineate the chromatin landscape in the human secondary reprogramming system towards naive and primed pluripotency. We identified several transcription factors and epigenetic factors which were crucial to reprogramming chromatin remodeling. We found that two isoforms of the same gene PRDM1, PRDM1alpha and PRDM1beta, targeted different genomic loci to function in divergent roles during naive reprogramming. We proposed a cross-regulation model of PRDM1alpha and PRDM1beta function. Together, this research highlights the diversity of the transcription factors in determining the chromatin landscape dynamics and regulating pluripotent cell fates. Overall design: We examined the genomic binding sites of PRDM1alpha and PRDM1beta proteins on day 10 of reprogramming using CUT&Tag technology.