BMP4 resets mouse epiblast stem cells to naive pluripotency through ZBTB7A/B-mediated chromatin remodelling

Chromatin accessibility dynamics during cell fate reprogramming

“…Somatic enhancers are rapidly closed (OC processing) while pluripotent enhancers are activated in a stepwise manner (CO processing) (Cheloufi et al , 2015; Di Stefano et al , 2016; Knaupp et al , 2017). Furthermore, similar OC/CO chromatin dynamics were observed in chemically induced pluripotent stem cells (ciPSCs), BMP4‐driven primed to naive transition (PNT) and human iPSCs formation (Cao et al , 2018; Liu et al , 2020; Yu et al , 2020). The open chromatin in the starting cell population was quickly closed after small chemical treatment and the pluripotent loci were opened step by step, accompanied by somatic TF inactivation and pluripotency TF activation.…”

Single Cell Sequencing Reveals Early PGC-like Intermediates During Mouse Primed to Naïve Transition

“…In this report, by performing scRNA-seq to a previously well-established PNT process driven by BMP4 (BiPNT) 18 , we generated a cell fate continuum between primed and naive pluripotency states. Surprisingly, we found that BiPNT, in single cell level, goes through cell fate stages previously unexpected, i.e., a Prdm1 + PGC-like stage, before the establishment of naïve pluripotent cell fate.…”

“…We have established a robust BMP4-dependent primed to naive transition (PNT) system, which consisting of two stages, a 3-day incubation with BMP4, EPZ5676, EPZ6438 and 5-day culturing with 2iL 18 , that can convert ~80% EpiSCs to chimera competent naive colonies. To map the cell fate continuum, we performed scRNA-seq from cells that are at D0, 1, 2, 3, 5 and 8 (Fig.…”

“…TFs are powerful cell fate regulators that can overcome barriers established during development through multiple processes involving chromatin remodeling, metabolic switches, cell morphology changes. Recently, we have achieved a BMP4-dependent primed to naive transition (PNT) in a similar way as the reprogramming and show that a 3-day exposure of EpiSCs in BMP4, Dot1L inhibitor and EZH2 inhibitor followed by a 5-day culture in 2iL can convert the majority (~80%) of the primed cells into chimeracompetent naive colonies 18 . Through RNA-seq and ATAC-seq bulk analyses, we demonstrated that many downstream targets of BMP4, including the previously unrecognized Zbtb7 family members, are activated through chromatin remodeling events for the resetting of primed to naïve states 18 .…”

“…Recently, we have achieved a BMP4-dependent primed to naive transition (PNT) in a similar way as the reprogramming and show that a 3-day exposure of EpiSCs in BMP4, Dot1L inhibitor and EZH2 inhibitor followed by a 5-day culture in 2iL can convert the majority (~80%) of the primed cells into chimeracompetent naive colonies 18 . Through RNA-seq and ATAC-seq bulk analyses, we demonstrated that many downstream targets of BMP4, including the previously unrecognized Zbtb7 family members, are activated through chromatin remodeling events for the resetting of primed to naïve states 18 . Even though, it is still unclear if there are intermediates governing the resetting of primed fate into a naive one by BMP4 or the precise cell dynamics during this resetting process, as distinct molecular routes have been shown to mediate the acquisition of naïve pluripotency with different TFs and signals 19 .…”