Abstract
Porcine-induced pluripotent stem cells (piPSCs) could serve as a great model system for human stem cell preclinical research. However, the pluripotency gene network of piPSCs, especially the function for the core transcription factor estrogen-related receptor beta (ESRRB), was poorly understood. Here, we constructed ESRRB-overexpressing piPSCs (ESRRB-piPSCs). Compared with the control piPSCs (CON-piPSCs), the ESRRB-piPSCs showed flat, monolayered colony morphology. Moreover, the ESRRB-piPSCs showed greater chimeric capacity into trophectoderm than CON-piPSCs. We found that ESRRB could directly regulate the expressions of trophoblast stem cell (TSC)-specific markers, including KRT8, KRT18 and CDX2, through binding to their promoter regions. Mutational analysis proved that the N-terminus zinc finger domain is indispensable for ESRRB to regulate the TSC markers. Furthermore, this regulation needs the participation of OCT4. Accordingly, the cooperation between ESRRB and OCT4 facilitates the conversion from pluripotent state to the trophoblast-like state. Our results demonstrated a unique and crucial role of ESRRB in determining piPSCs fate, and shed new light on the molecular mechanism underlying the segregation of embryonic and extra-embryonic lineages.
Highlights
Pluripotent stem cells (PSCs) are capable of infinite self-renewal and retaining the developmental potential to differentiate into all cell types of an organism (Haider et al, 2018)
Recent scRNA-seq of porcine early embryos showed that estrogen-related receptor beta (ESRRB) was highly expressed in morula, ICM, and trophectoderm (TE) cells, and OCT4 was highly expressed in morula, ICM, TE, and late blastocysts (Supplementary Figure 1A)
We examined the differentiation capacity of ESRRB-pluripotent stem cells (piPSCs)
Summary
Pluripotent stem cells (PSCs) are capable of infinite self-renewal and retaining the developmental potential to differentiate into all cell types of an organism (Haider et al, 2018). Certain genes were found co-expressed in embryonic and extra-embryonic cell lineages in porcine embryos based on single-cell RNA-seq (scRNA-seq) studies (Boroviak et al, 2015; Petropoulos et al, 2016; Mohammed et al, 2017; Ramos-Ibeas et al, 2019; Kong et al, 2020). Some of these genes, including estrogen-related receptor beta (ESRRB, known as NR3B2 or ERR2), were considered to play critical roles in embryonic development and pluripotency maintenance
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