C/EBPα poises B cells for rapid reprogramming into iPS cells [array]. Mus musculus

Somatic cell reprogramming into pluripotent stem cells induced by Oct4, Sox2, Klf4 and Myc (OSKM) occurs at low frequencies and with a considerable delay involving a stochastic phase. In contrast, transdifferentiation of B cells into macrophages induced by C/EBPα is fully efficient and initiated almost immediately. We now discovered that a pulse of C/EBPα in B cell precursors followed by OSKM expression dramatically enhances reprogramming to pluripotency, overcoming the stochastic phase. The cells simultaneously activate mesenchymal-epithelial transition and pluripotency genes to high levels within 2 days, correlating with promoter demethylation and accessibility to Oct4 binding. The conditioning effect of C/EBPα is shared with C/EBPβ but not with transcription factors that induce erythroid, neuronal and muscle fates, which are innocuous or inhibitory. Surprisingly, OSKM induce the transient upregulation of macrophage genes in B cells, including Cebpa and Cebpb, as well as trophectoderm genes. Since both C/EBPs are functionally expressed in trophoblasts their unique pluripotency-conditioning capacity might reflect an early embryonic function. Our findings have removed a major hurdle in elucidating mechanisms that establish pluripotency. Overall design: Change in gene expression during reprogramming of B-cells into iPS cells, comparing the time 0h (B-cells) to cells induced with OKSM, pre-treated or not with estradiol to induce C/EBPa, at different time points.