Figure 7.

Model of Bmi1 function in extraembryonic endoderm lineage emergence. Nanog transcription factor protects the pluripotent state by repressing Bmi1 and Gata6 PrE-associated genes (depicted as black solid lines) and activating miR-200c, a microRNA also shown to modulate Bmi1 protein expression in ES cells (depicted as a black dotted line, indicating no evidence that this regulation is direct). (BS) Location of the Nanog-binding site upstream of the Bmi1 and miR-200c transcription start sites (arrows). Bmi1 physically interacts with and stabilizes Gata6 protein levels by protecting it from ubiquitination and proteasomal degradation (depicted as red triangles and dashed box). Formation of this complex enhances Gata6 transcriptional activity on target genes and promotes PrE emergence. Gata6 lies upstream of Gata4 and Sox17 in differentiation cascade (depicted as red dotted lines, indicating no evidence that these regulations are direct). Bmi1 expression also leads to a reduction in Nanog levels by an unknown mechanism (depicted as a black dotted line).