Arid4b alters cell cycle and cell death dynamics during mouse embryonic stem cell differentiation

Cell division and death play an important role in embryonic development. Cell specialization is accompanied with slow proliferation and quiescence. Cell death is important for morphogenesis. Gene expression changes during differentiation is coordinated by lineage-specific transcription factors and chromatin factors. It is not yet fully understood how alterations in gene expression and cell cycle/death mechanisms are connected. We previously identified a chromatin protein Arid4b as a critical factor for meso/endoderm differentiation of mouse embryonic stem cells (mESCs). The differentiation defect of Arid4b-deficient mESCs might be due to misregulation of cell proliferation or death. Here, we identified a role for Arid4b in cell cycle rewiring at the onset of differentiation. Arid4b-deficient differentiating cells have less proliferative capacity and their cell cycle profile is more similar to mESC stage than the differentiating wild-type cells. We found no evidence of increased DNA damage or checkpoint activation. Our investigation of cell death mechanisms found no contribution from autophagy but revealed a slight increase in Caspase-3 activation implying early apoptosis in Arid4b-deficient differentiating cells. Taken together, our data suggest Arid4b regulates cell cycle alterations during exit from pluripotency. Future studies will be instrumental in understanding whether these changes directly contribute to Arid4b-dependent differentiation control.