Human embryonic stem cells (hESCs) are delicate little creatures. Left to their own devices – especially in culture — they want to differentiate or die.
By now you’ve probably heard of the intricate network of factors that allow these cells to retain their stemness – some, like the transcription factors OCT4 and SOX2, prevent differentiation and even allow a cell to “reprogram” back to a pluripotent state. Other players, like miRNAs, have also intrigued stem cell researchers by exhibiting unique/different expression patterns in hESCs vs. differentiated embryoid bodies (EBs) suggesting they’re probably in on the action.
Today in Cell, you get the details on an effort led by researchers at UCSB and the University of Wisconsin-Madison that took a closer look at how miRNAs might be mingling directly with protein-coding genes involved with pluripotency maintenance. Using a combination of gain and loss of function assays, the team confirmed what target prediction algorithms TargetScan, miRBase, and Miranda had suggested all along, that miR-145 targets multiple hESC reprogramming factors including OCT4, SOX2, and KLF4.
In hESCs, key figures like OCT4, SOX2, and KLF4 levels are high in hESC, and miR-145 levels are low. But what goes up must … make something else go down. The team demonstrated that in hESC OCT4 binds the miR-145 promoter and represses its expression. Yet when cells begin to differentiate, the tables turn: miR-145 levels rise, and the microRNA binds to the 3’ UTRs of OCT4, SOX2, and KLF4 mRNA, inhibiting the transcription factors’ expression. Follow the ups and downs at Cell, April 2009