The role of Krüppel-like factors in generating induced pluripotent stem cells

Krüppel-like factors (KLFs) belong to a family of transcription factors that play fundamentally important role in various biological processes. The discovery of the Yamanaka factors in reprogramming of somatic cells into pluripotent stem cells has demonstrated that KLFs are required in various phases of reprogramming. Among these, KLF4, KLF2, or KLF5 can be exogenously expressed together with OCT4, SOX2, and MYC to generate induced pluripotent stem cells (iPSCs). With improved understanding of the mechanisms by which transcription factors govern cell identity, we now know that pluripotency is regulated by an autoregulated transcriptional feedback network. KLF4 is one of the key pluripotency factors that activates other pluripotency factors while its own expression is regulated by the same factors it activates. KLF4 plays a dual role in reprograming. It acts as a repressor of somatic-specific genes and as a pioneer factor to activate epigenetically suppressed pluripotency genes during early reprogramming. It also acts as an activator of pluripotency genes by binding to super-enhancers of pluripotency factors to facilitate long-range interactions among pluripotency factor binding sites. KLFs are also markers of naïve pluripotency. KLF17 is the newest KLF that has been identified to be a marker for naïve PSCs and has the ability to reprogram primed PSC to naïve PSC. The understanding of how protein structures of KLFs relate to their function in cellular reprogramming is incomplete. Knowledge of their structure and function relationship in reprogramming should significantly contribute to the clinical applications of iPSC technology.