Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming

Transcription-factor-directed reprogramming from somatic cells to induced pluripotent stem cells (iPSCs) is by nature an epigenetic process of cell fate change. Previous studies have demonstrated that this inefficient process can be facilitated by the inclusion of additional factors. To gain insight into the reprogramming mechanism, we aimed to identify epigenetic enzymes capable of promoting iPSC generation. Here we show that Kdm2b, a histone H3 Lys 36 dimethyl (H3K36me2)-specific demethylase, has the capacity to promote iPSC generation. This capacity depends on its demethylase and DNA-binding activities, but is largely independent of its role in antagonizing senescence. Kdm2b functions at the beginning of the reprogramming process and enhances activation of early responsive genes in reprogramming. Kdm2b contributes to gene activation by binding to and demethylating the gene promoters. Our studies not only identify an important epigenetic factor for iPSC generation, but also reveal the molecular mechanism underlying how Kdm2b contributes to reprogramming. Transcription-factor-directed reprogramming of somatic cells is inefficient but can be enhanced by the addition of enzymes that modulate chromatin modifications. Zhang and colleagues report that the Kdm2b H3K36me2 demethylase promotes reprogramming through its enzymatic activity and independently of its role in senescence, by enhancing the transcription of genes known to be activated early during the process, including cadherin.