KDM8 acts as a co-regulator of transcription factor SOX2 for promoting cell pluripotency [ChIP-Seq]

Since their discovery, iPSCs have drawn significant attention for their biomedical potential, yet reprogramming remains inefficient and the underlying mechanisms are incompletely defined. KDM8, a histone demethylase, is known to play critical roles in processes such as cell-cycle regulation and embryonic development; nevertheless, its function in reprogramming has not been reported. Here, we investigate the role of KDM8 in reprogramming. Our results demonstrate that KDM8 significantly enhances the reprogramming efficiency mediated by the canonical Yamanaka factors (OCT4, SOX2, KLF4 and MYC). Remarkably, KDM8, in combination with OCT4 alone, is sufficient to reprogram somatic cells. Further analyses reveal that KDM8 facilitates reprogramming through a dual regulatory mechanism. On the one hand, KDM8 leverages its canonical enzymatic activity to reduce the epigenetic barriers to iPSC formation. More importantly, KDM8 functions as a co-regulator of the transcription factor SOX2, modulating SOX2's DNA-binding affinity and transcriptional regulation of downstream target genes, thereby substantially promoting cellular pluripotency. Accordingly, we propose a novel regulatory framework that uncovers novel mechanisms and functions of KDM8 in cellular reprogramming.