Direct reprogramming from somatic cells to a pluripotent state can be achieved by the introduction of defined transcription factors, such as Oct4, Sox2, Klf4 and c-Myc (ref. 1
). The resultant iPSCs are molecularly and functionally similar to embryonic stem cells (ESCs) derived from the inner cell mass of a blastocyst2,3
. However, the process of iPSC generation is highly inefficient with a low frequency and a long latency before the establishment of pluripotency2,3
. A number of factors have been shown to affect reprogramming efficiency through cell-cycle-dependent or -independent mechanisms2,4
. For example, inhibition of the p53–p21 pathway and the Ink4a/Arf
locus increases the reprogramming efficiency and accelerates the reprogramming dynamics by affecting cell proliferation5–10
; whereas, ectopic expression of Nanog enhances reprogramming presumably through an epigenetic mechanism without changing the proliferation status6
A recent study indicates that reprogramming from fibroblasts to iPSCs involves a series of transcriptional changes11
. At the beginning, epithelial genes that alter the morphology of fibroblasts to an ESC-like state are first activated, followed by the activation of Nanog and other pluripotent factors. After these waves of activation, mesenchymal genes are repressed, followed by the activation of ‘mature’ pluripotent genes11
. Consistent with these sequential molecular events, factors facilitating mesenchymal-to-epithelial transition, such as BMPs, Tgf-β inhibitors and microRNA-200s, have been shown to promote iPSC generation11–14
, indicating that activation of an epithelial transcription program early in reprogramming is crucial for the establishment of pluripotency. However, how such a program is activated is unknown at present.
Given that cell fate reprogramming is essentially a resetting of epigenetic states15
, it is not surprising that chemical inhibitors of epigenetic enzymes16–19
, and certain chromatin-remodelling factors, are capable of promoting iPSC generation20
. Through studying epigenetic factors specifically enriched in ESCs, we found that Kdm2b (also known as Jhdm1b and Fbxl10), an H3K36me2-specific demethylase21,22
, is able to facilitate iPSC generation. This property is independent of its effect on cell proliferation, but relies on its demethylase and DNA-binding activities that contribute to the activation of the reprogramming transcription program in the early stage.