Suppression of cryptic intragenic transcripts is required for embryonic stem cell self-renewal.

Recent discoveries of histone demethylases have shown that the dynamic regulation of histone methylation is important in differentiation and development. A paper in this issue of The EMBO Journal demonstrates that an H3K4me3 demethylase, KDM5B, is required for the regulation of self-renewal and pluripotency of embryonic stem (ES) cells by removing intragenic H3K4me3 and repressing cryptic transcription. The pluripotency and self-renewal ability of ES cells has attracted great interest in uncovering the underlying mechanisms. Three transcription factors, Oct4, Sox2 and Nanog, are core regulators involved in pluripotency and self-renewal of ES cells (Boyer et al, 2005). It has been shown that the regulation of downstream targets by Oct4, Sox2 and Nanog is dependent on the epigenetic state of chromatin. In general, methylation on histone H3K4 and H3K36 is associated with active transcription, whereas methylation on H3K9 and H3K27 is linked to gene silencing (Li et al, 2007). Gene expression is tightly regulated by enzymes mediating histone modifications. Several histone demethylases (KDMs) have been shown to be involved in cellular pluripotency. Previous studies show that KDM3A and KDM4C positively regulate self-renewal genes through demethylating repressive H3K9me2/me3 marks at their promoters (Loh et al, 2007). In this issue of The EMBO Journal, Xie et al (2011) demonstrate a novel role of KDM5B as a transcriptional activator of selfrenewal-associated genes.