Dimethylations of histone H3 lysine 9 and lysine 27 are important epigenetic marks associated with transcription repression. Here, we identified KIAA1718 （KDM7A） as a novel histone demethylase specific for these two...Dimethylations of histone H3 lysine 9 and lysine 27 are important epigenetic marks associated with transcription repression. Here, we identified KIAA1718 （KDM7A） as a novel histone demethylase specific for these two repressing marks. Using mouse embryonic stem cells, we demonstrated that KIAA1718 expression increased at the early phase of neural differentiation. Knockdown of the gene blocked neural differentiation and the effect was rescued by the wild-type human gene, and not by a catalytically inactive mutant. In addition, overexpression of KIAA1718 accelerated neural differentiation. We provide the evidence that the pro-neural differentiation effect of KDM7A is mediated through direct transcriptional activation of FGF4, a signal molecule implicated in neural differentiation. Thus, our study identified a dual-specificity histone demethylase that regulates neural differentiation through FGF4.展开更多
H3K9me2 and H3K27me2 are important epigenetic marks associated with transcription repression, while H3K4me3 is associated with transcription activation. It has been shown that active and repressive histone methylation...H3K9me2 and H3K27me2 are important epigenetic marks associated with transcription repression, while H3K4me3 is associated with transcription activation. It has been shown that active and repressive histone methylations distribute in a mutually exclusive manner, but the underlying mechanism was poorly understood. Here we identified ceKDM7A, a PHD （plant homeodomain）- and JmjC domain-containing protein, as a histone demethylase specific for H3K9me2 and H3K27me2. We further demonstrated that the PHD domain of ceKDM7A bound H3K4me3 and H3K4me3 co-localized with ceKDM7A at the genome-wide level. Disruption of the PHD domain binding to H3K4me3 reduced the demethylase activity in vivo, and loss of ceKDM7A reduced the expression of its associated target genes. These results indicate that ceKDM7A is recruited to the promoter to demethylate H3K9me2 and H3K27me2 and activate gene expression through the binding of the PHD domain to H3K4me3. Thus, our study identifies a dual-specificity histone demethylase and provides novel insights into the regulation of histone methylation.展开更多
基金Supplementary information is linked to the online version of the paper on the Cell Research website.Acknowledgments We thank Anning Lin （The University of Chicago） for the critical reading of the paper, members in the Chen lab for technical help, the cell biology and molecular biology core facilities for confocal study and Q-PCR, and Shanghai Biochip Co Ltd. for microarray analysis. The H3K27me2 antibody was kindly provided by Li Tang （Fudan University） and Thomas Jenuwein （Research Institute of Molecular Pathology, The Vienna Biocenter）. This work was supported by the National Basic Research Program of China （2007CB957900, 2006CB943902, 2007CB947101, 2008KR0695, 2009CB941100, 2005CB522704）, the Chinese Academy of Sciences （KSCX2-YW-R-04）, the National Natural Science Foundation of China （90919026, 30870538,30623003, 30721065, 30830034, 90919046）, the Shanghai Pujiang Program （0757S11361）, the Shanghai Key Project of Basic Science Research （06DJ14001, 06DZ22032, 08DJ1400501）, and the Council of Shanghai Municipal Government for Science and Technology （088014199）.
文摘Dimethylations of histone H3 lysine 9 and lysine 27 are important epigenetic marks associated with transcription repression. Here, we identified KIAA1718 （KDM7A） as a novel histone demethylase specific for these two repressing marks. Using mouse embryonic stem cells, we demonstrated that KIAA1718 expression increased at the early phase of neural differentiation. Knockdown of the gene blocked neural differentiation and the effect was rescued by the wild-type human gene, and not by a catalytically inactive mutant. In addition, overexpression of KIAA1718 accelerated neural differentiation. We provide the evidence that the pro-neural differentiation effect of KDM7A is mediated through direct transcriptional activation of FGF4, a signal molecule implicated in neural differentiation. Thus, our study identified a dual-specificity histone demethylase that regulates neural differentiation through FGF4.
文摘H3K9me2 and H3K27me2 are important epigenetic marks associated with transcription repression, while H3K4me3 is associated with transcription activation. It has been shown that active and repressive histone methylations distribute in a mutually exclusive manner, but the underlying mechanism was poorly understood. Here we identified ceKDM7A, a PHD （plant homeodomain）- and JmjC domain-containing protein, as a histone demethylase specific for H3K9me2 and H3K27me2. We further demonstrated that the PHD domain of ceKDM7A bound H3K4me3 and H3K4me3 co-localized with ceKDM7A at the genome-wide level. Disruption of the PHD domain binding to H3K4me3 reduced the demethylase activity in vivo, and loss of ceKDM7A reduced the expression of its associated target genes. These results indicate that ceKDM7A is recruited to the promoter to demethylate H3K9me2 and H3K27me2 and activate gene expression through the binding of the PHD domain to H3K4me3. Thus, our study identifies a dual-specificity histone demethylase and provides novel insights into the regulation of histone methylation.
