Division of Newborn Medicine and Program in Epigenetics, Department of Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Genes Dev. 2012 Jun 15;26(12):1364-75. doi: 10.1101/gad.186056.111.
The histone H3 Lys 27 (H3K27) demethylase JMJD3 has been shown to play important roles in transcriptional regulation and cell differentiation. However, the mechanism underlying JMJD3-mediated transcriptional regulation remains incompletely understood. Here we show that JMJD3 is associated with KIAA1718, whose substrates include dimethylated H3K27 (H3K27me2), and proteins involved in transcriptional elongation. JMJD3 and KIAA1718 directly bind to and regulate the expression of a plethora of common target genes in both a demethylase activity-dependent and -independent manner in the human promyelocytic leukemia cell line HL-60. We found that JMJD3 and KIAA1718 collaborate to demethylate trimethylated H3K27 (H3K27me3) on a subset of their target genes, some of which are bivalently marked by H3K4me3 and H3K27me3 and associated with promoter-proximal, paused RNA polymerase II (Pol II) before activation. Reduction of either JMJD3 or KIAA1718 diminishes Pol II traveling along the gene bodies of the affected genes while having no effect on the promoter-proximal Pol II. Furthermore, JMJD3 and KIAA1718 also play a role in localizing elongation factors SPT6 and SPT16 to the target genes. Our results support the model whereby JMJD3 activates bivalent gene transcription by demethylating H3K27me3 and promoting transcriptional elongation. Taken together, these findings provide new insight into the mechanisms by which JMJD3 regulates gene expression.
组蛋白 H3 赖氨酸 27（H3K27）去甲基酶 JMJD3 已被证明在转录调控和细胞分化中发挥重要作用。然而，JMJD3 介导的转录调控机制仍不完全清楚。在这里，我们表明 JMJD3 与 KIAA1718 相关，其底物包括二甲基化的 H3K27（H3K27me2）和参与转录延伸的蛋白质。JMJD3 和 KIAA1718 直接结合并调节人类早幼粒细胞白血病细胞系 HL-60 中大量共同靶基因的表达，无论是在去甲基酶活性依赖还是非依赖的方式下，都是如此。我们发现 JMJD3 和 KIAA1718 合作，以去甲基化一组靶基因上的三甲基化 H3K27（H3K27me3），其中一些靶基因被 H3K4me3 和 H3K27me3 双价标记，并与激活前的启动子近端、暂停的 RNA 聚合酶 II（Pol II）相关。JMJD3 或 KIAA1718 的减少都减少了受影响基因的基因体中 Pol II 的移动，而对启动子近端的 Pol II 没有影响。此外，JMJD3 和 KIAA1718 还在将延伸因子 SPT6 和 SPT16 定位到靶基因中发挥作用。我们的结果支持这样的模型，即 JMJD3 通过去甲基化 H3K27me3 和促进转录延伸来激活双价基因转录。总之，这些发现为 JMJD3 调节基因表达的机制提供了新的见解。
