The Malignant Brain Tumor (MBT) Domain Protein SFMBT1 Is an Integral Histone Reader Subunit of the LSD1 Demethylase Complex for Chromatin Association and Epithelial-to-mesenchymal Transition
The Malignant Brain Tumor (MBT) Domain Protein SFMBT1 Is an Integral Histone Reader Subunit of the LSD1 Demethylase Complex for Chromatin Association and Epithelial-to-mesenchymal Transition
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DOI：
10.1074/jbc.m113.482349
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发表时间：
2013-09-20
影响因子：
4.8
通讯作者：
Lu, Jianrong
中科院分区：
文献类型：
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作者：
Tang, Ming;Shen, Huangxuan;Lu, Jianrong
染色质阅读器通过招募特定的效应复合物用于随后的表观遗传重编程来破译组蛋白修饰的功能读数。LSD 1（也称为KDM 1A）组蛋白去甲基化酶复合物通过催化二甲基化组蛋白H3赖氨酸4（H3 K4 me 2）的去甲基化来修饰染色质并部分抑制转录，二甲基化组蛋白H3赖氨酸4（H3 K4 me 2）是活跃转录的标志。然而，目前已知的亚基没有识别甲基化组蛋白。Snai 1家族转录因子是上皮细胞向间充质转化（EMT）的中心驱动因子，上皮细胞通过EMT获得增强的侵袭力。Snai 1介导的上皮基因转录抑制取决于其对LSD 1复合物的募集以及随后H3 K4 me 2在其靶基因上的去甲基化。通过生物化学纯化，我们确定了MBT结构域的蛋白SFMBT 1作为一个新的组成部分的LSD 1复合物与Snai 1。与迄今为止特征在于选择性识别单和二甲基化赖氨酸的其他哺乳动物MBT结构域蛋白不同，SFMBT 1结合二和三甲基H3 K4，这两者都在活性启动子处富集。我们发现，SFMBT 1是必不可少的Snai 1依赖招聘LSD 1染色质，去甲基化的H3 K4 me 2，上皮标记物的转录抑制，并诱导EMT的TGF β。致癌金属镍是一种广泛存在的环境和职业污染物。镍改变基因表达并诱导EMT。我们证明了镍引发的效应依赖于LSD 1-SFMBT 1介导的染色质修饰。此外，在人类癌症中，SFMBT 1的表达与间充质标志物和不利的预后相关。这些结果突出了SFMBT 1在表观遗传调控、EMT和癌症中的关键作用。
Chromatin readers decipher the functional readouts of histone modifications by recruiting specific effector complexes for subsequent epigenetic reprogramming. The LSD1 (also known as KDM1A) histone demethylase complex modifies chromatin and represses transcription in part by catalyzing demethylation of dimethylated histone H3 lysine 4 (H3K4me2), a mark for active transcription. However, none of its currently known subunits recognizes methylated histones. The Snai1 family transcription factors are central drivers of epithelial-to-mesenchymal transition (EMT) by which epithelial cells acquire enhanced invasiveness. Snai1-mediated transcriptional repression of epithelial genes depends on its recruitment of the LSD1 complex and ensuing demethylation of H3K4me2 at its target genes. Through biochemical purification, we identified the MBT domain-containing protein SFMBT1 as a novel component of the LSD1 complex associated with Snai1. Unlike other mammalian MBT domain proteins characterized to date that selectively recognize mono- and dimethylated lysines, SFMBT1 binds di- and trimethyl H3K4, both of which are enriched at active promoters. We show that SFMBT1 is essential for Snai1-dependent recruitment of LSD1 to chromatin, demethylation of H3K4me2, transcriptional repression of epithelial markers, and induction of EMT by TGF beta. Carcinogenic metal nickel is a widespread environmental and occupational pollutant. Nickel alters gene expression and induces EMT. We demonstrate the nickel-initiated effects are dependent on LSD1-SFMBT1-mediated chromatin modification. Furthermore, in human cancer, expression of SFMBT1 is associated with mesenchymal markers and unfavorable prognosis. These results highlight a critical role of SFMBT1 in epigenetic regulation, EMT, and cancer.