YEATS2 o - glcn酰化促进ATAC复合物的染色质关联和肺癌的发生。

IF 4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Biological Chemistry Pub Date : 2025-06-18 DOI:10.1016/j.jbc.2025.110388

Jianxin Zhao,Zheng Zhao,Wen Zhou,Jianzhi Zhang,Jinfeng Chen,Jianwei Sun,Jing Li

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引用次数: 0

摘要

已知细胞内o -连接n -乙酰氨基葡萄糖（O-GlcNAc）修饰富集于细胞核和染色质上，但其许多染色质靶点仍有待确定。在这里，我们展示了YEATS结构域2 （YEATS2）的o- glcn酰化，YEATS2是染色质Ada-two-A-containing （ATAC）复合体的一个亚基，也是组蛋白H3K27ac的一个读取器。我们发现YEATS2与O-GlcNAc转移酶（OGT）相互作用，并利用电子转移解离质谱进一步确定其主要的O-GlcNAc酰化位点为Thr604。o - glcn酰化促进了YEATS2的染色质结合，以及YEATS2与染色质上的其他ATAC成分（如ZZZ3、GCN5和PCAF）之间的亲和力。下游，YEATS2-T604A突变体减弱atac依赖性组蛋白H3K9ac水平，并灭活必需核糖体基因的表达，如染色质免疫沉淀试验所示。此外，异种移植实验表明，YEATS2 o - glcn酰化促进肺癌的发生。我们的工作揭示了YEATS2 o - glcn酰化在稳定染色质上的ATAC复合体和扩展OGT的染色质底物中的关键作用。

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YEATS2 O-GlcNAcylation Promotes Chromatin Association of the ATAC Complex and Lung Cancer Tumorigenesis.

The intracellular O-linked N-acetylglucosamine (O-GlcNAc) modification is known to be enriched in the nucleus and on chromatin, but many of its chromatin targets remain to be identified. Herein we demonstrate the O-GlcNAcylation of YEATS Domain Containing 2 (YEATS2), a subunit of the chromatin Ada-two-A-containing (ATAC) complex and a reader of histone H3K27ac. We show that YEATS2 interacts with the O-GlcNAc transferase (OGT) and further pinpoint its major O-GlcNAcylation site to be Thr604 using electron transfer dissociation mass spectrometry. O-GlcNAcylation promotes the chromatin association of YEATS2, and the affinity between YEATS2 and other ATAC components on chromatin, such as ZZZ3, GCN5 and PCAF. Downstream, YEATS2-T604A mutants attenuated the ATAC-dependent histone H3K9ac levels and inactivated the expression of essential ribosomal genes as shown in chromatin immunoprecipitation assays. Further, xenograft experiments show that YEATS2 O-GlcNAcylation promotes lung cancer tumorigenesis. Our work reveals the critical role of YEATS2 O-GlcNAcylation in stabilizing the ATAC complex on chromatin and expands the chromatin substrates of OGT.

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来源期刊

Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry

自引率

4.20%

发文量

1233

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