Dataset Information

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

ABSTRACT: The intracellular O-linked N-acetylglucosamine (O-GlcNAc) modification is known to be enriched in the nucleus and in particular 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 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Wen Zhou

LAB HEAD: Wen Zhou

PROVIDER: PXD060970 | Pride | 2025-07-28

REPOSITORIES: Pride

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YEATS2 O-GlcNAcylation promotes chromatin association of the ATAC complex and lung cancer tumorigenesis.

Zhao Jianxin J Zhao Zheng Z Zhou Wen W Zhang Jianzhi J Chen Jinfeng J Sun Jianwei J Li Jing J

The Journal of biological chemistry 20250618 7

The intracellular O-linked β-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 Yaf9, ENL, AF9, Taf14, Sas5 (YEATS) domain-containing 2 (YEATS2), a subunit of the chromatin Ada-two-A-containing (ATAC) complex and a reader of H3K27 acetylation levels. We show that YEATS2 interacts with the O-GlcNAc transferase and further pinpoint its major O-G ...[more]

PMID: 40541806

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Project description:Drosophila development is a complex and dynamic process regulated, in part, by members of the Polycomb (Pc), Trithorax (Trx) and Compass chromatin modifier complexes. O-GlcNAc Transferase (OGT/SXC) is essential for Pc repression suggesting that the O-GlcNAcylation of proteins plays a key role in regulating development. OGT transfers N-acetyl-D-glucosamine (GlcNAc) onto hydroxyl groups of serine or threonine residues of key transcriptional regulators using the nutrient-derived UDP-GlcNAc as a substrate, which is dynamically removed by O-GlcNAcase (OGA). We performed ChIP-chip and microarray analysis after OGT or OGA RNAi knockdown in Drosophila S2 cells and found that O-GlcNAc was elevated genome wide particularly at genes related to mitosis and cell cycle in OGA RNAi cells, but not at sites co-occupied by Pc member Pleiohomeotic (Pho), such as the Hox and NK homeobox gene clusters. Microarray analysis suggested that altered O-GlcNAc cycling perturbed the expression of genes associated with morphogenesis and cell cycle regulation. To examine the in vivo consequences of disturbed O-GlcNAc cycling in the whole animal, we produced a null allele of oga (ogadel.1) in Drosophila. Epigenetic activators including Trx group members Trithorax (Trx), Absent small or homeotic discs 1 (Ash1) and Compass member Set1 histone methyltransferases are O-GlcNAc modified in ogadel.1 mutants. ogadel.1 mutants displayed altered expression of a distinct set of cell cycle related genes in ovaries. Our results suggest that the loss of OGA could affect epigenetic machinery by accumulating O-GlcNAc on numerous chromatin factors including Trx, Ash1 and Set1 in Drosophila. We performed affymetrix tilingarray analysis after OGT or OGA RNAi knockdown in Drosophila S2 cells to find if that O-GlcNAc was elevated genome wide particularly at genes related to mitosis and cell cycle in OGA RNAi cells, but not at sites co-occupied by Pc member Pleiohomeotic (Pho), ------------------------------- This represents the gene expression component only

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