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The functional antagonism between SIRT2 and MOF regulates mitotic entry - MOF interactors

ABSTRACT: Mitosis entry is tightly regulated by a complex network of interconnected mechanisms involving epigenetic modifications, signaling pathways, transcriptional control, and structural changes. While significant progress has been made in understanding these processes individually, the mechanisms integrating chromatin dynamics with key mitotic regulators are still not fully understood. Here, we identify a functional antagonism between the deacetylase SIRT2 and the acetyltransferase MOF in the G2/M transition and mitotic progression. This interplay, which involves MOF deacetylation by SIRT2, regulates key histone marks, including H4K16ac deacetylation and H4K20me1 deposition, condensin II loading, the stability of the key mitotic regulator PLK1 and has a major impact on the transcription control of mitosis regulated by the FOXM1. Our findings reveal a previously unrecognized layer of regulation in G2/M progression, shedding light on the intricate crosstalk between chromatin dynamics and mitotic control, with potential implications for understanding chromosomal stability and cancer.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Joan Josep Bech-Serra

LAB HEAD: Alex Vaquero

PROVIDER: PXD065214 | Pride | 2026-04-29

REPOSITORIES: Pride

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			Action	DRS
	3595_CT_AVAQ003_Ctrl_1.raw	Raw
	3595_CT_AVAQ003_MOFTM_3.raw	Raw
	3595_CT_AVAQ003_MOFWT_2.raw	Raw
	3636_CT_AVAQ003_1_01.raw	Raw
	3636_CT_AVAQ003_3_01.raw	Raw

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The functional antagonism between SIRT2 and MOF regulates mitotic entry - PLK1 methylation

Project description:Mitosis entry is tightly regulated by a complex network of interconnected mechanisms involving epigenetic modifications, signaling pathways, transcriptional control, and structural changes. While significant progress has been made in understanding these processes individually, the mechanisms integrating chromatin dynamics with key mitotic regulators are still not fully understood. Here, we identify a functional antagonism between the deacetylase SIRT2 and the acetyltransferase MOF in the G2/M transition and mitotic progression. This interplay, which involves MOF deacetylation by SIRT2, regulates key histone marks, including H4K16ac deacetylation and H4K20me1 deposition, condensin II loading, the stability of the key mitotic regulator PLK1 and has a major impact on the transcription control of mitosis regulated by the FOXM1. Our findings reveal a previously unrecognized layer of regulation in G2/M progression, shedding light on the intricate crosstalk between chromatin dynamics and mitotic control, with potential implications for understanding chromosomal stability and cancer.

2026-04-29 | PXD065218 | Pride

Tiling path and RNAi of Drosophila KO MSL1, MLS3, and MOF reveals MOF as a key regulator of dosage compensation and gene expression

Project description:Effect of MSL1, MSL3 and MOF RNAi KOs in Drosophila SL-2 and Kc cells.

2008-06-09 | E-MEXP-1505 | biostudies-arrayexpress

Identificaiton of novel acetylation sites in UHRF1 mediated by acetyltransferase MOF

Project description:The multi-domain protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 for DNA methylation maintenance during DNA replication. Here, we show that MOF (Males absent On the First) is an acetyltransferase of UHRF1 to acetylate UHRF1 at Lys670 in the pre-RING linker region whereas HDAC1 is a deacetylase of UHRF1 at the same site. The MOF/HDAC1-mediated acetylation in UHRF1 is cell-cycle regulated and peaks at G1/S phase, in line with the function of UHRF1 in recruiting DNMT1 to maintain DNA methylation. In addition, UHRF1 acetylation significantly enhances its E3 ligase activity and elimination of UHRF1 acetylation at these sites attenuates UHRF1-mediated H3 ubiquitination, which in turn impairs the DNMT1 recruitment and DNA methylation. Taken together, these findings not only identify MOF as a new acetyltransferase for UHRF1 but also reveal a novel mechanism underlying the regulation of DNA methylation maintenance through MOF-mediated UHRF1 acetylation.

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Genome wide mapping of histone acetyltransferase MOF binding in murine ES cells (sequencing)

Project description:We report the application of illumina sequencing technology for high-throughput profiling of histone acetyltransferase Mof in mouse embryonic stem cells. By obtaining over four billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of mouse embryonic stem cells. We find that Mof widely binds to mouse genome and mark genes that are expressed, poised for expression, or stably repressed. Mof binds to both gene promoters and coding regions, exhibiting two modes of binding. This study provides a framework for understanding the function of Mof in regulating ESC core transcription network. Examination of Mof binding patterns in ES cells

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Mitochondrial MOF regulates energy metabolism in heart failure by ATP5B hyperacetylation

Project description:In current study, we found that the protein level of MOF in mitochondrial was significantly increased during the course of heart failure. Overexpression of mtMOF induced cardiac hypertrophy and energy metabolism disorder, as well as heart failure. When combined with mtMOF overexpression and SIRT3 deficiency, the acetylation level in cardiomyocytes was significantly upregulated, accompanied with serious enegergy abnormal and cardiac function injury. Mitochondrial substrates of MOF was identified by using acetylated proteomic analysis. We demonstrated that mtMOF and SIRT3 exhibited damage effect by regulating the acetylation level of the common substrate ATP5B. This study clarified the acetyltransferase activity of MOF in mitochondria, providing a new theoretical basis for the acetylation regulation mode of mitochondrial proteins. In addition, we provides a new research idea for exploring the relationship between hyperacetylation and energy metabolism disorder and heart failure.

2024-12-09 | PXD044074 | Pride

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2008-06-12 | E-MEXP-1508 | biostudies-arrayexpress

MOF-mediated PRDX1 acetylation regulates inflammatory macrophage activation

Project description:Macrophage activation undergoes signal-transduced changes in protein modifications, enabling the coordinated control of transcription and cellular metabolism. However, the role of protein acetylation in signal transduction during macrophage activation remains obscure. Here, we demonstrate that peroxiredoxin 1 (PRDX1), a key regulator of redox signaling, is a novel substrate of the MOF lysine acetyltransferase. Employing a gel based in vitro HAT assay followed by LC-MS, we mapped PRDX1 lysine acetylation sites. PRDX1 K197ac was identified as the most prominent MOF acetylation site. We show that MOF-dependent acetylation of lysine 197 of PRDX1 (PRDX1 K197ac) enhances its peroxidase activity. We find that PRDX1 K197ac is an inflammatory signal-regulated modification, which decreases in mouse macrophages stimulated with bacterial lipopolysaccharides (LPS) but not with IL-4 or IL-10. LPS-induced decrease of PRDX1 K197ac elevates cellular ROS accumulation and augments phosphorylation of ERK1/2 but not p38 or AKT phosphorylation. Concomitantly, diminished PRDX1 K197ac stimulates glycolysis, potentiates H3 serine 28 phosphorylation, and ultimately enhances the production of pro-inflammatory mediators such as IL-6. Collectively, our findings uncover a regulatory role for redox protein acetylation during inflammatory macrophage activation through modulating signal transduction and coordinating metabolic and transcriptional programs.

2024-10-25 | PXD046284 | Pride

MOF forms a positive feedback regulation with ERα to suppress endometrial cancer progression

Project description:MOF is a histone acetyltransferase specific for H4K16 acetylation. It has been demonstrated that MOF is lower expressed in series of human cancers. However, the molecular mechanism underlying the detailed biological function of MOF in endometrial carcinomas (ECa) has not been fully defined. The estrogen receptor α (ERα) action plays a crucial role in endometrial cancer tumorigenesis and progression. Here, our data have demonstrated that estrogen/ERα induces MOF gene transcription, meanwhile MOF stabilizes ERα via acetylating ERα in ECa, indicating that MOF forms a positive feedback loop with ERα. In the whole genome-wide level, RNA microarray analyses have shown that MOF modulates a subset of endogenous ERα-regulated genes, such as apoptosis associated factor DRAM1 and oncogene FXYD3. Knockdown of MOF leads to a G2/M cell cycle arrest and promotes ECa cell growth and proliferation. MOF depletion promotes xenograft tumor growth in mice. In addition, our results have demonstrated that MOF expression is lower in ECa than that in benign endometrial tissues. Importantly, the expression of MOF is positively correlated with that of ERα in clinical samples. Cumulatively, our results suggest a positive feedback regulation involving MOF and ERα is essential for suppression of endometrial cancer.

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MOF-mediated PRDX1 acetylation regulates LPS-induced macrophage activation.

Project description:Macrophages respond to environmental cues in a plastic manner and play a crucial role in host defense, inﬂammation, and tissue homeostasis. Macrophage activation undergoes metabolic and transcriptomic reprogramming to adapt and tailor an appropriate response, regulating inﬂammation. Reactive oxygen species (ROS) have been shown to play a pivotal role in macrophage activation. Nevertheless, the detailed molecular mechanism of how initial redox signals direct macrophage activation is not fully elucidated. Here, we uncover an unconventional role for histone acetyltransferase MOF (also known as KAT8) in regulating LPS-induced macrophage activation via modulating the acetylation of peroxiredoxin 1 (PRDX1), an H2O2 scavenger. We demonstrate that PRDX1 is a novel substrate of MOF and identify the major MOF-mediated acetylation site at lysine 197. K197 acetylation of PRDX1 (K197ac PRDX1) is dynamic and reversely regulated by HDAC6 or SIRT2. We observe that this acetylation is readily diminished in the immediate response to LPS. We demonstrate that K197ac PRDX1 fine-tunes its peroxidase activity, leading to the modulation of intracellular ROS levels in early response to LPS stimulation. Moreover, K197ac PRDX1 specifically regulates ERK1/2 phosphorylation, thereby modulating glycolytic metabolism in inflammatory macrophages. Consequently, K197ac PRDX1 tunes the expression and production of the proinflammatory cytokine, IL-6. Taken together, our findings describe a novel signaling module, MOF-PRDX1-ERK, which regulates LPS-induced macrophage activation at the metabolic and transcriptional levels.

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