Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity

Zhao, Xinyang; Janković, Vladimir; Gural, Alexander; Huang, Gang; Pardanani, Animesh; Menéndez, Sílvia; Zhang, Jin; Dunne, Richard F.; Xiao, Andrew; Erdjument‐Bromage, Hediye; Allis, C. David; Tempst, Paul; Nimer, Stephen D.

doi:10.1101/gad.1632608

Cited by 161 publications

(145 citation statements)

References 51 publications

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“…Thus, it is conceivable that citrullination of the N terminus of GSK3β may regulate the binding of additional proteins involved in destabilization or nuclear export of the kinase in much the same way that nearby or adjacent histone modifications, such as those embedded in relatively unstructured "tail domains," may regulate histone function through PTM effector ("reader") binding, drawing upon an emerging concept being described as "histone mimicry" in a wide range of biological processes (36)(37)(38)(39). Citrullination of the N terminus is an entirely new concept in GSK3β regulation, and we look forward to future studies aimed at addressing the function (s) of N-terminal citrullination of GSK3β and the pathway being described here.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of PAD4-mediated citrullination of nuclear GSK3β activates TGF-β signaling and induces epithelial-to-mesenchymal transition in breast cancer cells

Stadler

Vincent

Fedorov

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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121

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Peptidylarginine deiminase 4 (PAD4) is a Ca 2+ -dependent enzyme that converts arginine and methylarginine residues to citrulline, with histone proteins being among its best-described substrates to date. However, the biological function of this posttranslational modification, either in histones or in nonhistone proteins, is poorly understood. Here, we show that PAD4 recognizes, binds, and citrullinates glycogen synthase kinase-3β (GSK3β), both in vitro and in vivo. Among other functions, GSK3β is a key regulator of transcription factors involved in tumor progression, and its dysregulation has been associated with progression of human cancers. We demonstrate that silencing of PAD4 in breast cancer cells leads to a striking reduction of nuclear GSK3β protein levels, increased TGF-β signaling, induction of epithelial-to-mesenchymal transition, and production of more invasive tumors in xenograft assays. Moreover, in breast cancer patients, reduction of PAD4 and nuclear GSK3β is associated with increased tumor invasiveness. We propose that PAD4-mediated citrullination of GSK3β is a unique posttranslational modification that regulates its nuclear localization and thereby plays a critical role in maintaining an epithelial phenotype. We demonstrate a dynamic and previously unappreciated interplay between histone-modifying enzymes, citrullination of nonhistone proteins, and epithelial-to-mesenchymal transition.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of PAD4-mediated citrullination of nuclear GSK3β activates TGF-β signaling and induces epithelial-to-mesenchymal transition in breast cancer cells

Stadler

Vincent

Fedorov

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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121

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“…Second, knockdown of PRMT1 reduced the level of endogenous Axin whereas increasing the level of cytoplasmic b-catenin (Figures 4 and 6). In addition, several published reports show that the substrates of PRMT1, such as RGC-1, Stat-1 and Runx1, can contain a non-GAR motif (Mowen et al, 2001;Teyssier et al, 2005;Zhao et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Methylation by protein arginine methyltransferase 1 increases stability of Axin, a negative regulator of Wnt signaling

Cha

Kim

et al. 2011

Oncogene

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Axin, a negative regulator of Wnt signaling, is a key scaffold protein for the b-catenin destruction complex. It has been previously shown that multiple post-translational modification enzymes regulate the level of Axin. Here, we provide evidence that protein arginine methyltransferase 1 (PRMT1) directly interacts with and methylates the 378th arginine residue of Axin both in vitro and in vivo. We found that the transient expression of PRMT1 led to an increased level of Axin and that knockdown of endogenous PRMT1 by short hairpin RNA reduced the level of Axin. These results suggest that methylation by PRMT1 enhanced the stability of Axin. Methylation of Axin by PRMT1 also seemingly enhanced the interaction between Axin and glycogen synthase kinase 3b, leading to decreased ubiquitination of Axin. Consistent with the role of PRMT1 in the regulation of Axin, knockdown of PRMT1 enhanced the level of cytoplasmic b-catenin as well as b-catenin-dependent transcription activity. In summary, we show that the methylation of Axin occurred in vivo and controlled the stability of Axin. Therefore, methylation of Axin by PRMT1 may serve as a finely tuned regulation mechanism for Wnt/b-catenin signaling.

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“…In AML1, arginine methylation in this exact motif has been reported previously. 32 We therefore speculated that AE9a could also be methylated by PRMT1 at Arg142. To address this hypothesis, in vitro methyltransferase assay with the use of unlabeled SAM as methyl donor was performed.…”

Section: Ae9a Is Methylated At Arg142 By Prmt1mentioning

confidence: 99%

“…Method for generating Methyl RUNT (R142) Ab is essentially the same as described previously, with the exception that methyl R142 Runt peptide was used. 32 …”

Section: Antibodiesmentioning

confidence: 99%

PRMT1 interacts with AML1-ETO to promote its transcriptional activation and progenitor cell proliferative potential

Shia

Okumura

Yan

et al. 2012

Blood

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Fusion protein AML1-ETO, resulting from t(8;21) translocation, is highly related to leukemia development. It has been reported that full-length AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. We have previously shown that the expression of AE9a, a splice isoform of AML1-ETO, can rapidly cause leukemia in mice. To understand how AML1-ETO is involved in leukemia development, we took advantage of our AE9a leukemia model and sought to identify its interacting proteins from primary leukemic cells. Here, we report the discovery of a novel AE9a binding partner PRMT1 (protein arginine methyltransferase 1). PRMT1 not only interacts with but also weakly methylates arginine 142 of AE9a. Knockdown of PRMT1 affects expression of a specific group of AE9a-activated genes. We also show that AE9a recruits PRMT1 to promoters of AE9a-activated genes, resulting in enrichment of H4 arginine 3 methylation, H3 Lys9/14 acetylation, and transcription activation. More importantly, knockdown of PRMT1 suppresses the self-renewal capability of AE9a, suggesting a potential role of PRMT1 in regulating leukemia development. (Blood. 2012;119(21):4953-4962) IntroductionAcute myeloid leukemia (AML) is closely associated with chromosomal abnormalities. 1 The AML1 gene (also known as CBFA2, PEBP2␣B, and RUNX1) was initially identified as a target of chromosomal translocation in t(8;21), which is associated with 15% of de novo AML cases and Յ 40% in the AML subtype M2 of the French-American-British classification. 2,3 This specific translocation at t(8;21) involves the AML1 gene on chromosome 21 and the ETO (also known as MTG8) gene on chromosome 8 and generates an AML1-ETO fusion transcription factor. 4 AML1-ETO inherits the DNA binding RUNT domain from AML1 and is functionally characterized as a transcription factor for both gene repression and activation. 3,[5][6][7] It has been shown that AML1-ETO negatively regulates AML1 target genes, possibly through interaction with corepressor proteins such as mSin3A, N-CoR/SMRT (nuclear receptor corepressor/silencing mediator for retinoic acid receptor and thyroid hormone receptor), and HDACs (histone deacetylases). [8][9][10] AML1-ETO could also act as a transactivator on certain genes. One of the possible mechanisms is by recruiting histone modifiers to make chromatin structure more accessible to the transcription activation machinery, resulting in gene activation. A recent finding shows that p300 binds to NHR1 domain of AML1-ETO to facilitate transcription. 11 A variety of posttranslational modifications, including acetylation, methylation, and phosphorylation, on specific residues of histones and their corresponding enzymes has been discovered. 12 It is well documented that a specific histone modification on a promoter could determine the state of transcription. Specifically, methylation on histone H4 arginine 3 (Arg3) by PRMT1 (protein arginine methyltransferase 1) generally correlates with transcription activation. 13 PRMT1 is the most predominant arginine ...

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Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity

Cited by 161 publications

References 51 publications

Dysregulation of PAD4-mediated citrullination of nuclear GSK3β activates TGF-β signaling and induces epithelial-to-mesenchymal transition in breast cancer cells

Dysregulation of PAD4-mediated citrullination of nuclear GSK3β activates TGF-β signaling and induces epithelial-to-mesenchymal transition in breast cancer cells

Methylation by protein arginine methyltransferase 1 increases stability of Axin, a negative regulator of Wnt signaling

PRMT1 interacts with AML1-ETO to promote its transcriptional activation and progenitor cell proliferative potential

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