Knockdown of menin affects pre-mRNA processing and promoter fidelity at the interferon-gamma inducible IRF1 gene

Epigenetics & Chromatin

Melissa A Henriksen¹  Lara M Linden¹  Shaili Shah¹  Lauren B Auriemma² 

[1] Department of Biology, The University of Virginia, 485 McCormick Road, Charlottesville, VA 22903, USA;Hoffman-La Roche, 340 Kingsland Road, Building 102, Room C519, Nutley, NJ 07110, USA

关键词: transcription;    lysine methylation;    JAK-STAT;    histone;    HDACs;   

Others  :  813829
DOI  :  10.1186/1756-8935-5-2

 received in 2011-06-08, accepted in 2012-01-12,  发布年份 2012

【 摘 要 】

Background

The tumor suppressor menin (MEN1) is mutated in the inherited disease multiple endocrine neoplasia type I, and has several documented cellular roles, including the activation and repression of transcription effected by several transcription factors. As an activator, MEN1 is a component of the Set1-like mixed lineage leukemia (MLL) MLL1/MLL2 methyltransferase complex that methylates histone H3 lysine 4 (H3K4). MEN1 is localized to the signal transducer and activator of transcription 1 (STAT1)-dependent gene, interferon regulatory factor 1 (IRF1), and is further recruited when IRF1 transcription is triggered by interferon-γ signaling.

Results

RNAi-mediated knockdown of MEN1 alters the H3K4 dimethylation and H3 acetylation profiles, and the localization of histone deacetylase 3, at IRF1. While MEN1 knockdown does not impact the rate of transcription, IRF1 heteronuclear transcripts become enriched in MEN1-depleted cells. The processed mRNA and translated protein product are concomitantly reduced, and the antiviral state is attenuated. Additionally, the transcription start site at the IRF1 promoter is disrupted in the MEN1-depleted cells. The H3K4 demethylase, lysine specific demethylase 1, is also associated with IRF1, and its inhibition alters H3K4 methylation and disrupts the transcription start site as well.

Conclusions

Taken together, the data indicate that MEN1 contributes to STAT1-activated gene expression in a novel manner that includes defining the transcription start site and RNA processing.

【 授权许可】

   
2012 Auriemma et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Shilatifard A: Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation. Curr Opin Cell Biol 2008, 20:341-348.
• [2]Kouzarides T: Chromatin modifications and their function. Cell 2007, 128:693-705.
• [3]Wu M, Wang PF, Lee JS, Martin-Brown S, Florens L, Washburn MP, Shilatifard A: Molecular regulation of H3K4 trimethylation by Wdr82, a component of human Set1/COMPASS. Mol Cell Biol 2008, 28:7337-7344.
• [4]Wang P, Lin C, Smith ER, Guo H, Sanderson BW, Wu M, Gogol M, Alexander T, Seidel C, Wiedemann LM, Ge K, Krumlauf R, Shilatifard A: Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. Mol Cell Biol 2009, 29:6074-6085.
• [5]Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski T, Dressler GR, Copeland TD, Kalkum M, Ge K: PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J Biol Chem 2007, 282:20395-20406.
• [6]Balogh K, Patocs A, Hunyady L, Racz K: Menin dynamics and functional insight: take your partners. Mol Cell Endocrinol 2010, 326:80-84.
• [7]Karnik SK, Hughes CM, Gu X, Rozenblatt-Rosen O, McLean GW, Xiong Y, Meyerson M, Kim SK: Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc Natl Acad Sci USA 2005, 102:14659-14664.
• [8]Milne TA, Hughes CM, Lloyd R, Yang Z, Rozenblatt-Rosen O, Dou Y, Schnepp RW, Krankel C, Livolsi VA, Gibbs D, Hua X, Roeder RG, Meyerson M, Hess JL: Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc Natl Acad Sci USA 2005, 102:749-754.
• [9]Dreijerink KM, Lips CJ, Timmers HT: Multiple endocrine neoplasia type 1: a chromatin writer's block. J Intern Med 2009, 266:53-59.
• [10]Lee JS, Shilatifard A: A site to remember: H3K36 methylation a mark for histone deacetylation. Mutat Res 2007, 618:130-134.
• [11]Pena PV, Davrazou F, Shi X, Walter KL, Verkhusha VV, Gozani O, Zhao R, Kutateladze TG: Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. Nature 2006, 442:100-103.
• [12]Shi X, Hong T, Walter KL, Ewalt M, Michishita E, Hung T, Carney D, Pena P, Lan F, Kaadige MR, Lacoste N, Cayrou C, Davrazou F, Saha A, Cairns BR, Ayer DE, Kutateladze TG, Shi Y, Cote J, Chua KF, Gozani O: ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 2006, 442:96-99.
• [13]Kim T, Buratowski S: Dimethylation of H3K4 by Set1 recruits the Set3 histone deacetylase complex to 5' transcribed regions. Cell 2009, 137:259-272.
• [14]Pinskaya M, Gourvennec S, Morillon A: H3 lysine 4 di- and tri-methylation deposited by cryptic transcription attenuates promoter activation. Embo J 2009, 28:1697-1707.
• [15]Berretta J, Pinskaya M, Morillon A: A cryptic unstable transcript mediates transcriptional trans-silencing of the Ty1 retrotransposon in S. cerevisiae. Genes Dev 2008, 22:615-626.
• [16]Levy D, Darnell JE: Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002, 3:651-662.
• [17]Boehm U, Klamp T, Groot M, Howard JC: Cellular responses to interferon-gamma. Annu Rev Immunol 1997, 15:749-795.
• [18]Buro LJ, Chipumuro E, Henriksen MA: Menin and RNF20 recruitment is associated with dynamic histone modifications that regulate STAT1-activated transcription of the Interferon Regulatory Factor 1 (IRF1) gene. Epigenetics Chromatin 2010, 3:16. BioMed Central Full Text
• [19]Dreijerink K: Menin links estrogen receptor activation to histone H3K4 trimethylation. Cancer Res 2006, 66:4929-4935.
• [20]Dreijerink KM, Varier RA, van Beekum O, Jeninga EH, Hoppener JW, Lips CJ, Kummer JA, Kalkhoven E, Timmers HT: The multiple endocrine neoplasia type 1 (MEN1) tumor suppressor regulates peroxisome proliferator-activated receptor gamma-dependent adipocyte differentiation. Mol Cell Biol 2009, 29:5060-5069.
• [21]Dreijerink KM, Varier RA, van Nuland R, Broekhuizen R, Valk GD, van der Wal JE, Lips CJ, Kummer JA, Timmers HT: Regulation of vitamin D receptor function in MEN1-related parathyroid adenomas. Mol Cell Endocrinol 2009, 313:1-8.
• [22]Chang HM, Paulson M, Holko M, Rice CM, Williams BR, Marie I, Levy DE: Induction of interferon-stimulated gene expression and antiviral responses require protein deacetylase activity. Proc Natl Acad Sci USA 2004, 101:9578-9583.
• [23]Nusinzon I, Horvath CM: Interferon-stimulated transcription and innate antiviral immunity require deacetylase activity and histone deacetylase 1. Proc Natl Acad Sci USA 2003, 100:14742-14747.
• [24]Klampfer L, Huang J, Swaby LA, Augenlicht L: Requirement of histone deacetylase activity for signaling by STAT1. J Biol Chem 2004, 279:30358-30368.
• [25]Kim H, Lee JE, Cho EJ, Liu JO, Youn HD: Menin, a tumor suppressor, represses JunD-mediated transcriptional activity by association with an mSin3A-histone deacetylase complex. Cancer Res 2003, 63:6135-6139.
• [26]Wang A, Kurdistani SK, Grunstein M: Requirement of Hos2 histone deacetylase for gene activity in yeast. Science 2002, 298:1412-1414.
• [27]Cunliffe VT: Eloquent silence: developmental functions of Class I histone deacetylases. Curr Opin Genet Dev 2008, 18:404-410.
• [28]Elferink CJ, Reiners JJ Jr: Quantitative RT-PCR on CYP1A1 heterogeneous nuclear RNA: a surrogate for the in vitro transcription run-on assay. Biotechniques 1996, 20:470-477.
• [29]Taniguchi T, Tanaka N, Taki S: Regulation of the interferon system, immune response and oncogenesis by the transcription factor interferon regulatory factor-1. Eur Cytokine Netw 1998, 9:43-48.
• [30]Horvath CM, Darnell JE Jr: The antiviral state induced by alpha interferon and gamma interferon requires transcriptionally active Stat1 protein. J Virol 1996, 70:647-650.
• [31]Sims RJ, Millhouse S, Chen CF, Lewis BA, Erdjument-Bromage H, Tempst P, Manley JL, Reinberg D: Recognition of trimethylated histone H3 lysine 4 facilitates the recruitment of transcription postinitiation factors and pre-mRNA splicing. Mol Cell 2007, 28:665-676.
• [32]Pandit S, Wang D, Fu XD: Functional integration of transcriptional and RNA processing machineries. Curr Opin Cell Biol 2008, 20:260-265.
• [33]Carrozza MJ, Li B, Florens L, Suganuma T, Swanson SK, Lee KK, Shia WJ, Anderson S, Yates J, Washburn MP, Workman JL: Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell 2005, 123:581-592.
• [34]Joshi AA, Struhl K: Eaf3 chromodomain interaction with methylated H3-K36 links histone deacetylation to Pol II elongation. Mol Cell 2005, 20:971-978.
• [35]Keogh MC, Kurdistani SK, Morris SA, Ahn SH, Podolny V, Collins SR, Schuldiner M, Chin K, Punna T, Thompson NJ, Boone C, Emili A, Weissman JS, Hughes TR, Strahl BD, Grunstein M, Greenblatt JF, Buratowski S, Krogan NJ: Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell 2005, 123:593-605.
• [36]Pruitt KD, Tatusova T, Maglott DR: NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res 2007, 35:D61-65.
• [37]Parker KA, Bond U: Analysis of pre-rRNAs in heat-shocked HeLa cells allows identification of the upstream termination site of human polymerase I transcription. Mol Cell Biol 1989, 9:2500-2512.
• [38]Wassarman DA, Steitz JA: Structural analyses of the 7SK ribonucleoprotein (RNP), the most abundant human small RNP of unknown function. Mol Cell Biol 1991, 11:3432-3445.
• [39]Carninci P, Sandelin A, Lenhard B, Katayama S, Shimokawa K, Ponjavic J, Semple CA, Taylor MS, Engstrom PG, Frith MC, Forrest AR, Alkema WB, Tan SL, Plessy C, Kodzius R, Ravasi T, Kasukawa T, Fukuda S, Kanamori-Katayama M, Kitazume Y, Kawaji H, Kai C, Nakamura M, Konno H, Nakano K, Mottagui-Tabar S, Arner P, Chesi A, Gustincich S, Persichetti F, Suzuki H, Grimmond SM, Wells CA, Orlando V, Wahlestedt C, Liu ET, Harbers M, Kawai J, Bajic VB, Hume DA, Hayashizaki Y: Genome-wide analysis of mammalian promoter architecture and evolution. Nat Genet 2006, 38:626-635.
• [40]Lutz CS: Alternative polyadenylation: a twist on mRNA 3' end formation. ACS Chem Biol 2008, 3:609-617.
• [41]Lan F, Nottke AC, Shi Y: Mechanisms involved in the regulation of histone lysine demethylases. Curr Opin Cell Biol 2008, 20:316-325.
• [42]Yang M, Culhane JC, Szewczuk LM, Jalili P, Ball HL, Machius M, Cole PA, Yu H: Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans-2-phenylcyclopropylamine. Biochemistry 2007, 46:8058-8065.
• [43]Lee MG, Wynder C, Bochar DA, Hakimi MA, Cooch N, Shiekhattar R: Functional interplay between histone demethylase and deacetylase enzymes. Mol Cell Biol 2006, 26:6395-6402.
• [44]Kornblihtt AR: Coupling transcription and alternative splicing. Adv Exp Med Biol 2007, 623:175-189.
• [45]Cramer P, Pesce CG, Baralle FE, Kornblihtt AR: Functional association between promoter structure and transcript alternative splicing. Proc Natl Acad Sci USA 1997, 94:11456-11460.
• [46]Alexander R, Beggs JD: Cross-talk in transcription, splicing and chromatin: who makes the first call? Biochem Soc Trans 2010, 38:1251-1256.
• [47]Luco RF, Allo M, Schor IE, Kornblihtt AR, Misteli T: Epigenetics in alternative pre-mRNA splicing. Cell 2011, 144:16-26.
• [48]Gunderson FQ, Merkhofer EC, Johnson TL: Dynamic histone acetylation is critical for cotranscriptional spliceosome assembly and spliceosomal rearrangements. Proc Natl Acad Sci USA 2011, 108:2004-2009.
• [49]Pinskaya M, Morillon A: Histone H3 lysine 4 di-methylation: a novel mark for transcriptional fidelity? Epigenetics 2009, 4:302-306.
• [50]Thiel AT, Blessington P, Zou T, Feather D, Wu X, Yan J, Zhang H, Liu Z, Ernst P, Koretzky GA, Hua X: MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele. Cancer Cell 2010, 17:148-159.
• [51]Nusinzon I, Horvath CM: Unexpected roles for deacetylation in interferon- and cytokine-induced transcription. J Interferon Cytokine Res 2005, 25:745-748.
• [52]Buro LJ, Shah S, Henriksen MA: Chromatin immunoprecipitation (ChIP) to assay dynamic histone modification in activated gene expression in human cells. J Vis Exp 2010, 41:pii: 2053.
• [53]Cumming G, Fidler F, Vaux DL: Error bars in experimental biology. J Cell Biol 2007, 177:7-11.
• [54]Shuai K, Liao J, Song MM: Enhancement of antiproliferative activity of gamma interferon by the specific inhibition of tyrosine dephosphorylation of Stat1. Mol Cell Biol 1996, 16:4932-4941.
• [55]Shechter D, Dormann HL, Allis CD, Hake SB: Extraction, purification and analysis of histones. Nat Protoc 2007, 2:1445-1457.