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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2013

Open Access 01-12-2013 | Research

Structurally differentiated cis-elements that interact with PU.1 are functionally distinguishable in acute promyelocytic leukemia

Authors: Maoxiang Qian, Wen Jin, Xuehua Zhu, Xiaohong Jia, Xianwen Yang, Yanzhi Du, Kankan Wang, Ji Zhang

Published in: Journal of Hematology & Oncology | Issue 1/2013

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Abstract

Background

Transcription factor PU.1, a member of the ETS family, is a master regulator of myeloid differentiation whose functional disruption is often associated with acute myeloid leukemia (AML). Although much has been learned about PU.1 over the past decades, relatively little is known about cis-elements that interact with this factor under physiological or pathological conditions, especially in the whole-genome scale. We aimed to define the cistrome of PU.1 in acute promyelocytic leukemia (APL) cells and characterize the cis-elements bound by PU.1.

Methods

Chromatin immunoprecipitation with specific antibody coupled with deep sequencing (ChIP-seq) was used to investigate the in vivo PU.1 binding sites at the whole-genome scale in APL-derived NB4 cells. The ChIP-quantitative (q)-PCR and luciferase reporter assays were used to validate the binding events and trans-activity, respectively. Various computational analyses, including motif mining, evolutionary conservation analysis and functional enrichment analysis, were performed to characterize the cis-elements that interacted with PU.1.

Results

A total of 26,907 significantly enriched binding regions of PU.1 were identified under the false discovery rate 0.1% in NB4 cells. PU.1 bound to various types of genomic regions and acted as a promoter-enhancer dual binding transcription factor. Based on the sequence length and composition, two types of representative motifs were identified in PU.1 binding sites: a long and a short motif. The long motif, characterized by high sequence specificity and binding affinity, predominantly resided in the promoter-distal regions. In contrast, the short one, with strong evolutionary constraint, represented the primary PU.1 cis-elements in the promoter-proximal regions. Interestingly, the short one showed more preference to be correlated with the binding of other factors, especially PML/RARα. Moreover, genes targeted by both PU.1 and PML/RARα were significantly involved in categories associated with oncogenesis, hematopoiesis and the pathogenesis of acute myeloid leukemia.

Conclusions

Our results demonstrate that structurally differentiated cis-elements that interact with PU.1 are functionally distinguishable in APL, suggesting that the sequence diversity of cis-elements might be a critical mechanism by which cells interpret the genome, and contribute to distinct physiological and/or pathological function.
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Literature
1.
Wittkopp PJ, Kalay G: Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence. Nat Rev Genet. 2012, 13 (1): 59-69. 10.1038/nri3362.CrossRef
2.
Tenen DG: Disruption of differentiation in human cancer: AML shows the way. Nat Rev Cancer. 2003, 3 (2): 89-101.CrossRefPubMed
3.
Mueller BU, Pabst T, Fos J, Petkovic V, Fey MF, Asou N, Buergi U, Tenen DG: ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Blood. 2006, 107 (4): 3330-3338.PubMedCentralCrossRefPubMed
4.
Zhu X, Zhang H, Qian M, Zhao X, Yang W, Wang P, Zhang J, Wang K: The significance of low PU.1 expression in patients with acute promyelocytic leukemia. J Hematol Oncol. 2012, 5: 22-10.1186/1756-8722-5-22.PubMedCentralCrossRefPubMed
5.
Walter MJ, Park JS, Ries RE, Lau SK, McLellan M, Jaeger S, Wilson RK, Mardis ER, Ley TJ: Reduced PU.1 expression causes myeloid progenitor expansion and increased leukemia penetrance in mice expressing PML-RARalpha. Proc Natl Acad Sci USA. 2005, 102: 12513-12518. 10.1073/pnas.0504247102.PubMedCentralCrossRefPubMed
6.
Wang K, Wang P, Shi J, Zhu X, He M, Jia X, Yang X, Qiu F, Jin W, Qian M: PML/RARalpha targets promoter regions containing PU.1 consensus and RARE half sites in acute promyelocytic leukemia. Cancer Cell. 2010, 17: 186-197. 10.1016/j.ccr.2009.12.045.CrossRefPubMed
7.
Smith LT, Hohaus S, Gonzalez DA, Dziennis SE, Tenen DG: PU.1 (Spi-1) and C/EBP alpha regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells. Blood. 1996, 88: 1234-1247.PubMed
8.
Hohaus S, Petrovick MS, Voso MT, Sun Z, Zhang DE, Tenen DG: PU.1 (Spi-1) and C/EBP alpha regulate expression of the granulocyte-macrophage colony-stimulating factor receptor alpha gene. Mol Cell Biol. 1995, 15: 5830-5845.PubMedCentralCrossRefPubMed
9.
Zhang DE, Hetherington CJ, Chen HM, Tenen DG: The macrophage transcription factor PU.1 directs tissue-specific expression of the macrophage colony-stimulating factor receptor. Mol Cell Biol. 1994, 14: 373-381.PubMedCentralCrossRefPubMed
10.
Klemsz MJ, McKercher SR, Celada A, Van Beveren C, Maki RA: The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell. 1990, 61: 113-124. 10.1016/0092-8674(90)90219-5.CrossRefPubMed
11.
Nguyen VC, Ray D, Gross MS, de Tand MF, Frezal J, Moreau-Gachelin F: Localization of the human oncogene SPI1 on chromosome 11, region p11.22. Hum Genet. 1990, 84: 542-546.CrossRefPubMed
12.
Pahl HL, Scheibe RJ, Zhang DE, Chen HM, Galson DL, Maki RA, Tenen DG: The proto-oncogene PU.1 regulates expression of the myeloid-specific CD11b promoter. J Biol Chem. 1993, 268: 5014-5020.PubMed
13.
Galson DL, Hensold JO, Bishop TR, Schalling M, D’Andrea AD, Jones C, Auron PE, Housman DE: Mouse beta-globin DNA-binding protein B1 is identical to a proto-oncogene, the transcription factor Spi-1/PU.1, and is restricted in expression to hematopoietic cells and the testis. Mol Cell Biol. 1993, 13: 2929-2941.PubMedCentralCrossRefPubMed
14.
Gangenahalli GU, Gupta P, Saluja D, Verma YK, Kishore V, Chandra R, Sharma RK, Ravindranath T: Stem Cell Fate Specification: Role of Master Regulatory Switch Transcription Factor PU.1 in Differential Hematopoiesis. Stem Cells Dev. 2005, 14: 140-152. 10.1089/scd.2005.14.140.CrossRefPubMed
15.
Li SL, Schlegel W, Valente AJ, Clark RA: Critical flanking sequences of PU.1 binding sites in myeloid-specific promoters. J Biol Chem. 1999, 274: 32453-32460. 10.1074/jbc.274.45.32453.CrossRefPubMed
16.
Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nusbaum C, Myers RM, Brown M, Li W, Liu XS: Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008, 9: R137-10.1186/gb-2008-9-9-r137.PubMedCentralCrossRefPubMed
17.
Muller S, Sideras P, Smith CI, Xanthopoulos KG: Cell specific expression of human Bruton’s agammaglobulinemia tyrosine kinase gene (Btk) is regulated by Sp1- and Spi-1/PU.1-family members. Oncogene. 1996, 13: 1955-1964.PubMed
18.
van Dijk TB, Baltus B, Caldenhoven E, Handa H, Raaijmakers JA, Lammers JW, Koenderman L, de Groot RP: Cloning and characterization of the human interleukin-3 (IL-3)/IL-5/ granulocyte-macrophage colony-stimulating factor receptor betac gene: regulation by Ets family members. Blood. 1998, 92: 3636-3646.PubMed
19.
Eklund EA, Kakar R: Recruitment of CREB-binding protein by PU.1, IFN-regulatory factor-1, and the IFN consensus sequence-binding protein is necessary for IFN-gamma-induced p67phox and gp91phox expression. J Immunol. 1999, 163: 6095-6105.PubMed
20.
Li SL, Valente AJ, Qiang M, Schlegel W, Gamez M, Clark RA: Multiple PU.1 sites cooperate in the regulation of p40(phox) transcription during granulocytic differentiation of myeloid cells. Blood. 2002, 99: 4578-4587. 10.1182/blood.V99.12.4578.CrossRefPubMed
21.
Chen H, Ray-Gallet D, Zhang P, Hetherington CJ, Gonzalez DA, Zhang DE, Moreau-Gachelin F, Tenen DG: PU.1 (Spi-1) autoregulates its expression in myeloid cells. Oncogene. 1995, 11: 1549-1560.PubMed
22.
Kuhn RM, Karolchik D, Zweig AS, Wang T, Smith KE, Rosenbloom KR, Rhead B, Raney BJ, Pohl A, Pheasant M: The UCSC Genome Browser Database: update 2009. Nucleic Acids Res. 2009, 37: D755-D761. 10.1093/nar/gkn875.PubMedCentralCrossRefPubMed
23.
Brown RP, Feder ME: Reverse transcriptional profiling: non-correspondence of transcript level variation and proximal promoter polymorphism. BMC Genomics. 2005, 6: 110-10.1186/1471-2164-6-110.PubMedCentralCrossRefPubMed
24.
Wray GA: The evolutionary significance of cis-regulatory mutations. Nat Rev Genet. 2007, 8: 206-216.CrossRefPubMed
25.
Carroll JS, Meyer CA, Song J, Li W, Geistlinger TR, Eeckhoute J, Brodsky AS, Keeton EK, Fertuck KC, Hall GF: Genome-wide analysis of estrogen receptor binding sites. Nat Genet. 2006, 38: 1289-1297. 10.1038/ng1901.CrossRefPubMed
26.
Kim TH, Abdullaev ZK, Smith AD, Ching KA, Loukinov DI, Green RD, Zhang MQ, Lobanenkov VV, Ren B: Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell. 2007, 128: 1231-1245. 10.1016/j.cell.2006.12.048.PubMedCentralCrossRefPubMed
27.
Robertson G, Hirst M, Bainbridge M, Bilenky M, Zhao Y, Zeng T, Euskirchen G, Bernier B, Varhol R, Delaney A: Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat Methods. 2007, 4: 651-657. 10.1038/nmeth1068.CrossRefPubMed
28.
Lupien M, Eeckhoute J, Meyer CA, Wang Q, Zhang Y, Li W, Carroll JS, Liu XS, Brown M: FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell. 2008, 132: 958-970. 10.1016/j.cell.2008.01.018.PubMedCentralCrossRefPubMed
29.
Yu M, Riva L, Xie H, Schindler Y, Moran TB, Cheng Y, Yu D, Hardison R, Weiss MJ, Orkin SH: Insights into GATA-1-mediated gene activation versus repression via genome-wide chromatin occupancy analysis. MolCell. 2009, 36: 682-695.
30.
Fujiwara T, O’Geen H, Keles S, Blahnik K, Linnemann AK, Kang YA, Choi K, Farnham PJ, Bresnick EH: Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy. Mol Cell. 2009, 36: 667-681. 10.1016/j.molcel.2009.11.001.PubMedCentralCrossRefPubMed
31.
Robertson AG, Bilenky M, Tam A, Zhao Y, Zeng T, Thiessen N, Cezard T, Fejes AP, Wederell ED, Cullum R: Genome-wide relationship between histone H3 lysine 4 mono- and tri-methylation and transcription factor binding. Genome Res. 2008, 18: 1906-1917. 10.1101/gr.078519.108.PubMedCentralCrossRefPubMed
32.
Wormald S, Hilton DJ, Smyth GK, Speed TP: Proximal genomic localization of STAT1 binding and regulated transcriptional activity. BMC Genomics. 2006, 7: 254-10.1186/1471-2164-7-254.PubMedCentralCrossRefPubMed
33.
Okuno Y, Huang G, Rosenbauer F, Evans EK, Radomska HS, Iwasaki H, Akashi K, Moreau-Gachelin F, Li Y, Zhang P: Potential autoregulation of transcription factor PU.1 by an upstream regulatory element. Mol Cell Biol. 2005, 25: 2832-2845. 10.1128/MCB.25.7.2832-2845.2005.PubMedCentralCrossRefPubMed
34.
Shi J, Yang W, Chen M, Du Y, Zhang J, Wang K: AMD, an automated motif discovery tool using stepwise refinement of gapped consensuses. PLoS One. 2011, 6: e24576-10.1371/journal.pone.0024576.PubMedCentralCrossRefPubMed
35.
Bailey TL, Boden M, Buske FA, Frith M, Grant CE, Clementi L, Ren J, Li WW, Noble WS: MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res. 2009, 37: W202-W208. 10.1093/nar/gkp335.PubMedCentralCrossRefPubMed
36.
Consortium EP, Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M: An integrated encyclopedia of DNA elements in the human genome. Nature. 2012, 489: 57-74. 10.1038/nature11247.CrossRef
37.
Wang J, Zhuang J, Iyer S, Lin X, Whitfield TW, Greven MC, Pierce BG, Dong X, Kundaje A, Cheng Y: Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors. Genome Res. 2012, 22: 1798-1812. 10.1101/gr.139105.112.PubMedCentralCrossRefPubMed
38.
39.
40.
Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA, Szary AJ, Eeckhoute J, Shao W, Hestermann EV, Geistlinger TR: Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell. 2005, 122: 33-43. 10.1016/j.cell.2005.05.008.CrossRefPubMed
41.
Lin Z, Reierstad S, Huang CC, Bulun SE: Novel estrogen receptor-alpha binding sites and estradiol target genes identified by chromatin immunoprecipitation cloning in breast cancer. Cancer Res. 2007, 67: 5017-5024. 10.1158/0008-5472.CAN-06-3696.CrossRefPubMed
42.
Yoon H, Boss JM: PU.1 binds to a distal regulatory element that is necessary for B cell-specific expression of CIITA. J Immunol. 2010, 184: 5018-5028. 10.4049/jimmunol.1000079.PubMedCentralCrossRefPubMed
43.
Badis G, Berger MF, Philippakis AA, Talukder S, Gehrke AR, Jaeger SA, Chan ET, Metzler G, Vedenko A, Chen X: Diversity and complexity in DNA recognition by transcription factors. Science. 2009, 324: 1720-1723. 10.1126/science.1162327.PubMedCentralCrossRefPubMed
44.
Rosenbauer F, Wagner K, Kutok JL, Iwasaki H, Le Beau MM, Okuno Y, Akashi K, Fiering S, Tenen DG: Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet. 2004, 36: 624-630. 10.1038/ng1361.CrossRefPubMed
45.
Cawley S, Bekiranov S, Ng HH, Kapranov P, Sekinger EA, Kampa D, Piccolboni A, Sementchenko V, Cheng J, Williams AJ: Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell. 2004, 116: 499-509. 10.1016/S0092-8674(04)00127-8.CrossRefPubMed
Metadata
Title
Structurally differentiated cis-elements that interact with PU.1 are functionally distinguishable in acute promyelocytic leukemia
Authors
Maoxiang Qian
Wen Jin
Xuehua Zhu
Xiaohong Jia
Xianwen Yang
Yanzhi Du
Kankan Wang
Ji Zhang
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2013
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/1756-8722-6-25

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