Transcriptional regulation of haematopoietic transcription factors
© BioMed Central Ltd 2011
Published: 10 February 2011
The control of differential gene expression is central to all metazoan biology. Haematopoiesis represents one of the best understood developmental systems where multipotent blood stem cells give rise to a range of phenotypically distinct mature cell types, all characterised by their own distinctive gene expression profiles. Small combinations of lineage-determining transcription factors drive the development of specific mature lineages from multipotent precursors. Given their powerful regulatory nature, it is imperative that the expression of these lineage-determining transcription factors is under tight control, a fact underlined by the observation that their misexpression commonly leads to the development of leukaemia. Here we review recent studies on the transcriptional control of key haematopoietic transcription factors, which demonstrate that gene loci contain multiple modular regulatory regions within which specific regulatory codes can be identified, that some modular elements cooperate to mediate appropriate tissue-specific expression, and that long-range approaches will be necessary to capture all relevant regulatory elements. We also explore how changes in technology will impact on this area of research in the future.
Haematopoiesis represents one of the best studied models of adult stem cell development and differentiation [1, 2]. Powerful techniques allow purification and in vitro as well as in vivo functional assays of small subsets of cells, from haematopoietic stem cells (HSCs) via a plethora of intermediate progenitors to fully mature cell types. Transcription factors (TFs) directly regulate gene expression and thus control cellular phenotypes. It is no surprise, therefore, that TFs have emerged as some of the most powerful regulators of both normal development and disease.
The cis-regulatory regions of a gene locus can be thought of as different modules, each partaking in an important role, such as driving expression of the gene to a specific subset of cells or a specific tissue type. The activity of each regulatory region is controlled by a distinct set of upstream regulators. The individual regulatory regions within a given gene locus may have over-lapping or very distinct upstream regulators, and it is the combined activity of all these regions that ultimately controls gene expression. Comprehensive identification and characterisation of true functional cis-regulatory regions therefore represent an essential prerequisite to integrate important regulatory genes into wider transcriptional networks. Traditionally, DNaseI mapping was performed to identify regions of open/accessible chromatin. More recently, comparative genomic sequence analysis has been used to identify highly conserved sequences, which were taken to represent candidate regulatory elements based on the premise that sequence conservation indicated an important function [5–7]. The most recent development has been that of whole genome re-sequencing, which when coupled with chromatin immunoprecipitation assays allows genome-wide mapping of the chromatin status for a given histone modification . Though more predictive than previous approaches, these techniques still require functional validation of candidate elements, which involves in vivo and in vitro experiments to assess the true function of a given candidate regulatory region.
Several gene loci coding for TFs essential for haematopoiesis have been characterised using a combination of the above techniques. Collectively, these studies provided important insights into TF hierarchies and regulatory network core circuits [9–11]. This review will specifically focus on three haematopoietic loci, encoding the key haematopoietic regulators Scl/Tal1, Lmo2 and Gfi1.
Transcriptional regulation of Scl
The basic helix-loop-helix TF Scl/Tal1 is a key regulator of haematopoiesis with additional important roles in the development of the vascular and central nervous systems [12–16]. Within the haematopoietic system, Scl is essential for the development of HSCs as well as further differentiation into the erythroid and megakaryocytic lineages .
Taken together, these studies have highlighted the presence of three haematopoietic enhancers within the murine Scl locus, with distinct yet overlapping regulatory codes that contribute to the overall correct spatio-temporal expression of Scl. Interestingly, a recent study comparing the functionality of the mouse Scl enhancers with their corresponding chicken counterparts suggested that elements shared by mammals and lower vertebrates exhibit functional differences and binding site turnover between widely separated cis-regulatory modules . Remarkably, however, the regulatory inputs and overall expression patterns remain the same across different species. This in turn suggested that significant regulatory changes may be widespread, and not only apply to genes with altered expression patterns, but also to those where expression is highly conserved.
Transcriptional regulation of Lmo2
The Lim domain only 2 gene (Lmo2) encodes a transcriptional cofactor that is essential for haematopoiesis [27, 28]. The Lmo2 protein does not bind to DNA directly but rather participates in the formation of multipartite DNA-binding complexes with other TFs, such as Ldb1, Scl/Tal1, E2A and Gata1 or Gata2 [29–31]. Lmo2 is widely expressed across haematopoiesis with the exception of mature T-lymphoid cells where aberrant expression of Lmo2 results in T-cell leukaemias .
Transcriptional regulation of Gfi1
The Growth factor independence 1 gene (Gfi1) was originally identified in a retroviral screen designed to identify regulatory pathways that could initiate interleukin-2 independence in T cells . Within the haematopoietic system Gfi1 is expressed in HSCs , specific subsets of T cells , granulocytes, monocytes, and activated macrophages . Gfi1-/- mice lack neutrophils [41, 42] and Gfi1-/- HSCs are unable to maintain long-term haematopoiesis because elevated levels of proliferation lead to eventual exhaustion of the stem cell pool [39, 43]. Outside the haematopoietic system, Gfi1 is also specifically expressed in sensory epithelia, the lungs, neuronal precursors, the inner ear, intestinal epithelia and during mammary gland development [44–47].
A recent study used a combination of comparative genomics, locus-wide chromatin immunoprecipitation assays and functional validation within cell lines and transgenic animals to identify cis-regulatory regions within the Gfi1 locus . Four regulatory regions (-3.4 kb min pro, -1.2 kb min pro, +5.8 kb enhancer and +35 kb enhancer) were shown to recapitulate endogenous expression patterns of Gfi1 in the central nervous system, gut, limbs and developing mammary glands but no haematopoietic staining was observed. However, a recent genome-wide ChIP-Seq experiment  revealed binding of Scl/Tal1 to a region situated 35 kb upstream of the Gfi1 promoter within the last intron of its 5' flanking gene, Evi5. This element was subsequently validated in transgenic assays, which demonstrated lacz staining at multiple sites of haematopoietic stem/progenitor cell emergence (vitelline vessels, fetal liver, and dorsal aorta).
Transcriptional regulation of other key haematopoietic transcription factors
The transcriptional control of several other TFs known to play important roles within haematopoiesis have also been investigated. Runx1 has been shown to be transcribed from two promoter elements, both of which collaborate with the Runx1 +23 kb enhancer to drive expression of Runx1 to sites of HSC emergence [51–53]. Moreover, the Runx1 +23 kb region was shown to be regulated by important haematopoietic TFs (Gata2, Fli1, Elf1, Pu.1, Scl, Lmo2, Ldb1 and Runx1 itself) [53, 54]. Lyl1 is known to contain a promoter region that can be divided into two separate promoter elements that are responsible for driving the expression of Lyl1 within endothelial, haematopoietic progenitor, and megakaryocytic cells . These promoter elements were shown to contain conserved Ets and Gata motifs that were bound in vivo by Fli1, Elf1, Erg, Pu.1, and Gata2. Multiple elements within the Gata2 locus have been identified (-77 kb, -3.9 kb, -3 kb, -2.8 kb, -1.8 kb, +9.5 kb and 1 s promoter) [56–58] with the -1.8 kb region being essential for maintaining Gata2 repression in terminally differentiating cells . Elf1 contains four promoter elements (-55 kb, -49 kb, -21 kb and proximal), which are used in a cell-type-specific manner in combination with a lineage-specific -14 kb enhancer element . Enhancer elements utilising the Ets/Ets/Gata regulatory code, originally defined in the Scl +19 enhancer, were also identified in the Fli1, Gata2, Hhex/Prh and Smad6 gene loci [5, 57]. The picture emerging, therefore, is that transcriptional control of important haematopoietic TF loci is achieved through multiple regulatory elements but the number of upstream regulators may be relatively small. The same binding motifs are repeatedly found, but it is the precise arrangement within a single element as well as the interactions between elements that ultimately control expression.
Recent analysis of gene regulatory networks controlling pluripotency in embryonic stem cells suggests that a finite number of major combinatorial interactions are critical in controlling cellular phenotypes [60, 61]. Identification and subsequent functional characterisation of specific regulatory elements provides a powerful route into deciphering these combinatorial regulatory interactions. Whilst traditional methods of identifying regulatory elements should not be overlooked, it is essential to integrate new genome-wide methods to ensure that regulatory elements outside traditional gene loci boundaries are not overlooked. With the genome-wide mapping of TF binding events now eminently feasible, the importance of sequence conservation as a primary technique for identification of regulatory elements will diminish.
Nevertheless, genome-wide mapping of binding events is descriptive and therefore no substitute for conventional functional assays, which are therefore likely to remain an important component of any research programme aimed at elucidating transcriptional control mechanisms.
This article is part of a review series on Epigenetics and regulation. Other articles in the series can be found online at http://stemcellres.com/series/epigenetics
chromatin immunoprecipitation coupled with whole genome resequencing
haematopoietic stem cell
T-cell acute lymphoblastic leukemia
Work in the authors' laboratories is supported by Leukaemia and Lymphoma Research, the Leukaemia and Lymphoma Foundation and the UK Medical Research Council.
- Orkin SH, Zon LI: SnapShot: hematopoiesis. Cell. 2008, 132: 712-View ArticlePubMedGoogle Scholar
- Ottersbach K, Smith A, Wood A, Gottgens B: Ontogeny of haematopoiesis: recent advances and open questions. Br J Haematol. 2010, 148: 343-355. 10.1111/j.1365-2141.2009.07953.x.View ArticlePubMedGoogle Scholar
- Davidson EH: Emerging properties of animal gene regulatory networks. Nature. 2010, 468: 911-920. 10.1038/nature09645.PubMed CentralView ArticlePubMedGoogle Scholar
- modENCODE Consortium, Roy S, Ernst J, Kharchenko PV, Kheradpour P, Negre N, Eaton ML, Landolin JM, Bristow CA, Ma L, Lin MF, Washietl S, Arshinoff BI, Ay F, Meyer PE, Robine N, Washington NL, Di Stefano L, Berezikov E, Brown CD, Candeias R, Carlson JW, Carr A, Jungreis I, Marbach D, Sealfon R, Tolstorukov MY, Will S, Alekseyenko AA, Artieri C: Identification of functional elements and regulatory circuits by Drosophila modENCODE. Science. 2010, 330: 1787-1797. 10.1126/science.1198374.View ArticleGoogle Scholar
- Donaldson IJ, Chapman M, Kinston S, Landry JR, Knezevic K, Piltz S, Buckley N, Green AR, Gottgens B: Genome-wide identification of cis-regulatory sequences controlling blood and endothelial development. Hum Mol Genet. 2005, 14: 595-601. 10.1093/hmg/ddi056.View ArticlePubMedGoogle Scholar
- Göttgens B, Barton LM, Gilbert JG, Bench AJ, Sanchez MJ, Bahn S, Mistry S, Grafham D, McMurray A, Vaudin M, Amaya E, Bentley DR, Green AR, Sinclair AM: Analysis of vertebrate SCL loci identifies conserved enhancers. Nat Biotechnol. 2000, 18: 181-186.View ArticlePubMedGoogle Scholar
- Loots GG, Locksley RM, Blankespoor CM, Wang ZE, Miller W, Rubin EM, Frazer KA: Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science. 2000, 288: 136-140. 10.1126/science.288.5463.136.View ArticlePubMedGoogle Scholar
- Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K: High-resolution profiling of histone methylations in the human genome. Cell. 2007, 129: 823-837. 10.1016/j.cell.2007.05.009.View ArticlePubMedGoogle Scholar
- Foster SD, Oram SH, Wilson NK, Gottgens B: From genes to cells to tissues - modelling the haematopoietic system. Mol Biosyst. 2009, 5: 1413-1420. 10.1039/b907225j.View ArticlePubMedGoogle Scholar
- Miranda-Saavedra D, Gottgens B: Transcriptional regulatory networks in haematopoiesis. Curr Opin Genet Dev. 2008, 18: 530-535. 10.1016/j.gde.2008.09.001.View ArticlePubMedGoogle Scholar
- Pimanda JE, Gottgens B: Gene regulatory networks governing haematopoietic stem cell development and identity. Int J Dev Biol. 2010, 54: 1201-1211. 10.1387/ijdb.093038jp.View ArticlePubMedGoogle Scholar
- Kallianpur AR, Jordan JE, Brandt SJ: The SCL/TAL-1 gene is expressed in progenitors of both the hematopoietic and vascular systems during embryogenesis. Blood. 1994, 83: 1200-1208.PubMedGoogle Scholar
- Muroyama Y, Fujiwara Y, Orkin SH, Rowitch DH: Specification of astrocytes by bHLH protein SCL in a restricted region of the neural tube. Nature. 2005, 438: 360-363. 10.1038/nature04139.View ArticlePubMedGoogle Scholar
- Visvader JE, Fujiwara Y, Orkin SH: Unsuspected role for the T-cell leukemia protein SCL/tal-1 in vascular development. Genes Dev. 1998, 12: 473-479. 10.1101/gad.12.4.473.PubMed CentralView ArticlePubMedGoogle Scholar
- Robb L, Lyons I, Li R, Hartley L, Kontgen F, Harvey RP, Metcalf D, Begley CG: Absence of yolk sac hematopoiesis from mice with a targeted disruption of the scl gene. Proc Natl Acad Sci USA. 1995, 92: 7075-7079. 10.1073/pnas.92.15.7075.PubMed CentralView ArticlePubMedGoogle Scholar
- Shivdasani RA, Mayer EL, Orkin SH: Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature. 1995, 373: 432-434. 10.1038/373432a0.View ArticlePubMedGoogle Scholar
- Hall MA, Curtis DJ, Metcalf D, Elefanty AG, Sourris K, Robb L, Gothert JR, Jane SM, Begley CG: The critical regulator of embryonic hematopoiesis, SCL, is vital in the adult for megakaryopoiesis, erythropoiesis, and lineage choice in CFU-S12. Proc Natl Acad Sci USA. 2003, 100: 992-997. 10.1073/pnas.0237324100.PubMed CentralView ArticlePubMedGoogle Scholar
- Göttgens B, Broccardo C, Sanchez MJ, Deveaux S, Murphy G, Göthert JR, Kotsopoulou E, Kinston S, Delaney L, Piltz S, Barton LM, Knezevic K, Erber WN, Begley CG, Frampton J, Green AR: The scl +18/19 stem cell enhancer is not required for hematopoiesis: identification of a 5'bifunctional hematopoietic-endothelial enhancer bound by Fli-1 and Elf-1. Mol Cell Biol. 2004, 24: 1870-1883.PubMed CentralView ArticlePubMedGoogle Scholar
- Sanchez MJ, Bockamp EO, Miller J, Gambardella L, Green AR: Selective rescue of early haematopoietic progenitors in Scl(-/-) mice by expressing Scl under the control of a stem cell enhancer. Development. 2001, 128: 4815-4827.PubMedGoogle Scholar
- Sanchez M, Gottgens B, Sinclair AM, Stanley M, Begley CG, Hunter S, Green AR: An SCL 3'enhancer targets developing endothelium together with embryonic and adult haematopoietic progenitors. Development. 1999, 126: 3891-3904.PubMedGoogle Scholar
- Silberstein L, Sanchez MJ, Socolovsky M, Liu Y, Hoffman G, Kinston S, Piltz S, Bowen M, Gambardella L, Green AR, Gottgens B: Transgenic analysis of the stem cell leukemia +19 stem cell enhancer in adult and embryonic hematopoietic and endothelial cells. Stem Cells. 2005, 23: 1378-1388. 10.1634/stemcells.2005-0090.View ArticlePubMedGoogle Scholar
- Gottgens B, Nastos A, Kinston S, Piltz S, Delabesse EC, Stanley M, Sanchez MJ, Ciau-Uitz A, Patient R, Green AR: Establishing the transcriptional programme for blood: the SCL stem cell enhancer is regulated by a multiprotein complex containing Ets and GATA factors. EMBO J. 2002, 21: 3039-3050. 10.1093/emboj/cdf286.PubMed CentralView ArticlePubMedGoogle Scholar
- Smith AM, Sanchez MJ, Follows GA, Kinston S, Donaldson IJ, Green AR, Gottgens B: A novel mode of enhancer evolution: the Tal1 stem cell enhancer recruited a MIR element to specifically boost its activity. Genome Res. 2008, 18: 1422-1432. 10.1101/gr.077008.108.PubMed CentralView ArticlePubMedGoogle Scholar
- Ogilvy S, Ferreira R, Piltz SG, Bowen JM, Gottgens B, Green AR: The SCL +40 enhancer targets the midbrain together with primitive and definitive hematopoiesis and is regulated by SCL and GATA proteins. Mol Cell Biol. 2007, 27: 7206-7219. 10.1128/MCB.00931-07.PubMed CentralView ArticlePubMedGoogle Scholar
- Delabesse E, Ogilvy S, Chapman MA, Piltz SG, Gottgens B, Green AR: Transcriptional regulation of the SCL locus: identification of an enhancer that targets the primitive erythroid lineage in vivo. Mol Cell Biol. 2005, 25: 5215-5225. 10.1128/MCB.25.12.5215-5225.2005.PubMed CentralView ArticlePubMedGoogle Scholar
- Göttgens B, Ferreira R, Sanchez MJ, Ishibashi S, Li J, Spensberger D, Lefevre P, Ottersbach K, Chapman M, Kinston S, Knezevic K, Hoogenkamp M, Follows GA, Bonifer C, Amaya E, Green AR: Cis-regulatory remodeling of the SCL locus during vertebrate evolution. Mol Cell Biol. 2010, 30: 5741-5751.PubMed CentralView ArticlePubMedGoogle Scholar
- Yamada Y, Warren AJ, Dobson C, Forster A, Pannell R, Rabbitts TH: The T cell leukemia LIM protein Lmo2 is necessary for adult mouse hematopoiesis. Proc Natl Acad Sci USA. 1998, 95: 3890-3895. 10.1073/pnas.95.7.3890.PubMed CentralView ArticlePubMedGoogle Scholar
- Warren AJ, Colledge WH, Carlton MB, Evans MJ, Smith AJ, Rabbitts TH: The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development. Cell. 1994, 78: 45-57. 10.1016/0092-8674(94)90571-1.View ArticlePubMedGoogle Scholar
- Osada H, Grutz G, Axelson H, Forster A, Rabbitts TH: Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1. Proc Natl Acad Sci USA. 1995, 92: 9585-9589. 10.1073/pnas.92.21.9585.PubMed CentralView ArticlePubMedGoogle Scholar
- Valge-Archer V, Forster A, Rabbitts TH: The LMO1 and LDB1 proteins interact in human T cell acute leukaemia with the chromosomal translocation t(11;14)(p15;q11). Oncogene. 1998, 17: 3199-3202. 10.1038/sj.onc.1202353.View ArticlePubMedGoogle Scholar
- Wadman IA, Osada H, Grutz GG, Agulnick AD, Westphal H, Forster A, Rabbitts TH: The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins. EMBO J. 1997, 16: 3145-3157. 10.1093/emboj/16.11.3145.PubMed CentralView ArticlePubMedGoogle Scholar
- Rabbitts TH, Axelson H, Forster A, Grutz G, Lavenir I, Larson R, Osada H, Valge-Archer V, Wadman I, Warren A: Chromosomal translocations and leukaemia: a role for LMO2 in T cell acute leukaemia, in transcription and in erythropoiesis. Leukemia. 1997, 11 (Suppl 3): 271-272.PubMedGoogle Scholar
- Landry JR, Kinston S, Knezevic K, Donaldson IJ, Green AR, Gottgens B: Fli1, Elf1, and Ets1 regulate the proximal promoter of the LMO2 gene in endothelial cells. Blood. 2005, 106: 2680-2687. 10.1182/blood-2004-12-4755.View ArticlePubMedGoogle Scholar
- Crable SC, Anderson KP: A PAR domain transcription factor is involved in the expression from a hematopoietic-specific promoter for the human LMO2 gene. Blood. 2003, 101: 4757-4764. 10.1182/blood-2002-09-2702.View ArticlePubMedGoogle Scholar
- Oram SH, Thoms JA, Pridans C, Janes ME, Kinston SJ, Anand S, Landry JR, Lock RB, Jayaraman PS, Huntly BJ, Pimanda JE, Göttgens B: A previously unrecognized promoter of LMO2 forms part of a transcriptional regulatory circuit mediating LMO2 expression in a subset of T-acute lymphoblastic leukaemia patients. Oncogene. 2010, 29: 5796-5808. 10.1038/onc.2010.320.View ArticlePubMedGoogle Scholar
- Landry JR, Bonadies N, Kinston S, Knezevic K, Wilson NK, Oram SH, Janes M, Piltz S, Hammett M, Carter J, Hamilton T, Donaldson IJ, Lacaud G, Frampton J, Follows G, Kouskoff V, Göttgens B: Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors. Blood. 2009, 113: 5783-5792. 10.1182/blood-2008-11-187757.View ArticlePubMedGoogle Scholar
- Pimanda JE, Chan WY, Wilson NK, Smith AM, Kinston S, Knezevic K, Janes ME, Landry JR, Kolb-Kokocinski A, Frampton J, Tannahill D, Ottersbach K, Follows GA, Lacaud G, Kouskoff V, Göttgens B: Endoglin expression in blood and endothelium is differentially regulated by modular assembly of the Ets/Gata hemangioblast code. Blood. 2008, 112: 4512-4522. 10.1182/blood-2008-05-157560.PubMed CentralView ArticlePubMedGoogle Scholar
- Gilks CB, Bear SE, Grimes HL, Tsichlis PN: Progression of interleukin-2 (IL-2)- dependent rat T cell lymphoma lines to IL-2-independent growth following activation of a gene (Gfi -1) encoding a novel zinc finger protein. Mol Cell Biol. 1993, 13: 1759-1768.PubMed CentralView ArticlePubMedGoogle Scholar
- Hock H, Hamblen MJ, Rooke HM, Schindler JW, Saleque S, Fujiwara Y, Orkin SH: Gfi -1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature. 2004, 431: 1002-1007. 10.1038/nature02994.View ArticlePubMedGoogle Scholar
- Yucel R, Kosan C, Heyd F, Moroy T: Gfi 1:green fluorescent protein knock-in mutant reveals differential expression and autoregulation of the growth factor independence 1 (Gfi 1) gene during lymphocyte development. J Biol Chem. 2004, 279: 40906-40917. 10.1074/jbc.M400808200.View ArticlePubMedGoogle Scholar
- Karsunky H, Zeng H, Schmidt T, Zevnik B, Kluge R, Schmid KW, Duhrsen U, Moroy T: Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi 1. Nat Genet. 2002, 30: 295-300. 10.1038/ng831.View ArticlePubMedGoogle Scholar
- Hock H, Hamblen MJ, Rooke HM, Traver D, Bronson RT, Cameron S, Orkin SH: Intrinsic requirement for zinc finger transcription factor Gfi -1 in neutrophil differentiation. Immunity. 2003, 18: 109-120. 10.1016/S1074-7613(02)00501-0.View ArticlePubMedGoogle Scholar
- Zeng H, Yucel R, Kosan C, Klein-Hitpass L, Moroy T: Transcription factor Gfi 1 regulates self-renewal and engraftment of hematopoietic stem cells. EMBO J. 2004, 23: 4116-4125. 10.1038/sj.emboj.7600419.PubMed CentralView ArticlePubMedGoogle Scholar
- Clarkson RW, Wayland MT, Lee J, Freeman T, Watson CJ: Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression. Breast Cancer Res. 2004, 6: R92-109. 10.1186/bcr754.PubMed CentralView ArticlePubMedGoogle Scholar
- Kazanjian A, Wallis D, Au N, Nigam R, Venken KJ, Cagle PT, Dickey BF, Bellen HJ, Gilks CB, Grimes HL: Growth factor independence-1 is expressed in primary human neuroendocrine lung carcinomas and mediates the differentiation of murine pulmonary neuroendocrine cells. Cancer Res. 2004, 64: 6874-6882. 10.1158/0008-5472.CAN-04-0633.View ArticlePubMedGoogle Scholar
- Shroyer NF, Wallis D, Venken KJ, Bellen HJ, Zoghbi HY: Gfi 1 functions downstream of Math1 to control intestinal secretory cell subtype allocation and differentiation. Genes Dev. 2005, 19: 2412-2417. 10.1101/gad.1353905.PubMed CentralView ArticlePubMedGoogle Scholar
- Wallis D, Hamblen M, Zhou Y, Venken KJ, Schumacher A, Grimes HL, Zoghbi HY, Orkin SH, Bellen HJ: The zinc finger transcription factor Gfi 1, implicated in lymphomagenesis, is required for inner ear hair cell differentiation and survival. Development. 2003, 130: 221-232. 10.1242/dev.00190.View ArticlePubMedGoogle Scholar
- Wilson NK, Timms RT, Kinston SJ, Cheng YH, Oram SH, Landry JR, Mullender J, Ottersbach K, Gottgens B: Gfi 1 expression is controlled by five distinct regulatory regions spread over 100 kilobases, with Scl/Tal1, Gata2, PU.1, Erg, Meis1, and Runx1 acting as upstream regulators in early hematopoietic cells. Mol Cell Biol. 2010, 30: 3853-3863. 10.1128/MCB.00032-10.PubMed CentralView ArticlePubMedGoogle Scholar
- Wilson NK, Miranda-Saavedra D, Kinston S, Bonadies N, Foster SD, Calero-Nieto F, Dawson MA, Donaldson IJ, Dumon S, Frampton J, Janky R, Sun XH, Teichmann SA, Bannister AJ, Göttgens B: The transcriptional program controlled by the stem cell leukemia gene Scl/Tal1 during early embryonic hematopoietic development. Blood. 2009, 113: 5456-5465. 10.1182/blood-2009-01-200048.View ArticlePubMedGoogle Scholar
- Wilson NK, Foster SD, Wang X, Knezevic K, Schütte J, Kaimakis P, Chilarska PM, Kinston S, Ouwehand WH, Dzierzak E, Pimanda JE, de Bruijn MF, Göttgens B: Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators. Cell Stem Cell. 2010, 7: 532-544. 10.1016/j.stem.2010.07.016.View ArticlePubMedGoogle Scholar
- Bee T, Ashley EL, Bickley SR, Jarratt A, Li PS, Sloane-Stanley J, Gottgens B, de Bruijn MF: The mouse Runx1 +23 hematopoietic stem cell enhancer confers hematopoietic specificity to both Runx1 promoters. Blood. 2009, 113: 5121-5124. 10.1182/blood-2008-12-193003.View ArticlePubMedGoogle Scholar
- Bee T, Liddiard K, Swiers G, Bickley SR, Vink CS, Jarratt A, Hughes JR, Medvinsky A, de Bruijn MF: Alternative Runx1 promoter usage in mouse developmental hematopoiesis. Blood Cells Mol Dis. 2009, 43: 35-42. 10.1016/j.bcmd.2009.03.011.View ArticlePubMedGoogle Scholar
- Nottingham WT, Jarratt A, Burgess M, Speck CL, Cheng JF, Prabhakar S, Rubin EM, Li PS, Sloane-Stanley J, Kong ASJ, de Bruijn MF: Runx1-mediated hematopoietic stem-cell emergence is controlled by a Gata/Ets/SCLregulated enhancer. Blood. 2007, 110: 4188-4197. 10.1182/blood-2007-07-100883.PubMed CentralView ArticlePubMedGoogle Scholar
- Landry JR, Kinston S, Knezevic K, de Bruijn MF, Wilson N, Nottingham WT, Peitz M, Edenhofer F, Pimanda JE, Ottersbach K, Gottgens B: Runx genes are direct targets of Scl/Tal1 in the yolk sac and fetal liver. Blood. 2008, 111: 3005-3014. 10.1182/blood-2007-07-098830.View ArticlePubMedGoogle Scholar
- Chan WY, Follows GA, Lacaud G, Pimanda JE, Landry JR, Kinston S, Knezevic K, Piltz S, Donaldson IJ, Gambardella L, Sablitzky F, Green AR, Kouskoff V, Göttgens B: The paralogous hematopoietic regulators Lyl1 and Scl are coregulated by Ets and GATA factors, but Lyl1 cannot rescue the early Scl-/- phenotype. Blood. 2007, 109: 1908-1916. 10.1182/blood-2006-05-023226.View ArticlePubMedGoogle Scholar
- Grass JA, Jing H, Kim SI, Martowicz ML, Pal S, Blobel GA, Bresnick EH: Distinct functions of dispersed GATA factor complexes at an endogenous gene locus. Mol Cell Biol. 2006, 26: 7056-7067. 10.1128/MCB.01033-06.PubMed CentralView ArticlePubMedGoogle Scholar
- Pimanda JE, Ottersbach K, Knezevic K, Kinston S, Chan WY, Wilson NK, Landry JR, Wood AD, Kolb-Kokocinski A, Green AR, Tannahill D, Lacaud G, Kouskoff V, Göttgens B: Gata2, Fli1, and Scl form a recursively wired gene-regulatory circuit during early hematopoietic development. Proc Natl Acad Sci USA. 2007, 104: 17692-17697. 10.1073/pnas.0707045104.PubMed CentralView ArticlePubMedGoogle Scholar
- Snow JW, Trowbridge JJ, Fujiwara T, Emambokus NE, Grass JA, Orkin SH, Bresnick EH: A single cis element maintains repression of the key developmental regulator Gata2. PLoS Genet. 2010, 6: 10.1371/journal.pgen.1001103. pii:e1001103Google Scholar
- Calero-Nieto FJ, Wood AD, Wilson NK, Kinston S, Landry JR, Gottgens B: Transcriptional regulation of Elf-1: locus-wide analysis reveals four distinct promoters, a tissue-specific enhancer, control by PU.1 and the importance of Elf-1 downregulation for erythroid maturation. Nucleic Acids Res. 2010, 38: 6363-6374. 10.1093/nar/gkq490.PubMed CentralView ArticlePubMedGoogle Scholar
- Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, Orlov YL, Zhang W, Jiang J, Loh YH, Yeo HC, Yeo ZX, Narang V, Govindarajan KR, Leong B, Shahab A, Ruan Y, Bourque G, Sung WK, Clarke ND, Wei CL, Ng HH: Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell. 2008, 133: 1106-1117. 10.1016/j.cell.2008.04.043.View ArticlePubMedGoogle Scholar
- Kim J, Chu J, Shen X, Wang J, Orkin SH: An extended transcriptional network for pluripotency of embryonic stem cells. Cell. 2008, 132: 1049-1061. 10.1016/j.cell.2008.02.039.View ArticlePubMedGoogle Scholar