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Genome-wide analysis of transcriptional regulators in human HSPCs reveals a densely interconnected network of coding and noncoding genes
Abstract
Genome-wide combinatorial binding patterns for key transcription factors (TFs) have not been reported for primary human hematopoietic stem and progenitor cells (HSPCs), and have constrained analysis of the global architecture of molecular circuits controlling these cells. Here we provide high-resolution genome-wide binding maps for a heptad of key TFs (FLI1, ERG, GATA2, RUNX1, SCL, LYL1, and LMO2) in human CD34(+) HSPCs, together with quantitative RNA and microRNA expression profiles. We catalog binding of TFs at coding genes and microRNA promoters, and report that combinatorial binding of all 7 TFs is favored and associated with differential expression of genes and microRNA in HSPCs. We also uncover a previously unrecognized association between FLI1 and RUNX1 pairing in HSPCs, we establish a correlation between the density of histone modifications that mark active enhancers and the number of overlapping TFs at a peak, we demonstrate bivalent histone marks at promoters of heptad target genes in CD34(+) cells that are poised for later expression, and we identify complex relationships between specific microRNAs and coding genes regulated by the heptad. Taken together, these data reveal the power of integrating multifactor sequencing of chromatin immunoprecipitates with coding and noncoding gene expression to identify regulatory circuits controlling cell identity.
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“For instance, the combinatorial occupancy of chromatin by multiple master TFs has revealed regulatory networks that are important for hematopoiesis (Beck et al., 2013; Schütte et al., 2016), as well as key regulatory elements necessary for HSC self-renewal (Bahr et al., 2018).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Beck et al., 2013
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“We also re-analyzed 45 previously published ChIP-seq datasets of TFs and chromatin regulators obtained in the same cell populations (Abraham et al., 2013; Beck et al., 2013; Dogan Figure 3.”
MethodHaematopoietic and immune defects associated with GATA2 mutation
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“…adult haematopoiesis, GATA2 is required for HSC survival and self-renewal, interacting with a complex network of transcription factors that specify early lineage commitment, including SPI1 (PU.1), FLI1, TAL1 (SCL), LMO2 and RUNX1, among others (Dore et al, 2012; Beck et al, 2013; May et al, 2013).”
BackgroundCai, X., Gao, L., Teng, L., Ge, J., Oo, Z. M., Kumar, A. R., Gilliland, D. G., Mason, P. J., Tan, K., & Speck, N. A. (2015) · Cell stem cell · doi:10.1016/j.stem.2015.06.002 · Cited by 237
“We analyzed the genome-wide occupancy of RUNX1 using previously published chromatin immunoprecipitation sequencing (ChIP-seq) data generated in human CD34+ HSPCs (Beck et al., 2013).”
InfluentialAdelman, E. R., Huang, H.-T., Roisman, A., Olsson, A., Colaprico, A., Qin, T., Lindsley, R. C., Bejar, R. L., Salomonis, N., Grimes, H. L., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1474 · Cited by 234
“1341 1342 Adelman et al Epigenetic reprogramming in aging human HSC enhancer enriched clusters J-L.”
BackgroundMethodInfluentialThe GATA factor revolution in hematology
Katsumura, K. R., Bresnick, E. H., & the GATA Factor Mechanisms Group (2017) · Blood · doi:10.1182/blood-2016-09-687871 · Cited by 184
Unraveling Hematopoiesis through the Lens of Genomics
Liggett, L. A., & Sankaran, V. G. (2020) · Cell · doi:10.1016/j.cell.2020.08.030 · Cited by 163
“For instance, the combinatorial occupancy of chromatin by multiple master TFs has revealed regulatory networks that are important for hematopoiesis (Beck et al., 2013; Schütte et al., 2016), as well as key regulatory elements necessary for HSC self-renewal (Bahr et al.”
The non-coding RNA landscape of human hematopoiesis and leukemia
Schwarzer, A., Emmrich, S., Schmidt, F., Beck, D., Ng, M. S. W., Reimer, C., Adams, F. F., Grasedieck, S., Witte, D., Käbler, S., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00212-4 · Cited by 158
Hsu, A. P., McReynolds, L. J., & Holland, S. M. (2014) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/aci.0000000000000126 · Cited by 145
DNA methylation at enhancers identifies distinct breast cancer lineages
Fleischer, T., Tekpli, X., Mathelier, A., Wang, S., Nebdal, D. J. H., Dhakal, H. P., Sahlberg, K. K., Schlichting, E., Sauer, T., Geisler, J., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00510-x · Cited by 148
Jing, D., Bhadri, V. A., Beck, D., Thoms, J. A. I., Yakob, N. A., Wong, J. W. H., Knezevic, K., Pimanda, J. E., & Lock, R. B. (2014) · Blood · doi:10.1182/blood-2014-05-576470 · Cited by 124
Kartalaei, P. S., Yamada-Inagawa, T., Vink, C. S., de Pater, E., van der Linden, R., Marks-Bluth, J., van der Sloot, A., van den Hout, M. C. G. N., Yokomizo, T., van Schaick-Solernó, M. L., et al. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20140767 · Cited by 123
“Real-time imaging of transgenic zebrafish embryos similarly revealed the transition of aortic ECs to HCs (Bertrand et al., 2010; Kissa and Herbomel, 2010), indicating that EHT is an evolutionarily conserved process by which the definitive hematopoietic system of vertebrates is generated.”
BackgroundAranda-Orgillés, B., Saldaña-Meyer, R., Wang, E., Trompouki, E., Fassl, A., Lau, S., Mullenders, J., Rocha, P. P., Raviram, R., Guillamot, M., et al. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.08.004 · Cited by 111
“Further comparison with ChIP-seq experiments of diverse histone marks in CD34+ cells available from Human Reference Epigenome Mapping Project (Table S2) revealed that MED12 mostly co-localized with histone modifications characteristic of active enhancers (H3K4me1 and H3K27Ac) (Figure 5B).”
InfluentialGillespie, M. A., Palii, C. G., Sanchez-Taltavull, D., Shannon, P., Longabaugh, W. J. R., Downes, D. J., Sivaraman, K., Espinoza, H. M., Hughes, J. R., Price, N. D., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.03.031 · Cited by 110
Gata2 as a Crucial Regulator of Stem Cells in Adult Hematopoiesis and Acute Myeloid Leukemia
Menendez-Gonzalez, J. B., Vukovic, M., Abdelfattah, A., Saleh, L., Almotiri, A., Thomas, L.-A., Lizaso, A. A., Azevedo, A., Menezes, A. C., Tornillo, G., et al. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2019.07.005 · Cited by 97
“Hematopoiesis is contingent on a rare pool of self-renewing hematopoietic stem cells (HSCs) and progenitors that are regulated by a combination of a cell-extrinsic program, imparted by the bone marrow (BM) niche in which they reside, and a cell-autonomous program driven by transcription factors (TFs), which regulate g…”
BackgroundAn autonomous CEBPA enhancer specific for myeloid-lineage priming and neutrophilic differentiation
Avellino, R., Havermans, M., Erpelinck-Verschueren, C. A. J., Sanders, M. A., Hoogenboezem, R. M., van de Werken, H. J. G., Rombouts, E. J. C., van Lom, K., van Strien, P. M. H., Gebhard, C., et al. (2016) · Blood · doi:10.1182/blood-2016-01-695759 · Cited by 87
Regulatory network control of blood stem cells
Göttgens, B. (2015) · Blood · doi:10.1182/blood-2014-08-570226 · Cited by 82
Pijuan-Sala, B., Wilson, N. K., Xia, J., Hou, X., Hannah, R., Kinston, S., Calero‐Nieto, F. J., Poirion, O., Preißl, S., Liu, F., et al. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0489-9 · Cited by 73
Lund, K., Cole, J. J., VanderKraats, N. D., McBryan, T., Pchelintsev, N. A., Clark, W. A., Copland, M., Edwards, J. R., & Adams, P. D. (2014) · Genome biology · doi:10.1186/s13059-014-0406-2 · Cited by 72
“…identified all those genes whose expression is downregulated in AML3 compared to HSPC, based on two previously published HSPC gene expression datasets [29,30], and whose expression is significantly regulated by AzaC treatment of AML3 (Additional file 5: Dataset 6, ‘ HSPC_AML_Expr both Down_259 ’ ).”
InfluentialGATA Factor-Dependent Positive-Feedback Circuit in Acute Myeloid Leukemia Cells
Katsumura, K. R., Ong, I. M., DeVilbiss, A., Sanalkumar, R., & Bresnick, E. H. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.07.058 · Cited by 70
“GATA-2 occupied the same sites in human CD34-positive cells and TF-1 myeloerythroid cells (Beck et al., 2013; Mazumdar et al., 2015), and the sites were DNase hypersensitive in CD34-positive cells (Figure 2C).”
BackgroundMethodThe chromatin landscape and transcription factors in T cell programming
Rothenberg, E. V. (2014) · Trends in Immunology · doi:10.1016/j.it.2014.03.001 · Cited by 74
The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops
Ottema, S., Mulet‐Lazaro, R., Erpelinck-Verschueren, C. A. J., van Herk, S., Havermans, M., Varea, A. A., Vermeulen, M., Beverloo, H. B., Gröschel, S., Haferlach, T., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25862-3 · Cited by 74
Single-Cell Analysis Identifies Distinct Stages of Human Endothelial-to-Hematopoietic Transition
Guibentif, C., Rönn, R. E., Böiers, C., Lang, S., Saxena, S. A., Soneji, S., Enver, T., Karlsson, G., & Woods, N. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.03.023 · Cited by 67
A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia
Voit, R. A., Tao, L., Yu, F., Cato, L. D., Cohen, B., Fleming, T. J., Antoszewski, M., Liao, X., Fiorini, C., Nandakumar, S. K., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01370-4 · Cited by 70
Schütte, J., Wang, H., Antoniou, S., Jarratt, A., Wilson, N. K., Riepsaame, J., Calero-Nieto, F. J., Moignard, V., Basilico, S., Kinston, S. J., et al. (2016) · eLife · doi:10.7554/elife.11469 · Cited by 63
“This led to the removal of the Gata2-3, which is not bound by any of the nine TFs in either cell type, Gata2-92 and Gfi1b+13, which are only bound by one or no TFs in 416b cells, and Fli1-15, which is not acetylated in 416b cells (Figure 2c, Figure 2—figure supplements 1– 3).”
BackgroundInfluentialTranscription factor mutations as a cause of familial myeloid neoplasms
Churpek, J. E., & Bresnick, E. H. (2019) · Journal of Clinical Investigation · doi:10.1172/jci120854 · Cited by 60
Rothenberg, E. V., Ungerbäck, J., & Champhekar, A. (2016) · Advances in Immunology · doi:10.1016/bs.ai.2015.09.002 · Cited by 61
Wilson, N. K., Schoenfelder, S., Hannah, R., Castillo, M. S., Schütte, J., Ladopoulos, V., Mitchelmore, J., Goode, D. K., Calero‐Nieto, F. J., Moignard, V., et al. (2016) · Blood · doi:10.1182/blood-2015-10-677393 · Cited by 61
Subramanian, S., Thoms, J. A. I., Huang, Y., Cornejo-Páramo, P., Koch, F. C., Jacquelin, S., Shen, S., Song, E., Joshi, S., Brownlee, C., et al. (2023) · Blood · doi:10.1182/blood.2023021120 · Cited by 57
“We previously described combinatorial binding of heptad factors in bulk human HSPCs 21 , and now extend these observations to specific cell populations.”
InfluentialBergiers, I., Andrews, T. S., Bölükbaşı, Ö. V., Buneß, A., Janosz, E., López-Anguita, N., Ganter, K., Kosim, K., Celen, C., Perçin, G. I., et al. (2018) · eLife · doi:10.7554/elife.29312 · Cited by 56
“The additional seed genes were selected if they appeared in networks published by at least two different authors (Beck et al., 2013; Bonzanni et al., 2013; Moignard et al., 2013; Moignard et al., 2015; Tanaka et al., 2012).”
BackgroundSotoca, A. M., Prange, K. H. M., Reijnders, B., Mandoli, A., Nguyen, L. N. M., Stunnenberg, H. G., & Martens, J. H. A. (2015) · Oncogene · doi:10.1038/onc.2015.261 · Cited by 51
Asparaginase in Acute Lymphoblastic Leukemia
Kawedia, J. D., & Rytting, M. (2014) · Clinical Lymphoma Myeloma & Leukemia · doi:10.1016/j.clml.2014.06.017 · Cited by 51
Chacon, D., Beck, D., Perera, D., Wong, J., & Pimanda, J. (2013) · Nucleic Acids Res. · doi:10.1093/nar/gkt1036 · Cited by 50
Shen, N., Zhao, J., Schipper, J. L., Zhang, Y., Bepler, T., Leehr, D., Bradley, J., Horton, J., Lapp, H., & Gordân, R. (2018) · Cell Systems · doi:10.1016/j.cels.2018.02.009 · Cited by 50
“…Runx1 and Runx2 were retrieved from the NCBI Gene Expression Omnibus database (Edgar et al., 2002), with accession number GSE45144 for Runx1 in human hematopoietic stem and progenitor cells (HSPCs) (Beck et al., 2013), and GSE49585 for Runx2 in cultured human osteoblasts (Hakelien et al., 2014).”
MethodIntegrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program
Mehta, C., Johnson, K. D., Gao, X., Ong, I. M., Katsumura, K. R., McIver, S. C., Ranheim, E. A., & Bresnick, E. H. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.090 · Cited by 50
Yoshino, S., Yokoyama, T., Sunami, Y., Takahara, T., Nakamura, A., Yamazaki, Y., Tsutsumi, S., Aburatani, H., & Nakamura, T. (2020) · Blood · doi:10.1182/blood.2019004586 · Cited by 50
Mehtonen, J., Teppo, S., Lahnalampi, M., Kokko, A., Kaukonen, R., Oksa, L., Bouvy‐Liivrand, M., Malyukova, A., Mäkinen, A., Laukkanen, S., et al. (2020) · Genome Medicine · doi:10.1186/s13073-020-00799-2 · Cited by 49
A novel role for Lyl1 in primitive erythropoiesis
Chiu, S. K., Saw, J., Huang, Y., Sonderegger, S., Wong, N. C., Powell, D., Beck, D., Pimanda, J. E., Tremblay, C. S., & Curtis, D. J. (2018) · Development · doi:10.1242/dev.162990 · Cited by 46
“This functional redundancy is consistent with genome-wide chromatin immunoprecipitation (ChIP)-seq studies showing shared binding of Scl and Lyl1 along with other crucial hematopoietic TFs in HSCs (Beck et al., 2013; Chacon et al., 2014; Wilson et al., 2010).”
BackgroundMethodInfluentialHuman NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation
Li, Y., Jin, C., Bai, H., Gao, Y., Sun, S. F., Chen, L., Qin, L., Liu, P., Cheng, L., & Wang, Q. (2017) · Blood · doi:10.1182/blood-2017-04-780379 · Cited by 46
Understanding transcriptional regulatory networks using computational models
He, B., & Tan, K. (2016) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2016.02.002 · Cited by 49
Germline RUNX1 variation and predisposition to childhood acute lymphoblastic leukemia
Li, Y., Yang, W., Devidas, M., Winter, S. S., Kesserwan, C. A., Yang, W., Dunsmore, K. P., Smith, C. J., Qian, M., Zhao, X., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci147898 · Cited by 44
Thoms, J. A. I., Truong, P., Subramanian, S., Knezevic, K., Harvey, G., Huang, Y., Seneviratne, J. A., Carter, D. R., Joshi, S. M., Skhinas, J. N., et al. (2021) · Blood · doi:10.1182/blood.2020009707 · Cited by 42
Yu, K., Deuitch, N. T., Merguerian, M., Cunningham, L., Davis, J., Bresciani, E., Diemer, J. L., Andrews, E. T., Young, A., Donovan, F. X., et al. (2023) · Blood Advances · doi:10.1182/bloodadvances.2023011165 · Cited by 42
Hematopoietic Signaling Mechanism Revealed from a Stem/Progenitor Cell Cistrome
Hewitt, K. J., Kim, D. H., Devadas, P., Prathibha, R., Zuo, C., Sanalkumar, R., Johnson, K. D., Kang, Y.-A., Kim, J., Dewey, C. N., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.05.020 · Cited by 42
“GATA-2 occupied Samd14 +2.5 in human bone marrow-derived CD34+ HSPCs (Beck et al., 2013), K562 erythroleukemia cells (Fujiwara et al., 2009), and human umbilical vein endothelial cells (HUVECs) (Linnemann et al., 2011).”
InfluentialDomain-adaptive neural networks improve cross-species prediction of transcription factor bindingPreprint
Cochran, K., Srivastava, D., Shrikumar, A., Balsubramani, A., Hardison, R. C., Kundaje, A. B., & Mahony, S. (2022) · Genome Research · doi:10.1101/gr.275394.121 · Cited by 42
“…data targeting orthologous TFs in erythroid progenitor, megakaryocyte, macrophage, and hematopoietic progenitor cell types (Hu et al. 2011; Tijssen et al. 2011; Pham et al. 2012; Beck et al. 2013; Kaikkonen et al. 2013; Pencovich et al. 2013; Yue et al. 2014; Goode et al. 2016; Huang et al. 2016).”
The PD-1 pathway as a therapeutic target to overcome immune escape mechanisms in cancer
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Oncogenic transcriptional program driven by TAL1 in T-cell acute lymphoblastic leukemia
Tan, T. K., Zhang, C., & Sanda, T. (2018) · International Journal of Hematology · doi:10.1007/s12185-018-2518-z · Cited by 42
Selective Requirement of MYB for Oncogenic Hyperactivation of a Translocated Enhancer in Leukemia
Smeenk, L., Ottema, S., Mulet‐Lazaro, R., Ebert, A., Havermans, M., Varea, A. A., Fellner, M., Pastoors, D., van Herk, S., Erpelinck-Verschueren, C. A. J., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1793 · Cited by 41
GATA Factor-Mediated Gene Regulation in Human Erythropoiesis
Romano, O., Petiti, L., Félix, T., Meneghini, V., Portafax, M., Antoniani, C., Amendola, M., Bicciato, S., Peano, C., & Miccio, A. (2020) · iScience · doi:10.1016/j.isci.2020.101018 · Cited by 40
GATA factor transcriptional activity: Insights from genome‐wide binding profiles
Romano, O., & Miccio, A. (2019) · IUBMB Life · doi:10.1002/iub.2169 · Cited by 38
“71–73 In HSPCs, GATA2 marks a subset of bivalent H3K27me3 H3K4me3 regulatory regions that are bound by GATA1 upon erythroid differentiation and tend to be located close to erythroid-specific genes—suggesting that GATA2 is at least partially involved in lineage priming.(16,41,51,71,72) Lastly, upon activation of the BM…”
BackgroundMolecular basis of crosstalk between oncogenic Ras and the master regulator of hematopoiesis GATA‐2
Katsumura, K. R., Yang, C., Boyer, M. E., Li, L., & Bresnick, E. H. (2014) · EMBO Reports · doi:10.15252/embr.201438808 · Cited by 38
“ChIP-seq profiles for GATA-2 in HUVEC cells [33] and human CD34positive cells [34] were generated using the UCSC Genome Browser (http://genome.”
Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemiaPreprint
Teppo, S., Laukkanen, S., Liuksiala, T., Nordlund, J., Oittinen, M., Teittinen, K. J., Grönroos, T., St-Onge, P., Sinnett, D., Syvänen, A., et al. (2016) · Genome Research · doi:10.1101/gr.193649.115 · Cited by 34
Transcriptional network control of normal and leukaemic haematopoiesis
Sive, J. I., & Göttgens, B. (2014) · Experimental Cell Research · doi:10.1016/j.yexcr.2014.06.021 · Cited by 35
“Subsequent research has confirmed a similar binding pattern of the TF “heptad” in human primary CD34þ cells [66].”
BackgroundTranscriptional networks in acute myeloid leukemia
Thoms, J. A. I., Beck, D., & Pimanda, J. E. (2019) · Genes Chromosomes and Cancer · doi:10.1002/gcc.22794 · Cited by 33
“and regulate their own regulatory elements such that they form an interconnected circuit.(100,186,211) The heptad circuit appears to be”
BackgroundInfluentialMatsumura, T., Nakamura‐Ishizu, A., Muddineni, S. S. N. A., Tan, D. Q., Wang, C. Q., Tokunaga, K., Tirado-Magallanes, R., Sian, S., Benoukraf, T., Okuda, T., et al. (2020) · Blood · doi:10.1182/blood.2019004292 · Cited by 31
Estevez, B., Borst, S., Jarocha, D. J., Sudunagunta, V. S., Gonzalez, M. V., Garifallou, J. P., Hakonarson, H. H., Gao, P., Tan, K., Liu, P., et al. (2021) · Blood · doi:10.1182/blood.2020006389 · Cited by 30
Bresnick, E. H., & Johnson, K. D. (2019) · Blood Advances · doi:10.1182/bloodadvances.2019000378 · Cited by 32
“This configuration can confer GATA1- or GATA2-dependent enhancer activity in transfection assays,(82-84) and multiple transcription factors (eg, Tal1 and Fli1) and coregulators (eg, Lmo2 and Ldb1) can co-occupy these motifs with the GATA factor.(82,85,86) As the human genomes contain ;8900 CATCTG 6- to 14-bp spacer AG…”
BackgroundRao, T. N., Marks-Bluth, J., Sullivan, J., Gupta, M. K., Chandrakanthan, V., Fitch, S. R., Ottersbach, K., Jang, Y. C., Piao, X., Kulkarni, R., et al. (2015) · Stem Cell Research · doi:10.1016/j.scr.2015.02.001 · Cited by 28
“Recent studies have identified several transcription factors as master regulators of HSC homeostasis, including Runx1, Evi1, Gata2, Scl, Erg, Lyl1, Lmo2, among others (Wilson et al., 2010; Ling et al., 2004; Beck et al., 2013).”
The transcriptional regulation of normal and malignant blood cell development
Edginton‐White, B., & Bonifer, C. (2021) · FEBS Journal · doi:10.1111/febs.15735 · Cited by 27
Embryonic Origins of the Hematopoietic System: Hierarchies and Heterogeneity
Vink, C. S., Mariani, S. A., & Dzierzak, E. A. (2022) · HemaSphere · doi:10.1097/hs9.0000000000000737 · Cited by 27
The Clinical Spectrum, Diagnosis, and Management of GATA2 Deficiency
Santiago, M., Liquori, A., Such, E., Zúñiga, Á., & Cervera, J. (2023) · Cancers · doi:10.3390/cancers15051590 · Cited by 27
“Mean‐ while, during hematopoietic differentiation, GATA2 modulates downstream fate deci‐ sions by interacting with CEBPA, GATA1, and SPI1 [36,37].”
BackgroundHuang, Y., Thoms, J. A. I., Tursky, M. L., Knezevic, K., Beck, D., Chandrakanthan, V., Suryani, S., Olivier, J., Boulton, A. M., Glaros, E. N., et al. (2016) · Leukemia · doi:10.1038/leu.2016.55 · Cited by 27
PLAG1 and USF2 Co-regulate Expression of Musashi-2 in Human Hematopoietic Stem and Progenitor Cells
Belew, M. S., Bhatia, S., Chahi, A. K., Rentas, S., Draper, J. S., & Hope, K. J. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.03.006 · Cited by 28
“Using gene set enrichment analysis (GSEA) we created ranked lists with publicly available gene expression profiles assembled from sub-fractions of the human hematopoietic hierarchy ranging from primitive (Lin-CD34+) to mature (Lin+) (Beck et al., 2013) and then used the 621 genes associated with the most high-confiden…”
MethodRichards, L. A., Kumari, A., Knezevic, K., Thoms, J. A. I., von Jonquières, G., Napier, C. E., Ali, Z., O’Brien, R., Marks-Bluth, J., Maritz, M. F., et al. (2019) · Haematologica · doi:10.3324/haematol.2018.215699 · Cited by 25
“as previously described.(24) Briefly, 2 x 10(7) cells were treated with”
MethodMiR-24 Is Required for Hematopoietic Differentiation of Mouse Embryonic Stem Cells
Roy, L., Bikorimana, E., Lapid, D., Choi, H., Nguyen, T. A., & Dahl, R. E. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1004959 · Cited by 25
Tursky, M. L., Beck, D., Thoms, J. A. I., Huang, Y., Kumari, A., Unnikrishnan, A., Knezevic, K., Evans, K., Richards, L. A., Lee, E., et al. (2014) · Leukemia · doi:10.1038/leu.2014.299 · Cited by 25
Shared roles for Scl and Lyl1 in murine platelet production and function
Chiu, S. K., Orive, S. L., Moon, M. J., Saw, J., Ellis, S. L., Kile, B. T., Huang, Y., Fajardo, D. C., Pimanda, J. E., Beck, D., et al. (2019) · Blood · doi:10.1182/blood.2019896175 · Cited by 23
Role of the pioneer transcription factor GATA2 in health and disease
Aktar, A., & Heit, B. (2023) · Journal of Molecular Medicine · doi:10.1007/s00109-023-02359-8 · Cited by 23
The clonal evolution of leukemic stem cells in T-cell acute lymphoblastic leukemia
Tremblay, C. S., & Curtis, D. J. (2014) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000058 · Cited by 24
“Consistent with the role of these master regulators to induce a stem cell identity, the LMO2 complex has been shown to bind the miR-223 promoter in normal human CD34þ stem cells [25].”
BackgroundTekpli, X., Urbanucci, A., Hashim, A., Vågbø, C. B., Lyle, R., Kringen, M. K., Staff, A. C., Dybedal, I., Mills, I. G., Klungland, A., et al. (2016) · Epigenetics & Chromatin · doi:10.1186/s13072-016-0070-8 · Cited by 22
“We therefore used publically available ChIP-seq data sets [17] and investigated whether the presence of 5hmC at gene regulatory regions could affect binding of FLI1, RUNX1, GATA2 and ERG, TFs crucial for blood development.”
MethodHematopoietic transcriptional mechanisms: From locus-specific to genome-wide vantage points
DeVilbiss, A., Sanalkumar, R., Johnson, K. D., Keleş, S., & Bresnick, E. H. (2014) · Experimental Hematology · doi:10.1016/j.exphem.2014.05.004 · Cited by 21
“A “heptad” of transcription factors [Scl/TAL1, GATA-2, RUNX1, ERG (Ets factor), LYL1 (basic-helix-loop-helix factor), LMO2, and FLI1 (Ets factor)] co-occupy differentially expressed genes in the M AN US CR IP T AC CE PT ED 19 multipotent HPC7 hematopoietic cell line [120], and this result was extended to primary human…”
BackgroundThe genome-wide molecular signature of transcription factors in leukemia
Prange, K. H. M., Singh, A. A., & Martens, J. H. A. (2014) · Experimental Hematology · doi:10.1016/j.exphem.2014.04.012 · Cited by 19
Unnikrishnan, A., Guan, Y. F., Huang, Y., Beck, D., Thoms, J. A. I., Peirs, S., Knezevic, K., Ma, S., de Walle, I. V., de Jong, I., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw804 · Cited by 20
“Previous ChIP studies have revealed that the binding of a heptad of transcription factors to the ERG +85 stem cell enhancer upstream regulates high ERG expression in healthy haematopoietic stem and progenitor cells (HSPCs) (2,28) as well in leukaemic cells (22,29).”
BackgroundInfluentialDifferent mutant RUNX1 oncoproteins program alternate haematopoietic differentiation trajectories
Kellaway, S. G., Keane, P., Edginton‐White, B., Regha, K., Kennett, E., & Bonifer, C. (2021) · Life Science Alliance · doi:10.26508/lsa.202000864 · Cited by 17
“…is not essential but helps to correctly pattern and maintain cells in the correct lineage balance (Cai et al, 2011; Chen et al, 2009; Tober et al, 2013), in concert with other transcription factors such as the GATA, C/EBP and ETS families (Beck et al, 2013; Burda et al, 2010; Goode et al, 2016).”
BackgroundRibosomes: An Exciting Avenue in Stem Cell Research
Han, Z., Zhang, Q., Zhu, Y., Chen, J., & Li, W. (2020) · Stem Cells International · doi:10.1155/2020/8863539 · Cited by 19
“Runx1 forms the core ribosomal promoter element with RUNX1, GATA2, and FLI1 that affects ribosomal biogenesis in conjunction with cooperative hematopoietic transcription factors [137, 138].”
BackgroundLogic and lineage impacts on functional transcription factor deployment for T-cell fate commitment
Rothenberg, E. V. (2021) · Biophysical Journal · doi:10.1016/j.bpj.2021.04.002 · Cited by 17
“Among the sites bound were sites that had previously been identified as functional enhancers, but a heptad of structurally different TFs binding together to the same sites was unexpectedly prevalent in the pattern (42).”
BackgroundDing, N., Xi, J., Li, Y., Xie, X., Shi, J., Zhang, Z., Li, Y., Fang, F., Wang, S., Yue, W., et al. (2016) · Frontiers of Medicine · doi:10.1007/s11684-016-0452-0 · Cited by 17
Distinct mechanisms of regulation of the ITGA6 and ITGB4 genes by RUNX1 in myeloid cells
Phillips, J. L., Taberlay, P. C., Woodworth, A. M., Hardy, K., Brettingham‐Moore, K. H., Dickinson, J. L., & Holloway, A. F. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.26197 · Cited by 17
“Furthermore, analysis of publicly available ChIP-seq data revealed RUNX1 binding to the 5′ region in both CD34+ and Kasumi-1 cells (Beck et al., 2013; Ptasinska et al., 2014).”
BackgroundMethodYassin, M., Aqaqe, N., Yassin, A. A., van Galen, P., Kugler, E., Bernstein, B., Koren‐Michowitz, M., Canaani, J., Nagler, A., Lechman, E. R., et al. (2019) · Leukemia · doi:10.1038/s41375-019-0386-z · Cited by 18
Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes
Fernandes, P., Waldron, N., Chatzilygeroudi, T., Naji, N. S., & Karantanos, T. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25116256 · Cited by 16
“ETS transcription factors contain a highly conserved ETS DNA-binding domain that interacts together with other transcription factors to enhance the elements [44].”
BackgroundCore-binding factor leukemia hijacks the T-cell–prone PU.1 antisense promoter
van der Kouwe, E., Heller, G., Czibere, A. G., Pulikkan, J. A., Agreiter, C., Castilla, L. H., Delwel, R., Ruscio, A. D., Ebralidze, A. K., Forte, M., et al. (2021) · Blood · doi:10.1182/blood.2020008971 · Cited by 16
Stoner, S. A., Liu, K. T. H., Andrews, E. T., Liu, M., Arimoto, K., Yan, M., Davis, A. G., Weng, S., Dow, M. T., Su, X., et al. (2020) · Blood Cancer Journal · doi:10.1038/s41408-020-0282-9 · Cited by 15
Telonis, A. G., Yang, Q., Huang, H.-T., & Figueroa, M. E. (2022) · Nature Communications · doi:10.1038/s41467-022-34211-x · Cited by 14
“We used hypergeometric tests to evaluate the overlap of the mCpGs with significant correlations with poised and active enhancers from the Adelman et al. study26, with DBP/C binding sites from Beck et al.21 and DBP/C binding sites from ENCODE22.”
BackgroundMethodInfluentialvan Lier, Y. F., de Bree, G. J., Jonkers, R. E., Roelofs, J. J. T. H., ten Berge, I. J. M., Rutten, C. E., Nur, E., Kuijpers, T. W., Hazenberg, M. D., & Zeerleder, S. S. (2020) · Clinical Immunology · doi:10.1016/j.clim.2020.108522 · Cited by 14
GATA Factor-G-Protein-Coupled Receptor Circuit Suppresses Hematopoiesis
Gao, X., Wu, T., Johnson, K. D., Lahvic, J. L., Ranheim, E. A., Zon, L. I., & Bresnick, E. H. (2016) · Stem Cell Reports · doi:10.1016/j.stemcr.2016.01.008 · Cited by 13
“…co-localize at cis elements of target genes in hematopoietic stem and progenitor cells (HSPCs) to establish genetic networks that control hematopoiesis (Beck et al., 2013; Fujiwara et al., 2009; May et al., 2013; Tripic et al., 2008; Wilson et al., 2010; Wozniak et al., 2008; Yu et al., 2009).”
BackgroundJayne, N. D., Liang, Z., Lim, D., Chen, P. B., Diaz, C., Arimoto, K., Xia, L., Liu, M., Ren, B., Fu, X., et al. (2024) · Blood Advances · doi:10.1182/bloodadvances.2023011484 · Cited by 13
Aqaqe, N., Yassin, M., Yassin, A. A., Ershaid, N., Katz-Even, C., Zipin‐Roitman, A., Kugler, E., Lechman, E. R., Gan, O. I., Mitchell, A., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-3215 · Cited by 11
RNA-regulatory exosome complex confers cellular survival to promote erythropoiesis
Mehta, C., de Andrade, I. F., Matson, D. R., Dewey, C. N., & Bresnick, E. H. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab367 · Cited by 11
“In G1E cells, GATA2 occupied this site, as well as TAL1, which often co-localizes with GATA2 on chromatin (39,41–43).”
EVI1-mediated Programming of Normal and Malignant Hematopoiesis
Lux, S., & Milsom, M. D. (2023) · HemaSphere · doi:10.1097/hs9.0000000000000959 · Cited by 11
“83,84 This enhancer module facilitates the interaction of the enhancer with the EVI1 promoter via promoter-enhancer looping, and is essential for the overexpression of EVI1.”
Thoms, J. A. I., Koch, F. C., Raei, A., Subramanian, S., Wong, J. W. H., Vafaee, F., & Pimanda, J. E. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad918 · Cited by 9
Gillespie, M. A. K., Palii, C. G., Sánchez‐Taltavull, D., Shannon, P. T., Longabaugh, W. J. R., Downes, D. J., Sivaraman, K., Hughes, J. R., Price, N. D., Perkins, T. J., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/812123 · Cited by 12
“88 Intersection of GRN putative links with published ChIP-seq data: Published ChIP-seq data for ERG (GSM1097879), FLI1 (GSM1097880), GATA1 (GSM1278240, GSM1816081, GSM970258, GSM1816080, GSM970257), GATA2 (GSM1097883, GSM1816093, GSM722396), GFI1B (GSM1278242), KLF1 (GSM2575041-GSM2575049), RUNX1 (GSM1816092, GSM10978…”
Wang, C., Hu, M., Yu, K., Liu, W., Hu, A., Kuang, Y., Huang, L., Gajendran, B., Zacksenhaus, E., Xiao, X., et al. (2024) · Molecular Medicine Reports · doi:10.3892/mmr.2024.13231 · Cited by 10
Johnson, K. D., Jung, M. M., Tran, V. L., & Bresnick, E. H. (2023) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000763 · Cited by 9
“Multifactor occupancy occurs at hundreds of genomic sites and has been characterized as a heptad complex [23,25,26].”
BackgroundFrom Genotype to Phenotype: How Enhancers Control Gene Expression and Cell Identity in Hematopoiesis
Mulet‐Lazaro, R., & Delwel, R. (2023) · HemaSphere · doi:10.1097/hs9.0000000000000969 · Cited by 11
“60,61 At least 4 of these regulators establish protein-protein interactions that stabilize their DNA-binding and facilitate complex formation.”
BackgroundBeck, D., Cao, H., Tian, F., Huang, Y., Jiang, M., Zhao, H., Tai, X., Xu, W., Kosasih, H. J., Kealy, D. J., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54096-2 · Cited by 9
“Chromatin conformation provides a structural framework for TF binding and thus gene regulation 40,41 .”
Self-citationHegde, M. B., Ahmad, M. H., Mulet‐Lazaro, R., Sugita, M., Li, R., Hu, K., Gebhard, C., Guzmán, M. L., Bushweller, J. H., Zhu, L. J., et al. (2024) · Leukemia · doi:10.1038/s41375-024-02471-9 · Cited by 9
“These results demonstrate that NRP1 expression and function increase the leukemogenic potential in inv(16) AML while being dispensable in MLL::AF9 associated AML.”
A novel GATA2 distal enhancer mutation results in MonoMAC syndrome in 2 second cousins
West, R. R., Bauer, T. R., Tuschong, L. M., Embree, L. J., Calvo, K. R., Tillo, D., Davis, J., Holland, S. M., & Hickstein, D. D. (2023) · Blood Advances · doi:10.1182/bloodadvances.2023010458 · Cited by 9
“15,17,33,29 The Gata2 +9.5 intronic composite element (human intron 5) plays an essential role in hematopoiesis and has been directly implicated in MonoMAC syndrome.”
BackgroundInfluentialTranscriptional activation of regenerative hematopoiesis via microenvironmental sensing
Itkin, T., Houghton, S., Schreiner, R. P., Lin, Y., Badwe, C. R., Voisin, V., Murison, A., Seyedhassantehrani, N., Kaufmann, K. B., García‐Prat, L., et al. (2025) · Nature Immunology · doi:10.1038/s41590-025-02087-w · Cited by 10
“To ascertain the role of human HSC FLI-1 as an activation modulator, we reanalyzed the previously described scATAC-seq dataset for human HSPCs 47 together with the reported FLI-1 ChIP–seq peaks signature in human HSPCs 48 .”
Ediriwickrema, A., Nakauchi, Y., Fan, A. C., Köhnke, T., Hu, X., Luca, B. A., Kim, Y., Ramakrishnan, S., Nakamoto, M. A., Karigane, D., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116236 · Cited by 10
“67,68 These observations may be particularly relevant for HSPCs, which can be regulated by small variations in several unique TFs. 66,68 We therefore evaluated if HSPC states could be characterized by individual TFs or a combination of factors.”
Metadata
- Authors
- Beck, D., Thoms, J. A. I., Perera, D., Schütte, J., Unnikrishnan, A., Knezevic, K., Kinston, S. J., Wilson, N. K., O’Brien, T. A., Göttgens, B., Wong, J. W. H., & Pimanda, J. E.
- Affiliations
- UNSW Sydney (AU)
- University of Cambridge (GB)
- Centre for Children’s Cancer & Blood Disorders, Sydney Children’s Hospital, Sydney, Australia;
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2013-10-03
- Volume
- 122
- Issue
- 14
- Pages
- e12-e22
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W1976712740
- Cited by
- 133
- References
- 57
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 9 · 2023: 12 · 2022: 6 · 2021: 15 · 2020: 16 · 2019: 12 · 2018: 7 · 2017: 12 · 2016: 15 · 2015: 10 · 2014: 14 · 2013: 1
- FWCI
- 5.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- UTS ePRESS (University of Technology Sydney) (submittedVersion)
- Funders
- University of California, Santa Cruz
- Wellcome Trust (079249, 100140)
- Cancer Research UK (12765)
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (G0900729/1)
- University of New South Wales
- Medical Research Council (MC_PC_12009)
- Biotechnology and Biological Sciences Research Council (BB/I00050X/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- hematopoietic stem and progenitor cells, transcription factors, FLI1, RUNX1, GATA2, ERG, SCL, LYL1, LMO2, microRNA promoters, CD34+ cells, gene regulatory networks, cell identity, chromatin immunoprecipitation
- MeSH terms
- Cell Differentiation, Flow Cytometry, Hematopoiesis, Hematopoietic Stem Cells, Humans, Transcription Factors, Transcription, Genetic, Cluster Analysis, RNA, Untranslated, Chromatin Immunoprecipitation, Genome-Wide Association Study
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