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Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin
Open accessAbstract
Reactivating the fetal globin gene: Mutation of adult-type globin genes causes sickle cell disease and thalassemia. Although treating these hemoglobinopathies with gene therapy is possible, there is a pressing need for pharmacologic approaches to treat general patient populations. One promising approach is to reactivate repressed expression of fetal-type hemoglobin (HbF) in adult erythroid cells. Masuda et al. reveal a molecular mechanism governing HbF repression as mediated by the LRF/ZBTB7A transcription factor. The study may encourage the development of new HbF reactivation therapies for hemoglobinopathies. Science , this issue p. 285
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“Its inactivation in HUDEP-2 cells led to ;50% HbF; BCL11A plus ZBTB7A knockout caused .90% HbF. 25”
From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [25]
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“Quite recently, another potent silencer, called leukemia/ lymphoma-related factor (LRF)/Pokemon/ZBTB7A, was identified through focused studies of its role in erythroid differentiation by Maeda and coworkers (26).”
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Morrison, T. A., Wilcox, I., Luo, H., Farrell, J. J., Kurita, R., Nakamura, Y., Murphy, G. J., Cui, S., Steinberg, M. H., & Chui, D. H. K. (2017) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2017.11.003 · Cited by 46
“HUDEP-2 cells, which do not have the 3-bp deletion at rs66650371 (data not shown) and synthesize almost exclusively HBB have been used to study the regulation of HBG expression [6,13,14].”
BackgroundMethodSelf-citationSwitching from fetal to adult hemoglobin
Wang, X., & Thein, S. L. (2018) · Nature Genetics · doi:10.1038/s41588-018-0094-z · Cited by 48
Self-citationPittol, J. M. R., Oruba, A., Mittler, G., Saccani, S., & van Essen, D. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2004526 · Cited by 43
Sickle cell disease: progress towards combination drug therapy
Pace, B. S., Starlard‐Davenport, A., & Kutlar, A. (2021) · British Journal of Haematology · doi:10.1111/bjh.17312 · Cited by 46
“Correction of the HBB or high-level pancellular HbF expression could be curative, therefore we will discuss gene therapy drugs currently in clinical trials to achieve both approaches.(112,113) In 2014, the first SCA patient was successfully treated with gene therapy as part of a phase 1/2 clinical trial (HGB-205).”
MethodAntoniani, C., Romano, O., & Miccio, A. (2017) · Stem Cells Translational Medicine · doi:10.1002/sctm.17-0192 · Cited by 50
Gene Therapy and Gene Editing for β-Thalassemia
Christakopoulos, G. E., Telange, R., Yen, J. S., & Weiss, M. J. (2023) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2022.12.012 · Cited by 43
Dual function NFI factors control fetal hemoglobin silencing in adult erythroid cells
Qin, K., Huang, P., Feng, R., Keller, C. A., Peslak, S. A., Khandros, E., Saari, M. S., Lan, X., Mayuranathan, T., Doerfler, P. A., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01076-1 · Cited by 43
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
“Moreover, undifferentiated HUDEP-2 cells present accessible chromatin regions mapping to the E-Prog-specific KIT enhancers (Figure S8C), suggesting that these regulatory elements are active in this cell line (Masuda et al., 2016).”
BackgroundShang, S., Li, X., Azzo, A., Truong, T., Dozmorov, M. G., Lyons, C. E., Manna, A. K., Williams, D. C., & Ginder, G. D. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2302254120 · Cited by 40
“Previous studies from our lab and others showed that knockout of either BCL11A or MBD2 in HUDEP2 cells and knockdown of either in CD34 cells result in very similar levels of transcriptional activation of the HBG genes (1, 3, 8, 10), further supporting the concept that these two factors act in conjunction to enforce si…”
Khandros, E., Huang, P., Peslak, S. A., Sharma, M., Abdulmalik, O., Giardine, B. M., Zhang, Z., Keller, C. A., Hardison, R. C., & Blobel, G. A. (2020) · Blood · doi:10.1182/blood.2020005058 · Cited by 40
Mehta, S., Buyanbat, A., Yan, K., Karayel, Ö., Goldman, S. R., Seruggia, D., Zhang, K., Fujiwara, Y., Donovan, K. A., Zhu, Q., et al. (2022) · Cell chemical biology · doi:10.1016/j.chembiol.2022.06.007 · Cited by 42
Self-citationHematopoietic Stem Cell-Targeted Gene-Addition and Gene-Editing Strategies for β-hemoglobinopathies
Drysdale, C. M., Nassehi, T., Gamer, J., Yapundich, M., Tisdale, J. F., & Uchida, N. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.01.001 · Cited by 39
Pharmacological and molecular approaches for the treatment of β‐hemoglobin disorders
Lohani, N., Bhargava, N., Munshi, A., & Ramalingam, S. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.26292 · Cited by 38
“Multiple research groups have used genome wide association studies (GWAS) to find associations between common genetic modifiers of β-hemoglobin disorders and alterations in HbF levels (Masuda et al., 2016; Xu et al., 2011) Table 1.”
BackgroundCRISPR/Cas9-based gene-editing technology for sickle cell disease
Ma, L., Yang, S., Peng, Q., Zhang, J., & Zhang, J. (2023) · Gene · doi:10.1016/j.gene.2023.147480 · Cited by 45
Revolutionising healing: Gene Editing's breakthrough against sickle cell disease
Dimitrievska, M., Bansal, D., Vitale, M., Strouboulis, J., Miccio, A., Nicolaides, K. H., Hoss, S. E., Shangaris, P., & Jackow, J. (2024) · Blood Reviews · doi:10.1016/j.blre.2024.101185 · Cited by 41
Soni, S. (2020) · American Journal of Hematology · doi:10.1002/ajh.25909 · Cited by 37
Non-Transfusion-Dependent Thalassemia: A Panoramic Review
Shash, H. A. (2022) · Medicina · doi:10.3390/medicina58101496 · Cited by 37
“One of the potential targets for gene editing is the erythroid-specific transcription factor BCL11A, which normally represses the expression of γ-globin [88,89,91].”
BackgroundStructural basis for human ZBTB7A action at the fetal globin promoter
Yang, Y., Ren, R., Ly, L. C., Horton, J. R., Li, F., Quinlan, K. G. R., Crossley, M., Shi, Y., & Cheng, X. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109759 · Cited by 37
“Our results firmly establish ZBTB7A/LRF as a key molecular regulator of fetal globin expression and inform genome-editing strategies that inhibit repressor binding and boost fetal globin expression to treat hemoglobinopathies.”
BackgroundResultInfluentialSelf-citationElevating fetal hemoglobin: recently discovered regulators and mechanisms
Khandros, E., & Blobel, G. A. (2024) · Blood · doi:10.1182/blood.2023022190 · Cited by 32
The E3 ligase adaptor molecule SPOP regulates fetal hemoglobin levels in adult erythroid cells
Lan, X., Khandros, E., Huang, P., Peslak, S. A., Bhardwaj, S. K., Grevet, J. D., Abdulmalik, O. Y., Wang, H., Keller, C. A., Giardine, B. M., et al. (2019) · Blood Advances · doi:10.1182/bloodadvances.2019032318 · Cited by 33
Epigenetic inactivation of ERF reactivates γ-globin expression in β-thalassemia
Bao, X., Zhang, X., Wang, L., Wang, Z., Huang, J., Zhang, Q., Ye, Y., Liu, Y., Chen, D., Zuo, Y., et al. (2021) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2021.03.005 · Cited by 34
Self-citationKing, A. J., & Higgs, D. R. (2018) · Hematology · doi:10.1182/asheducation-2018.1.353 · Cited by 35
“356 American Society of Hematology The zinc finger transcriptional repressor LRF (also known as Pokemon, osteoclast-derived ZF, FBI-1, and ZBTB7A) is a member of the BTB/POZ-ZF family; it is known to bind directly to DNA as a homodimer and leads to transcriptional silencing via chromatin modifications.33 Recent work p…”
BackgroundInfluentialSelf-citationC2H2 proteins: Evolutionary aspects of domain architecture and diversification
Bonchuk, A. N., & Georgiev, P. G. (2024) · BioEssays · doi:10.1002/bies.202400052 · Cited by 37
“These include well-studied human transcription factors that function as tumor suppressors, such as ZBTB7, [105–110] ZBTB20 [111] and HIC (hypermethylated in cancer).”
Molecular Medicine: Found in Translation
Orkin, S. H. (2021) · Med · doi:10.1016/j.medj.2020.12.011 · Cited by 36
Self-citationA unified model of human hemoglobin switching through single-cell genome editing
Shen, Y., Verboon, J. M., Zhang, Y., Liu, N., Kim, Y. J., Marglous, S., Nandakumar, S. K., Voit, R. A., Fiorini, C., Ejaz, A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25298-9 · Cited by 34
Self-citationBiomarker signatures of sickle cell disease severity
Du, M., Ness, S. E. V., Gordeuk, V. R., Nouraie, M. S., Nekhai, S. A., Gladwin, M. T., Steinberg, M. H., & Sebastiani, P. (2018) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2018.05.001 · Cited by 33
Ueda, T., Yokota, T., Okuzaki, D., Uno, Y., Mashimo, T., Kubota, Y., Sudo, T., Ishibashi, T., Shingai, Y., Doi, Y., et al. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2019.11.002 · Cited by 31
“In addition, the globin switch to the adult-type is mediated by chromatin looping and repressive transcription factors during the maturation of fetuses (Kingsley et al., 2006; Masuda et al., 2016; Noordermeer and de Laat, 2008; Palis, 2008), which is likely promoted by ESAM-mediated inter-”
BackgroundDas, S. S., Das, S., Byram, P. K., Rahaman, M., Dolai, T. K., Chatterjee, A., & Chakravorty, N. (2020) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2020.102523 · Cited by 31
Genetic therapies for the first molecular disease
Doerfler, P. A., Sharma, A., Porter, J. S., Zheng, Y., Tisdale, J. F., & Weiss, M. J. (2021) · Journal of Clinical Investigation · doi:10.1172/jci146394 · Cited by 30
Metadata
- Authors
- Masuda, T., Wang, X., Maeda, M., Canver, M. C., Sher, F., Funnell, A. P. W., Fisher, C., Suciu, M., Martyn, G. E., Norton, L. J., Zhu, C., Kurita, R., Nakamura, Y., Xu, J., Higgs, D. R., Crossley, M., Bauer, D. E., Orkin, S. H., Kharchenko, P. V., & Maeda, T.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Boston Children's Hospital (US)
- UNSW Sydney (AU)
- Medical Research Council, Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK.
- University of Oxford (GB)
- RIKEN BioResource Research Center (JP)
- University of Tsukuba (JP)
- Corresponding author
- Kharchenko, Peter V.
- Maeda, Takahiro
- ORCID
- Venue
- Science
- Published
- 2016-01-15
- Volume
- 351
- Issue
- 6270
- Pages
- 285-289
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4778394
- OpenAlex
- W2266790363
- Semantic Scholar
- c79067255bc10df384cd93d45af5c2fd24b7b528
- Cited by
- 373
- References
- 64
- Citations by year
- 2026: 27 · 2025: 34 · 2024: 51 · 2023: 34 · 2022: 34 · 2021: 54 · 2020: 44 · 2019: 24 · 2018: 26 · 2017: 27 · 2016: 16
- FWCI
- 22.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (F30DK103359-01A1)
- NIDDK Career Development (K08DK093705)
- Doris Duke Charitable Foundation Innovations in Clinical Research (2013137)
- Ellison Medical Foundation (AG-NS-0965-12)
- NIH (P01HL032262, P30DK049216, 5K25AG037596, R01 AI084905, R56 DK105001)
- American Society of Hematology Bridge Program
- Topics
- Health Sciences › Medicine › Genetics (clinical) › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- fetal hemoglobin, BCL11A, transcriptional repression, nucleosome density, sickle cell disease, thalassemia, hemoglobinopathies, fetal hemoglobin induction
- MeSH terms
- Anemia, Sickle Cell, Animals, Carrier Proteins, Cell Line, Chromatin, DNA-Binding Proteins, Erythroblasts, Erythropoiesis, Fetal Hemoglobin, Humans, Nuclear Proteins, Repressor Proteins, Thalassemia, Transcription Factors, Sequence Deletion, Mice, Knockout, Gene Silencing, Mice, gamma-Globins
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