GFI1B has a dual function in platelet formation and wound healing

GFI1B has a dual function in platelet formation and wound healing

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Megakaryocytes are the largest cells in our bone marrow. Their main function is to produce platelets that are released in the blood stream to repair wounds together with clotting factors. Hematologists treat patients with hereditary bleeding disorders. These disorders are often caused by mutations in clotting factor genes1. However, bleeding disorders are also caused by mutations in genes that result in impaired platelet function. A group of genes that is mutated in platelet disorders encode transcription factors. Normally, these factors bind DNA to control gene expression in developing megakaryocytes enabling them to produce platelets. Mutations in the DNA-interacting transcription factor GFI1B are causal to such a platelet bleeding disorder because the platelets lack important proteins implicated in wound healing2-5.

In this paper we determined changes in gene expression caused by four different GFI1B mutations observed in families with bleeding disorders with different severity. We expressed the mutant proteins in a megakaryocyte cell line model and subsequently determined changes in gene expression by whole transcriptome RNA-sequencing. This revealed that different mutations affect the expression of different sets of genes. Additionally, we found that the GFI1B mutation causing the severest bleedings in patients6 resulted in the activation of genes that play a role in immune cells that combat infections. To verify these results in a relevant physiological setting we used control and patient-derived pluripotent stem cells that we differentiated into blood stem cells and subsequently to megakaryocytes. Next, we determined gene expression in single cells to determine their nature. We noticed that the presence of mutant GFI1B resulted in an increased production of immune cells at the expense of megakaryocytes. Subsequently, we used bioinformatic algorithms to determine which transcription factors are active in these cells by determining the expression of genes that they normally regulate. As expected, this revealed that the activity of transcription factors that stimulate megakaryocyte development was impaired in mutant megakaryocytes. We also confirmed that transcription factors that are key to immune cell development were activated in mutant megakaryocytes. This may explain the increased immune cell production relative to megakaryocyte production caused by impaired GFI1B function. It also indicates that GFI1B has a dual function in megakaryocyte biology: it stimulates gene programs relevant for proper platelet formation and at the same time suppresses the development of immune cell gene programs.

GFI1B is known to regulate gene expression in megakaryocytes in part by recruiting an epigenetic protein complex to the DNA. This complex, called CoREST, removes methyl and acetyl group from histone proteins. DNA is wrapped around these histones and the removal of histone methyl and acetyl groups results in inactivation of gene expression7,8. Interestingly, small molecules exist that abrogate the GFI1B-CoREST interaction. One of these small molecules, Bomedemstat, is clinically studied to determine whether it can alleviate high platelet levels in patients with a rare form of blood cancer called essential thrombocythemia9. We wanted to know whether the GFI1B-CoREST interaction is required to prevent developing megakaryocytes from turning into immune cells. Thus, we treated the cells with a small molecule that disrupts the GFI1B-CoREST interaction. This yielded an increase in immune cells relative to megakaryocytes in our model system. In addition, megakaryocyte specific transcription factor activity was impaired while those required for the development of immune cells were activated. This shows that GFI1B and CoREST work together to inhibit the expression of immune cell genes during the development of megakaryocytes. Failure of this inhibition due to mutant GFI1B or by inhibiting its CoREST interaction leads to disturbed megakaryocyte development and defects in platelet function.



1              Doherty, T. M. & Kelley, A. in StatPearls     (2024).

2              Saleque, S., Cameron, S. & Orkin, S. H. The zinc-finger proto-oncogene Gfi-1b is essential for development of the erythroid and megakaryocytic lineages. Genes Dev 16, 301-306 (2002).

3              van Oorschot, R. et al. Inherited missense variants that affect GFI1B function do not necessarily cause bleeding diatheses. Haematologica 104, e260-e264 (2019).

4              Stevenson, W. S. et al. GFI1B mutation causes a bleeding disorder with abnormal platelet function. J Thromb Haemost 11, 2039-2047 (2013).

5              Kitamura, K. et al. Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia. J Thromb Haemost 14, 1462-1469 (2016).

6              Monteferrario, D. et al. A dominant-negative GFI1B mutation in the gray platelet syndrome. N Engl J Med 370, 245-253 (2014).

7              Casey, M. J. et al. The scaffolding function of LSD1/KDM1A reinforces a negative feedback loop to repress stem cell gene expression during primitive hematopoiesis. iScience 26, 105737 (2023).

8              Tammen, S. A., Friso, S. & Choi, S. W. Epigenetics: the link between nature and nurture. Mol Aspects Med 34, 753-764 (2013).

9              Gill, H. et al. A Phase 2 Study of the LSD1 Inhibitor Bomedemstat (IMG-7289) for the Treatment of Essential Thrombocythemia (ET). Blood 140, 1784-1787 (2022).

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Molecular Biology
Life Sciences > Biological Sciences > Molecular Biology
Life Sciences > Biological Sciences > Anatomy > Haemic and Immune Systems > Haematopoietic System > Megakaryocytes
Innate Immune Cells
Life Sciences > Biological Sciences > Immunology > Innate Immunity > Innate Immune Cells
Transcription factors
Life Sciences > Biological Sciences > Molecular Biology > Protein Biochemistry > Proteins > Transcription factors

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