Biology:HEMGN
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Hemogen is a protein that in humans is encoded by the HEMGN gene.[1] It plays a crucial role in erythropoiesis, the process of red blood cell formation, by acting as a nuclear transcriptional regulator. Hemogen modulates gene expression involved in the proliferation, differentiation, and survival of erythroid progenitor cells, thereby contributing to the maintenance of normal red blood cell counts and responding to erythropoietic stress.
Function
Hemogen functions primarily as a nuclear transcriptional regulator that actively promotes erythroid differentiation and maturation by modulating chromatin structure and gene expression during erythropoiesis. It recruits the SWI/SNF chromatin-remodeling ATPase BRG1 as a coactivator to enhance nucleosome accessibility and enrich histone H3K27 acetylation at promoters and enhancers of erythroid genes,[2] facilitating their activation. Hemogen also antagonizes the binding of corepressors such as the NuRD complex, promoting an open chromatin state and enabling LDB1 complex-mediated chromatin looping critical for erythroid gene transcription.[3] Loss of Hemogen impairs the production of mature erythroblasts by reducing the expression of genes involved in heme and hemoglobin synthesis, underscoring its essential role in erythroid maturation and hemoglobin production.[2] Proteomic studies further suggest Hemogen interacts with transcription regulators, chromatin modifiers, and histones, possibly acting as a tissue-specific histone chaperone to regulate transcription during erythroid differentiation.[4]
Mechanism of action
Hemgn, a gene with anti-apoptotic properties, is a key downstream target of GFI1 (growth factor independence 1), a transcriptional repressor involved in hematopoiesis. GFI1 plays a crucial role in protecting hematopoietic cells from stress-induced apoptosis. The Hemgn gene is regulated by GFI1 through a 16-bp promoter region located between +47 and +63 bp relative to the transcription start site (TSS). This regulation is dependent on GFI1's interaction with the histone demethylase LSD1. GFI1 activates Hemgn expression through promoter binding, and this activation is enhanced by LSD1-mediated epigenetic modifications that promote transcription of Hemgn.
Hemgn expression is further increased through the synergistic action of Ikaros, another transcription factor.[5] Although Ikaros enhances Hemgn expression, it is not strictly required for GFI1-mediated upregulation.[6] Together, GFI1 and Ikaros cooperate to maximize transcriptional activation of Hemgn.
Hemgn is negatively regulated by PU.1, a transcription factor that functions as a repressor of its expression.[7] GFI1 represses PU.1 expression,[8] leading to derepression and subsequent upregulation of Hemgn. In the absence of PU.1, such as in knockdown or deficiency models, Hemgn expression is enhanced, demonstrating that GFI1 promotes Hemgn expression indirectly by inhibiting PU.1.
Hemgn upregulation contributes significantly to the anti-apoptotic function of GFI1, enabling hematopoietic cells to survive under stress conditions. This protective effect is independent of the p53 pathway and instead relies specifically on Hemgn-mediated mechanisms.[6]
References
- ↑ "Entrez Gene: HEMGN hemogen". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=55363.
- ↑ 2.0 2.1 "Hemogen/BRG1 cooperativity modulates promoter and enhancer activation during erythropoiesis". Blood 139 (24): 3532–3545. June 2022. doi:10.1182/blood.2021014308. PMID 35297980.
- ↑ "Multifaceted Actions of GFI1 and GFI1B in Hematopoietic Stem Cell Self-Renewal and Lineage Commitment". Frontiers in Genetics 11. 2020. doi:10.3389/fgene.2020.591099. PMID 33193732.
- ↑ Somasundaram B (2012). Proteomic Characterization of Hemogen in Erythropoiesis (Ph.D. thesis). University of Ottawa). doi:10.20381/ruor-3353.
- ↑ "Ikaros and leukaemia". British Journal of Haematology 169 (4): 479–491. May 2015. doi:10.1111/bjh.13342. PMID 25753742.
- ↑ 6.0 6.1 "Upregulation of nuclear protein Hemgn by transcriptional repressor GFI1 through repressing PU.1 contributes to the anti-apoptotic activity of GFI1". The Journal of Biological Chemistry 300 (11). November 2024. doi:10.1016/j.jbc.2024.107860. PMID 39374784. Bibcode: 2024JBiCh.300j7860G.
- ↑ "PU.1: a crucial and versatile player in hematopoiesis and leukemia". The International Journal of Biochemistry & Cell Biology 40 (1): 22–27. 2008. doi:10.1016/j.biocel.2007.01.026. PMID 17374502.
- ↑ "The transcriptional repressor GFI-1 antagonizes PU.1 activity through protein-protein interaction". The Journal of Biological Chemistry 282 (9): 6473–6483. March 2007. doi:10.1074/jbc.M607613200. PMID 17197705.
Further reading
- "Hemogen is a novel nuclear factor specifically expressed in mouse hematopoietic development and its human homologue EDAG maps to chromosome 9q22, a region containing breakpoints of hematological neoplasms". Mechanisms of Development 104 (1–2): 105–111. June 2001. doi:10.1016/S0925-4773(01)00376-8. PMID 11404085.
- "Gene expression profiling in human fetal liver and identification of tissue- and developmental-stage-specific genes through compiled expression profiles and efficient cloning of full-length cDNAs". Genome Research 11 (8): 1392–1403. August 2001. doi:10.1101/gr.175501. PMID 11483580.
- "Alternative promoters and polyadenylation regulate tissue-specific expression of Hemogen isoforms during hematopoiesis and spermatogenesis". Developmental Dynamics 228 (4): 606–616. December 2003. doi:10.1002/dvdy.10399. PMID 14648837.
- "Down-regulation of human NDR gene in megakaryocytic differentiation of erythroleukemia K562 cells". Journal of Biomedical Science 11 (1): 104–116. 2004. doi:10.1159/000075293. PMID 14730214.
- "EDAG regulates the proliferation and differentiation of hematopoietic cells and resists cell apoptosis through the activation of nuclear factor-kappa B". Cell Death and Differentiation 11 (12): 1299–1308. December 2004. doi:10.1038/sj.cdd.4401490. PMID 15332117.
- "High expression of EDAG and its significance in AML". Leukemia 19 (8): 1499–1502. August 2005. doi:10.1038/sj.leu.2403808. PMID 15920494.
- "The GATA site-dependent hemogen promoter is transcriptionally regulated by GATA1 in hematopoietic and leukemia cells". Leukemia 20 (3): 417–425. March 2006. doi:10.1038/sj.leu.2404105. PMID 16437149.
- "Down-regulation of EDAG expression by retrovirus-mediated small interfering RNA inhibits the growth and IL-8 production of leukemia cells". Oncology Reports 18 (3): 659–664. September 2007. doi:10.3892/or.18.3.659. PMID 17671716.
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