HEMGN

Last updated

HEMGN
Identifiers
Aliases HEMGN , CT155, EDAG, EDAG-1, NDR, hemogen
External IDs OMIM: 610715; MGI: 2136910; HomoloGene: 14223; GeneCards: HEMGN; OMA:HEMGN - orthologs
Orthologs
SpeciesHumanMouse
Entrez

55363

93966

Ensembl

ENSG00000136929

ENSMUSG00000028332

UniProt

Q9BXL5

Q9ERZ0

RefSeq (mRNA)

NM_018437
NM_197978

NM_053149

RefSeq (protein)

NP_060907
NP_932095

NP_444379

Location (UCSC) Chr 9: 97.93 – 97.94 Mb Chr 4: 46.39 – 46.41 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Hemogen is a protein that in humans is encoded by the HEMGN gene. [5] 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.

Contents

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, [6] 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. [7] 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. [6] 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. [8]

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. [9] Although Ikaros enhances Hemgn expression, it is not strictly required for GFI1-mediated upregulation. [10] 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. [11] GFI1 represses PU.1 expression, [12] 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. [10]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000136929 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028332 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: HEMGN hemogen".
  6. 1 2 Guo X, Zhao Y, Kim J, Dean A (June 2022). "Hemogen/BRG1 cooperativity modulates promoter and enhancer activation during erythropoiesis". Blood. 139 (24): 3532–3545. doi:10.1182/blood.2021014308. PMC   9203704 . PMID   35297980.
  7. ↑ Beauchemin H, Möröy T (2020). "Multifaceted Actions of GFI1 and GFI1B in Hematopoietic Stem Cell Self-Renewal and Lineage Commitment". Frontiers in Genetics. 11 591099. doi: 10.3389/fgene.2020.591099 . PMC   7649360 . PMID   33193732.
  8. ↑ Somasundaram B (2012). Proteomic Characterization of Hemogen in Erythropoiesis (Ph.D. thesis). University of Ottawa). doi:10.20381/ruor-3353.
  9. ↑ Olsson L, Johansson B (May 2015). "Ikaros and leukaemia". British Journal of Haematology. 169 (4): 479–491. doi:10.1111/bjh.13342. PMID   25753742.
  10. 1 2 Binod GC, Hoyt LJ, Dovat S, Dong F (November 2024). "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) 107860. Bibcode:2024JBiCh.300j7860G. doi: 10.1016/j.jbc.2024.107860 . PMC   11550643 . PMID   39374784.
  11. ↑ Kastner P, Chan S (2008). "PU.1: a crucial and versatile player in hematopoiesis and leukemia". The International Journal of Biochemistry & Cell Biology. 40 (1): 22–27. doi:10.1016/j.biocel.2007.01.026. PMID   17374502.
  12. ↑ Dahl R, Iyer SR, Owens KS, Cuylear DD, Simon MC (March 2007). "The transcriptional repressor GFI-1 antagonizes PU.1 activity through protein-protein interaction". The Journal of Biological Chemistry. 282 (9): 6473–6483. doi: 10.1074/jbc.M607613200 . PMC   3218793 . PMID   17197705.

Further reading

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