Regulation of Globin Gene Expression in Erythroid Cells

Orkin, Stuart H.

doi:10.1111/j.1432-1033.1995.0271e.x

Cited by 18 publications

(8 citation statements)

References 113 publications

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“…MEL cells have served as a valuable model to study the molecular mechanisms involved in erythroid differentiation. The control of globin gene expression, haem biosynthesis and iron metabolism in MEL cells has been studied extensively [36,37]. However, many aspects of the regulation of these pathways remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Antagonistic roles of the ERK and p38 MAPK signalling pathways in globin expression, haem biosynthesis and iron uptake1

Mardini

Gasiorek

Derjuga

et al. 2010

Biochemical Journal

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Late-stage erythroid cells synthesize large quantities of haemoglobin, a process requiring the co-ordinated regulation of globin and haem synthesis as well as iron uptake. In the present study, we investigated the role of the ERK (extracellular-signal-regulated kinase) and p38 MAPK (mitogen-activated protein kinase) signalling pathways in MEL (mouse erythroleukaemia) cell differentiation. We found that treatment of HMBA (hexamethylene bisacetamide)-induced MEL cells with the ERK pathway inhibitor UO126 results in an increase in intracellular haem and haemoglobin levels. The transcript levels of the genes coding for β(major)-globin, the haem biosynthesis enzyme 5-aminolevulinate synthase 2 and the mitochondrial iron transporter mitoferrin 1 are up-regulated. We also showed enhanced expression of globin and transferrin receptor 1 proteins upon UO126 treatment. With respect to iron uptake, we found that ERK inhibitor treatment led to an increase in both haem-bound and total iron. In contrast, treatment of MEL cells with the p38 MAPK pathway inhibitor SB202190 had the opposite effect, resulting in decreased globin expression, haem synthesis and iron uptake. Reporter assays showed that globin promoter and HS2 enhancer-mediated transcription was under the control of MAPKs, as inhibition of the ERK and p38 MAPK pathways led to increased and decreased gene activity respectively. Our present results suggest that the ERK1/2 and p38α/β MAPKs play antagonistic roles in HMBA-induced globin gene expression and erythroid differentiation. These results provide a novel link between MAPK signalling and the regulation of haem biosynthesis and iron uptake in erythroid cells.

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Section: Discussionmentioning

confidence: 99%

Antagonistic roles of the ERK and p38 MAPK signalling pathways in globin expression, haem biosynthesis and iron uptake1

Mardini

Gasiorek

Derjuga

et al. 2010

Biochemical Journal

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“…Since their identification in viral and mammalian genomes, enhancers have been defined primarily by their function: the ability to activate promoters independently of their distance and orientation [1][2][3] harboring transcription factor (TF) binding and extensive non-coding transcription 4,5 . These features were also observed from all enhancers identified from a recent CRISPR-Cas9 screen of the MYC locus 6 .…”

Section: Introductionmentioning

confidence: 99%

Transcription imparts architecture, function, and logic to enhancer units

Tippens

Liang

Leung

et al. 2019

Preprint

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Distal enhancers remain one of the least understood regulatory elements with pivotal roles in development and disease. We used massively parallel reporter assays to perform functional comparisons of two leading enhancer models and find that gene-distal transcription start sites (TSSs) are robust predictors of enhancer activity with higher resolution and specificity than histone modifications. We show that active enhancer units are precisely delineated by active TSSs, validate that these boundaries are sufficient to capture enhancer function, and confirm that core promoter sequences are required for this activity. Finally, we assay pairs of adjacent units and find that their cumulative activity is best predicted by the strongest unit within the pair.Synthetic fusions of enhancer units demonstrate that adjacency imposes winner-takes-all logic, revealing a simple design for a maximum-activity filter of enhancer unit outputs. Together, our results define fundamental enhancer units and a principle of non-cooperativity between adjacent units.

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“…heme | erythropoiesis | hemoglobin | hemeprotein | nonerythroid H emoglobin (Hb) functions in oxygen delivery by virtue of its heme prosthetic group (1)(2)(3). Its expression and maturation is tightly coordinated during erythropoiesis and is subject to multiple levels of regulation (4)(5)(6), with disregulation manifesting in some forms of β-thalassemia (7-9) and anemia (10)(11)(12). In mammals, erythropoiesis involves a coordinated synthesis of partner globin chains, heme insertion, and globin interaction steps that ultimately create functional fetal (α 2 γ 2 ) Hb or adult (α 2 β 2 ) Hb tetramers (13).…”

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confidence: 99%

Hsp90 chaperones hemoglobin maturation in erythroid and nonerythroid cells

Ghosh

Garee

Sweeny

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Maturation of adult (α2β2) and fetal hemoglobin (α2γ2) tetramers requires that heme be incorporated into each globin. While hemoglobin alpha (Hb-α) relies on a specific erythroid chaperone (alpha Hb-stabilizing protein, AHSP), the other chaperones that may help mature the partner globins (Hb-γ or Hb-β) in erythroid cells, or may enable nonerythroid cells to express mature Hb, are unknown. We investigated a role for heat-shock protein 90 (hsp90) in Hb maturation in erythroid precursor cells that naturally express Hb-α with either Hb-γ (K562 and HiDEP-1 cells) or Hb-β (HUDEP-2) and in nonerythroid cell lines that either endogenously express Hb-αβ (RAW and A549) or that we transfected to express the globins. We found the following: () AHSP and hsp90 associate with distinct globin partners in their immature heme-free states (AHSP with apo-Hbα, and hsp90 with apo-Hbβ or Hb-γ) and that hsp90 does not associate with mature Hb. () Hsp90 stabilizes the apo-globins and helps to drive their heme insertion reactions, as judged by pharmacologic hsp90 inhibition or by coexpression of an ATP-ase defective hsp90. () In nonerythroid cells, heme insertion into all globins became hsp90-dependent, which may explain how mixed Hb tetramers can mature in cells that do not express AHSP. Together, our findings uncover a process in which hsp90 first binds to immature, heme-free Hb-γ or Hb-β, drives their heme insertion process, and then dissociates to allow their heterotetramer formation with Hb-α. Thus, in driving heme insertion, hsp90 works in concert with AHSP to generate functional Hb tetramers during erythropoiesis.

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Regulation of Globin Gene Expression in Erythroid Cells

Cited by 18 publications

References 113 publications

Antagonistic roles of the ERK and p38 MAPK signalling pathways in globin expression, haem biosynthesis and iron uptake1

Antagonistic roles of the ERK and p38 MAPK signalling pathways in globin expression, haem biosynthesis and iron uptake1

Transcription imparts architecture, function, and logic to enhancer units

Hsp90 chaperones hemoglobin maturation in erythroid and nonerythroid cells

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