Molecular Insights into the Oxygen-Sensing Pathway and Erythropoietin Expression Regulation in Erythropoiesis

Abstract

Erythropoiesis is regulated by several factors, including the oxygen-sensing pathway as the main regulator of erythropoietin (EPO) synthesis in the kidney. The release of EPO from the kidney and its binding to the EPO receptor (EPOR) on erythrocyte progenitor cells in the bone marrow results in increased erythropoiesis. Any imbalance in these homeostatic mechanisms can lead to dysregulated erythropoiesis and hematological disorders. For example, mutations in genes encoding key players of oxygen-sensing pathway and regulation of EPO production (HIF-EPO pathway), namely VHL, EGLN, EPAS1 and EPO, are well known causative factors that contribute to the development of erythrocytosis. We aimed to investigate additional molecular mechanisms involved in the HIF-EPO pathway that correlate with erythropoiesis. To this end, we conducted an extensive literature search and used several in silico tools. We identified genes encoding transcription factors and proteins that control transcriptional activation or repression; genes encoding kinases, deacetylases, methyltransferases, conjugating enzymes, protein ligases, and proteases involved in post-translational modifications; and genes encoding nuclear transport receptors that regulate nuclear transport. All these genes may modulate the stability or activity of HIF2α and its partners in the HIF-EPO pathway, thus affecting EPO synthesis. The theoretical information we provide in this work can be a valuable tool for a better understanding of one of the most important regulatory pathways in the process of erythropoiesis. This knowledge is necessary to discover the causative factors that may contribute to the development of hematological diseases and improve current diagnostic and treatment solutions in this regard.

The Role of VHL in the Development of von Hippel-Lindau Disease and Erythrocytosis

“…The most important canonical role of VHL, through the EPO-VHL-HIF signaling axis, is its involvement in oxygen sensing and adaptive response to hypoxia ( Figure 2 ) [ 29 , 30 , 31 , 32 , 33 ]. VHL associates with Elongin-B ( ELOB ) and Elongin-C ( ELOC ), forming a VBC complex, and, together with Cullin-2 ( CUL2 ) and E3 ubiquitin-protein ligase RBX1 ( RBX , Ring-box1), constitutes a functional E3 ubiquitin ligase that specifically recognizes hydroxylated Hypoxia inducible factor (HIF) subunit α, targeting it for proteasome degradation by ubiquitination [ 34 , 35 , 36 , 37 , 38 , 39 ].…”

Using the Zebrafish as a Genetic Model to Study Erythropoiesis

“…In addition, erythropoiesis is regulated by recruiter lncRNAs, including LncHSC-2, lincRNA-EPS, and alncRNA-EC7/Bloodlinc, and decoy lncRNAs, including lnc-DC and lnc-MC [ 51 ]. For more detailed pathways and mechanisms regulating vertebrate erythropoiesis, please refer to the previous reviews [ 1 , 41 , 52 , 53 ]. In this section, we summarize recent progress on the regulation of erythropoiesis with emphasis on the studies in zebrafish.…”

Integration and Visualization of Regulatory Elements and Variations of the EPAS1 Gene in Human

“…The EP a component of CBP/p300 co-activator for transcription of HIF target genes. Besides actions deposited in STRING, the Reactome database includes additional six interac Mother against decapentaplegic homolog (SMAD) 3, fructose-1,6-bisphosphat (FBP1), Ubiquitin carboxyl-terminal hydrolase 8 and 20 (USP8 and USP20), RNA-bin protein 4 (RBM4), and Eukaryotic translation initiation factor 3 subunit E (EIF3E) Proteins SMAD3, FBP1, and EIF3E are repressors of EPAS1, by downregulating its scriptional activity or inducing EPAS1 degradation [49][50][51]. Deubiquitinases USP8 USP20 counteract VHL-mediated ubiquitylation and stabilize EPAS1 [52].…”

“…Deubiquitinases USP8 USP20 counteract VHL-mediated ubiquitylation and stabilize EPAS1 [52]. Protein R forms a transcription/translation activation complex with EPAS1 under hypoxia [30 extensive piece of research on EPAS1 interactions and other proteins in the HIF-EPO way and involvement in the molecular processes was recently published in two rev by Tomc and Debeljak (2021) [51,53].…”