Molecular insights into the oxygen-sensing pathway and erythropoietin expression regulation in erythropoiesis

Tomc, Jana (author), Debeljak, Nataša (author)

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.

• Language: English
• Keywords: erythropoiesis, erythropoietin, molecular mechanisms, oxygen-sensing pathway, hypoxia-inducible factor, post-translational modifications, protein interactions, nuclear transport, transcriptional regulation
• Work type: Article
• Typology: 1.02 - Review Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: 16 str.
• Numbering: Vol. 22, iss. 13, art. 7074
• PID: 20.500.12556/RUL-135740
• UDC: 61
• ISSN on article: 1422-0067
• DOI: 10.3390/ijms22137074
• COBISS.SI-ID: 69996547
• Publication date in RUL: 30.03.2022

Record is a part of a journal

• Title: International journal of molecular sciences
• Shortened title: Int. j. mol. sci.
• Publisher: MDPI
• ISSN: 1422-0067
• COBISS.SI-ID: 2779162

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 01.07.2021

Secondary language

• Language: Slovenian
• Keywords: eritropoeza, eritropoetin, molekularni mehanizmi

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: L3-9279
• Name: Genetska osnova eritrocitoz v Sloveniji

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0390
• Name: Funkcijska genomika in biotehnologija za zdravje