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Decreased PGC1beta expression results in disrupted human erythroid differentiation, impaired hemoglobinization and cell cycle exit

Sen, Taha LU ; Chen, Jun LU and Singbrant, Sofie LU (2021) In Scientific Reports 11(1). p.1-14
Abstract
Production of red blood cells relies on proper mitochondrial function, both for their increased energy demands during differentiation and for proper heme and iron homeostasis. Mutations in genes regulating mitochondrial function have been reported in patients with anemia, yet their pathophysiological role often remains unclear. PGC1β is a critical coactivator of mitochondrial biogenesis, with increased expression during terminal erythroid differentiation. The role of PGC1β has however mainly been studied in skeletal muscle, adipose and hepatic tissues, and its function in erythropoiesis remains largely unknown. Here we show that perturbed PGC1β expression in human hematopoietic stem/progenitor cells from both bone marrow and cord blood... (More)
Production of red blood cells relies on proper mitochondrial function, both for their increased energy demands during differentiation and for proper heme and iron homeostasis. Mutations in genes regulating mitochondrial function have been reported in patients with anemia, yet their pathophysiological role often remains unclear. PGC1β is a critical coactivator of mitochondrial biogenesis, with increased expression during terminal erythroid differentiation. The role of PGC1β has however mainly been studied in skeletal muscle, adipose and hepatic tissues, and its function in erythropoiesis remains largely unknown. Here we show that perturbed PGC1β expression in human hematopoietic stem/progenitor cells from both bone marrow and cord blood results in impaired formation of early erythroid progenitors and delayed terminal erythroid differentiation in vitro, with accumulations of polychromatic erythroblasts, similar to MDS-related refractory anemia. Reduced levels of PGC1β resulted in deregulated expression of iron, heme and globin related genes in polychromatic erythroblasts, and reduced hemoglobin content in the more mature bone marrow derived reticulocytes. Furthermore, PGC1β knock-down resulted in disturbed cell cycle exit with accumulation of erythroblasts in S-phase and enhanced expression of G1-S regulating genes, with smaller reticulocytes as a result. Taken together, we demonstrate that PGC1β is directly involved in production of hemoglobin and regulation of G1-S transition and is ultimately required for proper terminal erythroid differentiation. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
11
issue
1
article number
17129
pages
1 - 14
publisher
Nature Publishing Group
external identifiers
  • scopus:85113283256
  • pmid:34429458
ISSN
2045-2322
DOI
10.1038/s41598-021-96585-0
language
English
LU publication?
yes
id
d0f4cda6-d5b7-4b9b-a418-cd7ca1540225
date added to LUP
2021-10-21 16:42:46
date last changed
2024-02-20 14:37:03
@article{d0f4cda6-d5b7-4b9b-a418-cd7ca1540225,
  abstract     = {{Production of red blood cells relies on proper mitochondrial function, both for their increased energy demands during differentiation and for proper heme and iron homeostasis. Mutations in genes regulating mitochondrial function have been reported in patients with anemia, yet their pathophysiological role often remains unclear. PGC1β is a critical coactivator of mitochondrial biogenesis, with increased expression during terminal erythroid differentiation. The role of PGC1β has however mainly been studied in skeletal muscle, adipose and hepatic tissues, and its function in erythropoiesis remains largely unknown. Here we show that perturbed PGC1β expression in human hematopoietic stem/progenitor cells from both bone marrow and cord blood results in impaired formation of early erythroid progenitors and delayed terminal erythroid differentiation in vitro, with accumulations of polychromatic erythroblasts, similar to MDS-related refractory anemia. Reduced levels of PGC1β resulted in deregulated expression of iron, heme and globin related genes in polychromatic erythroblasts, and reduced hemoglobin content in the more mature bone marrow derived reticulocytes. Furthermore, PGC1β knock-down resulted in disturbed cell cycle exit with accumulation of erythroblasts in S-phase and enhanced expression of G1-S regulating genes, with smaller reticulocytes as a result. Taken together, we demonstrate that PGC1β is directly involved in production of hemoglobin and regulation of G1-S transition and is ultimately required for proper terminal erythroid differentiation.}},
  author       = {{Sen, Taha and Chen, Jun and Singbrant, Sofie}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{1--14}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Decreased PGC1beta expression results in disrupted human erythroid differentiation, impaired hemoglobinization and cell cycle exit}},
  url          = {{http://dx.doi.org/10.1038/s41598-021-96585-0}},
  doi          = {{10.1038/s41598-021-96585-0}},
  volume       = {{11}},
  year         = {{2021}},
}