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Title:
DNMT1 regulates human erythropoiesis by modulating cell cycle and endoplasmic reticulum stress in a stage-specific manner | Cell Death & Differentiation
Description:
The dynamic balance of DNA methylation and demethylation is required for erythropoiesis. Our previous transcriptomic analyses revealed that DNA methyltransferase 1 (DNMT1) is abundantly expressed in erythroid cells at all developmental stages. However, the role and molecular mechanisms of DNMT1 in human erythropoiesis remain unknown. Here we found that DNMT1 deficiency led to cell cycle arrest of erythroid progenitors which was partially rescued by treatment with a p21 inhibitor UC2288. Mechanically, this is due to decreased DNA methylation of p21 promoter, leading to upregulation of p21 expression. In contrast, DNMT1 deficiency led to increased apoptosis during terminal stage by inducing endoplasmic reticulum (ER) stress in a p21 independent manner. ER stress was attributed to the upregulation of RPL15 expression due to the decreased DNA methylation at RPL15 promoter. The upregulated RPL15 expression subsequently caused a significant upregulation of core ribosomal proteins (RPs) and thus ultimately activated all branches of unfolded protein response (UPR) leading to the excessive ER stress, suggesting a role of DNMT1 in maintaining protein homeostasis during terminal erythroid differentiation. Furthermore, the increased apoptosis was significantly rescued by the treatment of ER stress inhibitor TUDCA. Our findings demonstrate the stage-specific role of DNMT1 in regulating human erythropoiesis and provide new insights into regulation of human erythropoiesis.
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dnmt, cell, cells, fig, pubmed, article, analysis, erythroid, apoptosis, google, scholar, dna, expression, erythropoiesis, methylation, cas, erythroblasts, deficiency, cycle, stress, protein, terminal, levels, supplementary, stage, differentiation, human, central, control, quantitative, inhibitor, days, representative, dnmtdeficient, cultured, blot, experiments, knockdown, western, increased, independent, early, growth, rpl, mrna, promoter, level, findings, group, nature,
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nature portfolio c-myc-degradation-mediated therapeutic benefits privacy policy including burst-forming unit-erythroid advertising nature previous research io/cufflinks/ research demonstrated thermo fisher scientific social media shrna/cas9/dcas9-mediated approach rabbit polyclonal anti-5mc caspase-3 inhibitor z-devd-fmk research reprints original author crispr-dcas9 mediated knockdown dnmt1-deficient late-stage erythroblasts colony-forming unit-erythroid apolipoprotein e-deficient mice dnmt-deficient orthochromatic erythroblasts 50 ΞΌm o-propargyl-puromycin o-propargyl-puromycin experiments [33 er stress-mediated pathway dnmt1-deficient early-stage cells shrna-mediated dnmt1 knock chemical dnmt1-specific inhibitor er stress-related genes dcas9-dnmt1 knockdown group global high-level expression dnmt1-deficient orthochromatic erythroblasts form cyclin-cdk complexes cyclin-dependent kinase inhibitors dnmt1 deficiency-caused impairment dnmt1-knockdown orthochromatic erythroblasts facs-sorted orthochromatic erythroblasts dnmt1-deficient erythroid progenitors dnmt1 deficiency-induced upregulation dnmt1 deficiency-induced apoptosis conducted qrt-pcr dnmt1-deficient orthochromatic erythroblast real-time pcr revealed regulate erythrocyte size dnmt1-shrna-transduced cells performed shrna-mediated knockdown performing rna-seq analysis fluorescence-activated cell sorting dnmt1-deficient erythroid cells permissions
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headline:DNMT1 regulates human erythropoiesis by modulating cell cycle and endoplasmic reticulum stress in a stage-specific manner
description:The dynamic balance of DNA methylation and demethylation is required for erythropoiesis. Our previous transcriptomic analyses revealed that DNA methyltransferase 1 (DNMT1) is abundantly expressed in erythroid cells at all developmental stages. However, the role and molecular mechanisms of DNMT1 in human erythropoiesis remain unknown. Here we found that DNMT1 deficiency led to cell cycle arrest of erythroid progenitors which was partially rescued by treatment with a p21 inhibitor UC2288. Mechanically, this is due to decreased DNA methylation of p21 promoter, leading to upregulation of p21 expression. In contrast, DNMT1 deficiency led to increased apoptosis during terminal stage by inducing endoplasmic reticulum (ER) stress in a p21 independent manner. ER stress was attributed to the upregulation of RPL15 expression due to the decreased DNA methylation at RPL15 promoter. The upregulated RPL15 expression subsequently caused a significant upregulation of core ribosomal proteins (RPs) and thus ultimately activated all branches of unfolded protein response (UPR) leading to the excessive ER stress, suggesting a role of DNMT1 in maintaining protein homeostasis during terminal erythroid differentiation. Furthermore, the increased apoptosis was significantly rescued by the treatment of ER stress inhibitor TUDCA. Our findings demonstrate the stage-specific role of DNMT1 in regulating human erythropoiesis and provide new insights into regulation of human erythropoiesis.
datePublished:2024-05-08T00:00:00Z
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headline:DNMT1 regulates human erythropoiesis by modulating cell cycle and endoplasmic reticulum stress in a stage-specific manner
description:The dynamic balance of DNA methylation and demethylation is required for erythropoiesis. Our previous transcriptomic analyses revealed that DNA methyltransferase 1 (DNMT1) is abundantly expressed in erythroid cells at all developmental stages. However, the role and molecular mechanisms of DNMT1 in human erythropoiesis remain unknown. Here we found that DNMT1 deficiency led to cell cycle arrest of erythroid progenitors which was partially rescued by treatment with a p21 inhibitor UC2288. Mechanically, this is due to decreased DNA methylation of p21 promoter, leading to upregulation of p21 expression. In contrast, DNMT1 deficiency led to increased apoptosis during terminal stage by inducing endoplasmic reticulum (ER) stress in a p21 independent manner. ER stress was attributed to the upregulation of RPL15 expression due to the decreased DNA methylation at RPL15 promoter. The upregulated RPL15 expression subsequently caused a significant upregulation of core ribosomal proteins (RPs) and thus ultimately activated all branches of unfolded protein response (UPR) leading to the excessive ER stress, suggesting a role of DNMT1 in maintaining protein homeostasis during terminal erythroid differentiation. Furthermore, the increased apoptosis was significantly rescued by the treatment of ER stress inhibitor TUDCA. Our findings demonstrate the stage-specific role of DNMT1 in regulating human erythropoiesis and provide new insights into regulation of human erythropoiesis.
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