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O-GlcNAc homeostasis contributes to cell fate decisions during hematopoiesis.


ABSTRACT: The addition of a single β-d-GlcNAc sugar (O-GlcNAc) by O-GlcNAc-transferase (OGT) and O-GlcNAc removal by O-GlcNAcase (OGA) maintain homeostatic O-GlcNAc levels on cellular proteins. Changes in protein O-GlcNAcylation regulate cellular differentiation and cell fate decisions, but how these changes affect erythropoiesis, an essential process in blood cell formation, remains unclear. Here, we investigated the role of O-GlcNAcylation in erythropoiesis by using G1E-ER4 cells, which carry the erythroid-specific transcription factor GATA-binding protein 1 (GATA-1) fused to the estrogen receptor (GATA-1-ER) and therefore undergo erythropoiesis after β-estradiol (E2) addition. We observed that during G1E-ER4 differentiation, overall O-GlcNAc levels decrease, and physical interactions of GATA-1 with both OGT and OGA increase. RNA-Seq-based transcriptome analysis of G1E-ER4 cells differentiated in the presence of the OGA inhibitor Thiamet-G (TMG) revealed changes in expression of 433 GATA-1 target genes. ChIP results indicated that the TMG treatment decreases the occupancy of GATA-1, OGT, and OGA at the GATA-binding site of the lysosomal protein transmembrane 5 (Laptm5) gene promoter. TMG also reduced the expression of genes involved in differentiation of NB4 and HL60 human myeloid leukemia cells, suggesting that O-GlcNAcylation is involved in the regulation of hematopoietic differentiation. Sustained treatment of G1E-ER4 cells with TMG before differentiation reduced hemoglobin-positive cells and increased stem/progenitor cell surface markers. Our results show that alterations in O-GlcNAcylation disrupt transcriptional programs controlling erythropoietic lineage commitment, suggesting a role for O-GlcNAcylation in regulating hematopoietic cell fate.

SUBMITTER: Zhang Z 

PROVIDER: S-EPMC6349094 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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<i>O</i>-GlcNAc homeostasis contributes to cell fate decisions during hematopoiesis.

Zhang Zhen Z   Parker Matthew P MP   Graw Stefan S   Novikova Lesya V LV   Fedosyuk Halyna H   Fontes Joseph D JD   Koestler Devin C DC   Peterson Kenneth R KR   Slawson Chad C  

The Journal of biological chemistry 20181206 4


The addition of a single β-d-GlcNAc sugar (<i>O</i>-GlcNAc) by <i>O</i>-GlcNAc-transferase (OGT) and <i>O</i>-GlcNAc removal by <i>O</i>-GlcNAcase (OGA) maintain homeostatic <i>O</i>-GlcNAc levels on cellular proteins. Changes in protein <i>O</i>-GlcNAcylation regulate cellular differentiation and cell fate decisions, but how these changes affect erythropoiesis, an essential process in blood cell formation, remains unclear. Here, we investigated the role of <i>O</i>-GlcNAcylation in erythropoies  ...[more]

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