O-GlcNAc homeostasis contributes to cell fate decisions during hematopoiesis.
In: Journal of Biological Chemistry, 2019-01-25, Heft 4, S. 1363-1379
Online
academicJournal
Zugriff:
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, overallO-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 OGlcNAcylation in regulating hematopoietic cell fate. [ABSTRACT FROM AUTHOR]
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O-GlcNAc homeostasis contributes to cell fate decisions during hematopoiesis.
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Autor/in / Beteiligte Person: | Zhang, Zhen ; Parker, Matthew P. ; Graw, Stefan ; Novikova, Lesya V. ; Fedosyuk, Halyna ; Fontes, Joseph D. ; Koestler, Devin C. ; Peterson, Kenneth R. ; Slawson, Chad |
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Zeitschrift: | Journal of Biological Chemistry, 2019-01-25, Heft 4, S. 1363-1379 |
Veröffentlichung: | 2019 |
Medientyp: | academicJournal |
ISSN: | 0021-9258 (print) |
DOI: | 10.1074/jbc.RA118.005993 |
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