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Sumoylation of CCAAT/enhancer-binding protein α is implicated in hematopoietic stem/progenitor cell development through regulating runx1 in zebrafish.

Yuan H, Zhang T, Liu X, Deng M, Zhang W, Wen Z, Chen S, Chen Z, de The H, Zhou J, Zhu J - Sci Rep (2015)

Bottom Line: Impairment of sumoylation attenuates HSPC generation and proliferation.The hyposumoylation triggered HSPC defects are CCAAT/enhancer-binding protein α (C/ebpα) dependent.While C/ebpα-dependent transcription is involved in myeloid differentiation, our studies here reveal that C/ebpα sumoylation is essential for HSPC development during definitive hematopoiesis.

View Article: PubMed Central - PubMed

Affiliation: CNRS-LIA124, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

ABSTRACT
The small ubiquitin-related modifier (SUMO) participates in various cellular processes, including maintenance of genome integrity, nuclear transport, transcription and signal transduction. However, the biological function of sumoylation in hematopoiesis has not been fully explored. We show here that definitive hematopoietic stem/progenitor cells (HSPCs) are depleted in SUMO-deficient zebrafish embryos. Impairment of sumoylation attenuates HSPC generation and proliferation. The hyposumoylation triggered HSPC defects are CCAAT/enhancer-binding protein α (C/ebpα) dependent. Critically, a SUMO-C/ebpα fusion rescues the defective hematopoiesis in SUMO-deficient embryos, at least in part through restored runx1 expression. While C/ebpα-dependent transcription is involved in myeloid differentiation, our studies here reveal that C/ebpα sumoylation is essential for HSPC development during definitive hematopoiesis.

No MeSH data available.


Schematic depiction of the distinct functions of C/ebpα sumoylation in the regulation of HSPC and myeloid progenitor development during hematopoiesis.HSPC homeostasis is maintained by the fine-tuning of C/ebpα sumoylation. Sumoylated C/ebpα de-represses runx1 transcription, which in turn participates in regulating normal HSPC development (top panel, left). In SUMO-deficient embryos, C/ebpα is desumoylated, which subsequently inhibits Runx1 activity, likely through direct transcriptional repression. As a consequence, HSPC generation and proliferation is reduced (top panel, right). In contrast, during myeloid cell development, inactivation of C/ebpα triggered by sumoylation blocks myeloid progenitor differentiation (bottom panel, left), while the activated form triggered by desumoylation promotes myelopoiesis (bottom panel, right).
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f6: Schematic depiction of the distinct functions of C/ebpα sumoylation in the regulation of HSPC and myeloid progenitor development during hematopoiesis.HSPC homeostasis is maintained by the fine-tuning of C/ebpα sumoylation. Sumoylated C/ebpα de-represses runx1 transcription, which in turn participates in regulating normal HSPC development (top panel, left). In SUMO-deficient embryos, C/ebpα is desumoylated, which subsequently inhibits Runx1 activity, likely through direct transcriptional repression. As a consequence, HSPC generation and proliferation is reduced (top panel, right). In contrast, during myeloid cell development, inactivation of C/ebpα triggered by sumoylation blocks myeloid progenitor differentiation (bottom panel, left), while the activated form triggered by desumoylation promotes myelopoiesis (bottom panel, right).

Mentions: Mechanistically, our microarray analysis identified that upon the loss of SUMOs, runx1 (a critical transcription factor capable of regulating HSPC induction and proliferation35) was strongly down-regulated. Yet, SUMO-C/ebpα could largely restore its expression and rescue the definitive HSPC defects. Furthermore, runx1 mRNA was also able to rescue the hematopoietic defects in the SUMO-deficient embryos, implying that runx1 might be a downstream gene of C/ebpα. Based on our studies and those of others, we hypothesized that C/ebpα may exert distinct functions depending on its sumoylation status and specific given cell compartment (Fig. 6). The role of C/ebpα sumoylation in HSPCs appears to be quite distinct from its function in myeloid progenitor cells development. Within HSPCs, desumoylated C/ebpα acts as a transcriptional repressor and down-regulates runx1 directly or indirectly, which results in the attenuated HSPC generation and proliferation. Under physiological conditions, sumoylated C/ebpα, through an as yet unknown mechanism, likely promotes protein structural changes, de-represses runx1 transcription, and ultimately participates in controlling normal HSPC development (Fig. 6, top panel). In contrast, during myeloid development, the desumoylation-activated C/ebpα is required to promote myeloid progenitor cells differentiation through activation of myeloid-specific gene expression (Fig. 6, bottom panel).


Sumoylation of CCAAT/enhancer-binding protein α is implicated in hematopoietic stem/progenitor cell development through regulating runx1 in zebrafish.

Yuan H, Zhang T, Liu X, Deng M, Zhang W, Wen Z, Chen S, Chen Z, de The H, Zhou J, Zhu J - Sci Rep (2015)

Schematic depiction of the distinct functions of C/ebpα sumoylation in the regulation of HSPC and myeloid progenitor development during hematopoiesis.HSPC homeostasis is maintained by the fine-tuning of C/ebpα sumoylation. Sumoylated C/ebpα de-represses runx1 transcription, which in turn participates in regulating normal HSPC development (top panel, left). In SUMO-deficient embryos, C/ebpα is desumoylated, which subsequently inhibits Runx1 activity, likely through direct transcriptional repression. As a consequence, HSPC generation and proliferation is reduced (top panel, right). In contrast, during myeloid cell development, inactivation of C/ebpα triggered by sumoylation blocks myeloid progenitor differentiation (bottom panel, left), while the activated form triggered by desumoylation promotes myelopoiesis (bottom panel, right).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4355724&req=5

f6: Schematic depiction of the distinct functions of C/ebpα sumoylation in the regulation of HSPC and myeloid progenitor development during hematopoiesis.HSPC homeostasis is maintained by the fine-tuning of C/ebpα sumoylation. Sumoylated C/ebpα de-represses runx1 transcription, which in turn participates in regulating normal HSPC development (top panel, left). In SUMO-deficient embryos, C/ebpα is desumoylated, which subsequently inhibits Runx1 activity, likely through direct transcriptional repression. As a consequence, HSPC generation and proliferation is reduced (top panel, right). In contrast, during myeloid cell development, inactivation of C/ebpα triggered by sumoylation blocks myeloid progenitor differentiation (bottom panel, left), while the activated form triggered by desumoylation promotes myelopoiesis (bottom panel, right).
Mentions: Mechanistically, our microarray analysis identified that upon the loss of SUMOs, runx1 (a critical transcription factor capable of regulating HSPC induction and proliferation35) was strongly down-regulated. Yet, SUMO-C/ebpα could largely restore its expression and rescue the definitive HSPC defects. Furthermore, runx1 mRNA was also able to rescue the hematopoietic defects in the SUMO-deficient embryos, implying that runx1 might be a downstream gene of C/ebpα. Based on our studies and those of others, we hypothesized that C/ebpα may exert distinct functions depending on its sumoylation status and specific given cell compartment (Fig. 6). The role of C/ebpα sumoylation in HSPCs appears to be quite distinct from its function in myeloid progenitor cells development. Within HSPCs, desumoylated C/ebpα acts as a transcriptional repressor and down-regulates runx1 directly or indirectly, which results in the attenuated HSPC generation and proliferation. Under physiological conditions, sumoylated C/ebpα, through an as yet unknown mechanism, likely promotes protein structural changes, de-represses runx1 transcription, and ultimately participates in controlling normal HSPC development (Fig. 6, top panel). In contrast, during myeloid development, the desumoylation-activated C/ebpα is required to promote myeloid progenitor cells differentiation through activation of myeloid-specific gene expression (Fig. 6, bottom panel).

Bottom Line: Impairment of sumoylation attenuates HSPC generation and proliferation.The hyposumoylation triggered HSPC defects are CCAAT/enhancer-binding protein α (C/ebpα) dependent.While C/ebpα-dependent transcription is involved in myeloid differentiation, our studies here reveal that C/ebpα sumoylation is essential for HSPC development during definitive hematopoiesis.

View Article: PubMed Central - PubMed

Affiliation: CNRS-LIA124, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

ABSTRACT
The small ubiquitin-related modifier (SUMO) participates in various cellular processes, including maintenance of genome integrity, nuclear transport, transcription and signal transduction. However, the biological function of sumoylation in hematopoiesis has not been fully explored. We show here that definitive hematopoietic stem/progenitor cells (HSPCs) are depleted in SUMO-deficient zebrafish embryos. Impairment of sumoylation attenuates HSPC generation and proliferation. The hyposumoylation triggered HSPC defects are CCAAT/enhancer-binding protein α (C/ebpα) dependent. Critically, a SUMO-C/ebpα fusion rescues the defective hematopoiesis in SUMO-deficient embryos, at least in part through restored runx1 expression. While C/ebpα-dependent transcription is involved in myeloid differentiation, our studies here reveal that C/ebpα sumoylation is essential for HSPC development during definitive hematopoiesis.

No MeSH data available.