SENP1-mediated GATA1 deSUMOylation is critical for definitive erythropoiesis

Abstract

Small ubiquitin-like modifier (SUMO) modification of proteins (SUMOylation) and deSUMOylation have emerged as important regulatory mechanisms for protein function. SENP1 (SUMO-specific protease) deconjugates SUMOs from modified proteins. We have created SENP1 knockout (KO) mice based on a Cre–loxP system. Global deletion of SENP1 (SENP1 KO) causes anemia and embryonic lethality between embryonic day 13.5 and postnatal day 1, correlating with erythropoiesis defects in the fetal liver. Bone marrow transplantation of SENP1 KO fetal liver cells to irradiated adult recipients confers erythropoiesis defects. Protein analyses show that the GATA1 and GATA1-dependent genes are down-regulated in fetal liver of SENP1 KO mice. This down-regulation correlates with accumulation of a SUMOylated form of GATA1. We further show that SENP1 can directly deSUMOylate GATA1, regulating GATA1-dependent gene expression and erythropoiesis by in vitro assays. Moreover, we demonstrate that GATA1 SUMOylation alters its DNA binding, reducing its recruitment to the GATA1-responsive gene promoter. Collectively, we conclude that SENP1 promotes GATA1 activation and subsequent erythropoiesis by deSUMOylating GATA1.

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

“…Apart from virus infection, there is circumstantial evidence that IFN control over SUMO or PML abundance may be also important for other processes. Early progenitors are very SUMO rich, consistent with studies that have linked SUMOs to stem cell maintenance [48][49][50] . PML was also implicated in regulation of stem cell fate 51 , notably through TR2 sumoylation, which directly controls expression of Oct-4 (refs 52,53), or through p53 activation 54 .…”

Sumoylation of CCAAT/enhancer–binding protein α promotes the biased primitive hematopoiesis of zebrafish

“…Among the important transcription factors related to the myeloerythroid differentiation cascade, Gata1 may also be sumoylated, 25 although the impact of Gata1 sumoylation is still under debate. 25,43,44 Our luciferase data indicate that the nonsumoylatable Gata1 (K157R) mutant has slightly increased transcriptional activity, which is in agreement with the fact that Gata1 sumoylation inhibits erythropoiesis in SENP1-null mice. 44 However, in SUMOdeficient embryos, although Gata1 is normally positively autoregulated, 45 gata1 expression was reduced and this was followed by down-regulation of its downstream target genes.…”

“…25,43,44 Our luciferase data indicate that the nonsumoylatable Gata1 (K157R) mutant has slightly increased transcriptional activity, which is in agreement with the fact that Gata1 sumoylation inhibits erythropoiesis in SENP1-null mice. 44 However, in SUMOdeficient embryos, although Gata1 is normally positively autoregulated, 45 gata1 expression was reduced and this was followed by down-regulation of its downstream target genes. Accordingly, expression of EGFP in gata1-EGFP-transgenic embryos was reduced when SUMOs were knocked down.…”

Genetic Variation in SENP1 and ANP32D as Predictors of Chronic Mountain Sickness

“…SENP1 has been shown to regulate erythropoietin (EPO) production by regulating the stability of hypoxia-inducible factor 1a (HIF1a) during hypoxia (Yu et al, 2010) and indeed SENP1 -/ -mice die of anemia in early life (Cheng et al, 2007;Yu et al, 2010). SENP1 also mediates a positive feedback loop in hypoxic conditions that is responsible for vascular endothelial growth factor (VEGF) production and angiogenesis (Xu et al, 2010).…”

“…Two of these regions appeared significant (in the context of formal tests of selection) in a comparison of non-CMS versus either CMS or other matched population controls. One region contained the genes SENP1, an erythropoiesis regulator (Yu et al, 2010), and the other contained ANP32D, an oncogene (Kadkol et al, 1999). The authors validated the frequencies of these two haplotypes by conducting genotyping of two variants (rs7963934 (SENP1) and rs72644851 (ANP32D)) in an additional 10 case and 10 control subjects.…”