Eliminating SF-1 (NR5A1) Sumoylation In Vivo Results in Ectopic Hedgehog Signaling and Disruption of Endocrine Development

Abstract

Summary Sumoylation is generally considered a repressive mark for many transcription factors. However, the in vivo importance of sumoylation for any given substrate remains unclear and is questionable because the extent of sumoylation appears exceedingly low for most substrates. Here, we permanently eliminated SF-1/NR5A1 sumoylation in mice (Sf-1K119R,K194R or 2KR) and found that Sf-12KR/2KR mice failed to phenocopy a simple gain of SF-1 function or show elevated levels of well-established SF-1 target genes. Instead, mutant mice exhibited marked endocrine abnormalities and changes in cell fate that reflected an inappropriate activation of hedgehog signaling and other potential SUMO-sensitive targets. Further, unsumoylatable SF-1 mutants activated Shh and exhibited preferential recruitment to Shh genomic elements in cells. We propose that the sumoylation cycle greatly expands the functional capacity of transcription factors such as SF-1, and is leveraged during development to achieve cell type-specific gene expression in multi-cellular organisms.

A central region of Gli2 regulates its localization to the primary cilium and transcriptional activity

“…As Gli2 can be sumoylated in vitro (Cox et al, 2010;Lee et al, 2011) (supplementary material Fig. S3E), we substituted each of the four putatively sumoylatable lysines with unsumoylatable arginines to create Gli2K.R-GFP (Gli2K375R, K398R, K630R, K716R-GFP).…”

Dynamic SUMOylation Is Linked to the Activity Cycles of Androgen Receptor in the Cell Nucleus

“…Again, the SUMOylation also influenced MITF occupancy on its target loci (1,55). Notably, elimination of orphan nuclear receptor SF-1 (steroidogenic factor 1) SUMOylation in mice did not lead to a simple gain of SF-1 phenotype or increased levels of SF-1 target genes but resulted in abnormal Hedgehog signaling and endocrine development (21). The observed abnormalities may be linked to altered recognition of a group of target genes that are sensitive to modification of SF-1 (3).…”

“…The observed abnormalities may be linked to altered recognition of a group of target genes that are sensitive to modification of SF-1 (3). For most of the SUMO-sensitive target genes studied in the mouse model, interestingly, the SUMOylation-defective SF-1 allele prevailed even in the presence of wild-type SF-1 (21).…”

DNA Double-strand Breaks Lead to Activation of Hypermethylated in Cancer 1 (HIC1) by SUMOylation to Regulate DNA Repair

“…Ϫ/Ϫ ) (43,44) or silencing of MTA1 by RNAi in U2OS (45) each renders cells hypersensitive to ionizing radiation, demonstrating that MTA1 interferes with the DNA repair process. Interestingly, the mechanisms by which MTA1 regulates DNA repair have been shown to be both p53-dependent, by regulating p53 stability (therefore independent of its role as a co-repressor) (43,46) and p53-independent by repressing the transcription of the cdk inhibitor p21…”