Determining the Effect of NR5A Sumoylation on Genome-wide Chromatin Occupancy

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 389-413-Signaling and Transcriptional Control in Endocrine Systems
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-395
Karmela Ramos*, Benjamin Schiller and Holly A Ingraham
University of California San Francisco, San Francisco, CA
Nuclear receptor family 5A proteins, Steroidogenic Factor-1 (SF-1/NR5A1) and Liver Receptor Homolog-1 (LRH-1/NR5A2) are key transcriptional regulators in development and in steroid hormone and bile acid synthesis. Aside from temporal and tissue-specific expression, post-translational modifications of NR5As can fine-tune their function independent of ligands. A recently published study from our lab demonstrates that specifically eliminating SF-1 sumoylation, the conjugation by the small ubiquitin-like modifier (SUMO), in vivo results in ectopic activation of potent signaling, such as SHH (1). While sumoylation is generally considered repressive towards transcription, we demonstrated that SF-1 sumoylation is necessary for maintaining adrenal- and testes-specific transcriptional programs via “SUMO-sensitive genes.”  Additionally, we found that SF-1 sumoylation can regulate DNA binding to these SUMO-sensitive genes in vitro (2). To test the hypothesis that response elements in NR5A targets might be differentially occupied by wild type and mutant SF-1 (2KR), we used gene expression arrays and chromatin-immunoprecipitation followed by deep sequencing (ChIP-seq) for both WT and 2KR SF-1. Our preliminary results have identified SUMO-sensitive genes, as well as an SF-1 consensus motif, in HEK293 cells. Efforts are currently underway to test if NR5A ligands can affect recruitment to these SUMO-sensitive targets. Concomitantly, we are also exploring the importance of LRH-1 sumoylation in cultured human hepatocytes.

(1) Lee FY et al., Dev Cell 2011; 21(2):315-27.  (2) Campbell LA et al., Mol Cell Biol 2008; 28(24):7476-86.

Nothing to Disclose: KR, BS, HAI

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Sources of Research Support: National Institute of Diabetes and Digestive and Kidney Diseases Grant 3R01DK063592-15S1.