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Control of pro-inflammatory gene programs by active histone methylation and demethylation

Joshua Stender

Appointment Period: 2008-2010 / Grant Year: [25,25]

Joshua StenderUncontrolled chronic inflammation conditions contribute to several human cancers, including gastric, colorectal and liver cancer. This is the result of prolonged activation of macrophage gene expression programs, which release cytotoxic molecules that damage surrounding tissues, promote DNA damage, and facilitate tumor cell migration. Therefore we have been interested in identifying enzymes that function to repress inflammatory gene expression as potential therapeutic targets for the treatment of these inflammation dependent cancers. We implemented a high-throughput genome-wide siRNA approach to identify novel repressors of pro-inflammatory gene programs. This led to the identification of Smyd5, a 416 amino acid protein that contains SET and MYND domains, as a novel repressor of pro-inflammatory programs. Through a variety of biochemical approaches we have characterized Smyd5 as a methyltransferase that deposits the repressive epigenetic mark H4K20me3 on pro-inflammatory promoters. We find that Smyd5 associates with the corepressor NCoR complex, and it appears that NCoR serves as a beacon for Smyd5 recruitment to pro-inflammatory promoters. In addition, we find that Phf2, a member of the jumonji domain family of lysine demethylases, is recruited to pro-inflammatory gene promoters, removes this epigenetic mark, and is required for the activation of a subset of pro-inflammatory promoters, including several cytokines believed to be responsible for tumorigenesis. This is the first report of H4K20me3 demethylation, and collectively these results highlight a novel mechanism that repressor complexes utilize to repress the epigenetic landscape of pro-inflammatory gene promoters.

Stender JD, Kim K, Charn TH, Komm B, Chang KC, Kraus WL, Benner C, Glass CK, Katzenellenbogen BS. Genome-wide analysis of estrogen receptor alpha DNA binding and tethering mechanisms identifies Runx1 as a novel tethering factor in receptor-mediated transcriptional activation. Mol Cell Biol. (2010) 30:3943-55. PMID: 20547749; PMC2916448.

Kadandale P, Stender JD, Glass CK, Kiger AA. Conserved role for autophagy in Rho1-mediated cortical remodeling and blood cell recruitment.  Proc Natl Acad Sci USA. (2010) 107:10502-7. PMID: 20498061; PMC2890812.

Stender JD, Stossi F, Funk CC, Charn TH, Barnett DH, Katzenellenbogen BS. The estrogen-regulated transcription factor PITX1 coordinates gene-specific regulation by estrogen receptor-alpha in breast cancer cells. Mol Endocrinol. (2011) 25:1699-709. PMID: 21868451; PMCID: PMC3182422.

Escoubet-Lozach L, Benner C, Kaikkonen MU, Lozach J, Heinz S, Spann NJ, Crotti A, Stender J, Ghisletti S, Reichart D, Cheng CS, Luna R, Ludka C, Sasik R, Garcia-Bassets I, Hoffmann A, Subramaniam S, Hardiman G, Rosenfeld MG, Glass CK. PLoS Genet. (2011) 7(12):e1002401. PMID: 22174696.