The Department of Biomedicine

BBB seminar: Michael R. Stallcup

Role of protein methylation in transcriptional regulation by nuclear receptors

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Michael R. Stallcup
Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA

DNA-bound, hormone-activated nuclear receptors activate transcription by recruiting a variety of coactivator complexes. Each coactivator complex contributes in specific ways to chromatin remodeling or recruitment and activation of RNA polymerase II. Some coactivators catalyze post-translational modifications of histones and non-histone proteins. We have focused on various roles played by the arginine-specific protein methyltransferases, CARM1 and PRMT1. These proteins are recruited to hormone regulated promoters through their interactions with the C-terminal regions of the p160 coactivators (SRC-1, GRIP1, and ACTR), which in turn bind directly to nuclear receptors. CARM1 methylates histone H3 on Arg-2, Arg-17, and Arg-26, while PRMT1 methylates histone H4 on Arg-3. At present the mechanism by which these histone modifications contribute to transcriptional activation is unknown.

In addition to histone H3, CARM1 also methylates p300 and CBP in several different domains. We recently showed that CARM1 methylates the C-terminal p160-binding domain of p300. This methylation reduces the binding affinity between p300 and GRIP1 and alters the function of the coactivator complex. PAD4 can remove the methyl group by demethylimination, which restores the tight binding interaction between p300 and GRIP1. Thus, methylation and demethylimination can regulate coactivator complex association/dissociation or coactivator conformation and function.

In addition to histone H4, PRMT1 also methylates the coactivator PGC-1alpha. PGC-1alpha is inducible in various tissues by cold and fasting and is involved in regulating energy metabolism by activating genes required for mitochondrial biogenesis and function. PRMT1 enhances the coactivator function of PGC-1alpha, and mutation of the Arg residues of PGC-1alpha which are methylated by PRMT1 eliminates the ability of PRMT1 to enhance PGC-1alpha coactivator function. Furthermore, reduction of endogenous PRMT1 levels inhibits the coactivator function of PGC-1alpha. Thus, the coactivator function of PGC-1alpha is regulated by arginine methylation.

We also investigated the effects of histone H3 Lys-9 methyltransferases on transcriptional activation by nuclear receptors. Surprisingly, we found that the euchromatin-associated H3 Lys-9 methyltransferase G9a functioned synergistically with CARM1 as a coactivator for nuclear receptors. Other H3 Lys-9 methyltransferases did not exhibit this activity. The coactivator synergy depended strongly on the methyltransferase activity of CARM1 but only partially required the methyltransferase activity of G9a. These results suggest that G9a has two separate roles: gene repression by H3 Lys-9 methylation, and gene activation through a non-enzymatic mechanism.

Host: Gunnar Mellgren, Institute of Medicine

Michael R. Stallcup, who received his Ph.D. in 1974, is Professor and Acting Chair at the Department of Biochemistry and Molecular Biology, USC. The focus of his work is on how steroid hormones, thyroid hormone, and vitamins A and D modulate the activities of cells by regulating the transcription of specific genes. Prof. Stallcup has a long standing interest in hormonal regulation of gene expression by nuclear hormone receptors and their interacting proteins. His laboratory has discovered several such proteins, called transcriptional coactivators, and has further made the exciting finding that methylation of histones and perhaps other proteins by coactivators is an important part of the transcriptional activation process.