Functional dissection of the C-terminal part of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator alpha (PGC-1[alpha])

The superfamily of nuclear receptors is a class of transcriptional regulators that includes the receptors for steroid hormones, thyroid hormones, retinoids and vitamin D. The superfamily also includes so-called orphan receptors, for which an activating ligand is unknown or not required. They regulate diverse biological processes, such as homeostasis, reproduction, development, and metabolism. To exert their functions in the activation of transcription, they need to recruit so-called coactivator protein complexes, many of which remodel the chromatin structure in promoter regions and help to recruit the basal RNA polymerase II transcription machinery. We and others identified the transcriptional coactivator PGC-1α. Its expression is induced by physiological signals such as cold, fasting, and exercise, and it turned out to be a central regulator of cellular energy homeostasis. The N-terminal part of PGC-1α harbors a strong transcriptional activation function and a nuclear receptor interaction domain. The Cterminal half of PGC-1α harbors several interesting motifs, including two serine/argininerich sequences, a putative RNA-binding domain, and an amino acid stretch containing a high percentage of glutamate residues. In this work, we describe the identification of proteins interacting with the C-terminal part of PGC-1α and the functional interaction of two of the identified proteins with PGC-1α. We show that the acetyltransferase Tip60 has both positive and negative effects on PGC1α-dependent transcription. In collaboration, we also show that the methyltransferase PRMT1 methylates PGC-1α and thereby enhances the activity of PGC-1α as a transcriptional coactivator.