Novel Functions of Protein Arginine Methyltransferase 1 in Thyroid Hormone Receptor-Mediated Transcription and in the Regulation of Metamorphic Rate in Xenopus laevis

Abstract

Protein arginine methyltransferase 1 (PRMT1) acts as a transcription coactivator for nuclear receptors through histone H4 R3 methylation. The in vivo function of PRMT1 is largely unknown. Here we investigated the role of PRMT1 in thyroid hormone (T3) receptor (TR)-mediated transcription in vivo during vertebrate development. By using intestinal remodeling during T3-dependent Xenopus laevis metamorphosis for in vivo molecular analysis, we first showed that PRMT1 expression was upregulated during metamorphosis when both TR and T3 were present. We then demonstrated a role for PRMT1 in TR-mediated transcription by showing that PRMT1 enhanced transcriptional activation by liganded TR in the frog oocyte transcription system and was recruited to the T3 response element (TRE) of the target promoter in the oocyte, as well as to endogenous TREs during frog metamorphosis. Surprisingly, we found that PRMT1 was only transiently recruited to the TREs in the target during metamorphosis and observed no PRMT1 recruitment to TREs at the climax of intestinal remodeling when both PRMT1 and T3 were at peak levels. Mechanistically, we showed that overexpression of PRMT1 enhanced TR binding to TREs both in the frog oocyte model system and during metamorphosis. More importantly, transgenic overexpression of PRMT1 enhanced gene activation in vivo and accelerated both natural and T3-induced metamorphosis. These results thus indicate that PRMT1 functions transiently as a coactivator in TR-mediated transcription by enhancing TR-TRE binding and further suggest that PRMT1 has tissue-specific roles in regulating the rate of metamorphosis.

Thyroid Hormone Activates Protein Arginine Methyltransferase 1 Expression by Directly Inducing c-Myc Transcription during Xenopus Intestinal Stem Cell Development

“…41 and data not shown), suggesting conserved transcriptional regulation mechanisms in X. laevis and X. tropicalis, just like all other genes that we and others have studied during metamorphosis (58,59,61,66,67). Alignment of PRMT1 genomic sequences of X. laevis and X. tropicalis PRMT1 revealed several conserved segments with over 75% identity in the upstream regions and the first intron (Fig.…”

“…PRMT1 is a known coactivator for TR (41,75). In our studies on the role of TR during X. laevis metamorphosis, we discovered that PRMT1 is up-regulated during intestinal remodeling and, importantly, that its up-regulation in the intestinal larval epithelium is the first known molecular marker induced by T3 in the larval epithelial cells that are destined for dedifferentiation into stem cells.…”

“…Thus, it will be interesting to investigate the roles of these other putative transcription factor binding sites in PRMT1 promoter function in the future. PRMT1 is up-regulated by T3 during X. laevis metamorphosis (41). Interestingly, although this is an early event observed in the developing adult intestinal stem cells, the induction is kinetically slow, requiring 3-5 days of T3 treatment, suggesting that T3 indirectly regulates the expression of PRMT1.…”

“…In the absence of T3, TR/ retinoic acid receptor heterodimers function as repressors by recruiting corepressor complexes, and in the presence of T3, they act as activators by recruiting coactivator complexes (21, 23, 24, 27, 30 -45). We have shown recently that protein arginine methyltransferase 1 (PRMT1) plays an important role for gene activation and metamorphosis induced by liganded TR (41,46). Interestingly, PRMT1 expression is up-regulated in the intestine during both natural and T3-induced metamorphosis (41).…”

“…We have shown recently that protein arginine methyltransferase 1 (PRMT1) plays an important role for gene activation and metamorphosis induced by liganded TR (41,46). Interestingly, PRMT1 expression is up-regulated in the intestine during both natural and T3-induced metamorphosis (41). Spatiotemporal analyses suggest that at early stages of metamorphosis, PRMT1 is up-regulated in the larval epithelial cells that are destined to become adult epithelial stem cells during metamorphosis (46).…”