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Contrasting Effects of Two Alternative Splicing Forms of Coactivator-Associated Arginine Methyltransferase 1 on Thyroid Hormone Receptor-Mediated Transcription in Xenopus laevis

Section on Molecular Morphogenesis, Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Yun-Bo Shi, Building 18 T, Room 106, Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892. E-mail: Shi{at}helix.nih.gov.

Thyroid hormone receptors (TRs) can repress or activate target genes depending on the absence or presence of thyroid hormone (T₃), respectively. This hormone-dependent gene regulation is mediated by the recruitment of corepressors in the absence of T₃ and coactivators in its presence. Many TR-interacting coactivators have been characterized in vitro. Among them is coactivator-associated arginine methyltransferase 1 (CARM1), which methylates histone H3. We are interested in investigating the role of CARM1 in TR-mediated gene expression in vivo during postembryonic development by using T₃-dependent frog metamorphosis as a model. We first cloned the Xenopus laevis CARM1 and obtained two alternative splicing forms, CARM1a and CARM1b. Both isoforms are expressed throughout metamorphosis, supporting a role for these isoforms during the process. To investigate whether Xenopus CARM1s participate in gene regulation by TRs, transcriptional analysis was conducted in Xenopus oocyte, where the effects of cofactors can be studied in the context of chromatin in vivo. Surprisingly, overexpression of CARM1b had little effect on TR-mediated transcription, whereas CARM1a enhanced gene activation by liganded TR. Chromatin immunoprecipitation assays showed that both endogenous CARM1a and overexpressed CARM1a and b were recruited to the promoter by liganded TR. However, the binding of liganded TR to the target promoter was reduced when CARM1b was overexpressed, accompanied by a slight reduction in histone methylation at the promoter. These results suggest that CARM1 may play a role in TR-mediated transcriptional regulation during frog development and that its function is regulated by alternative splicing.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ  |  RXRα

Coregulators:   CARM1

Ligands:   Thyroid hormone

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