Abstract

We have investigated the function and mechanisms of the CARM1-SNF5 complex in T3-dependent transcriptional activation. Using specific small interfering RNAs (siRNA) to knock down coactivators in HeLa alpha2 cells, we found that coactivator associated arginine methyltransferase 1 (CARM1) and SWI/SNF complex component 5 (SNF5) are important for T3-dependent transcriptional activation. The CARM1- SWI/SNF chromatin remodeling complex serves as a mechanism for the rapid reversal of H3-K9 methylation. Importantly, siRNA treatment against CARM1 and/or SNF5 increased the recruitment of HMTase G9a to the type 1 deiodinase (D1) promoter even with T3. Knocking-down either CARM1 or SNF5 also inhibited the down-regulation of histone macroH2A, which is correlated with transcriptional activation. Finally, knocking down CARM1 and SNF5 by siRNA impaired the association of these coactivators to the D1 promoter, suggesting functional importance of CARM1- SNF5 complex in T3-dependent transcriptional activation.

Highlights

  • Thyroid hormone receptors (TRs) can bind to target promoter as monomers, homodimers, or heterodimers with retinoid X receptor (RXR) (An et al, 1997)

  • Transcription is a complex, multi-step process involving a large number of cofactors that affect chromatin remodeling, formation of RNA polymerase II preinitiation complex (PIC), transcription elongation and the RNA processing (Levine and Tjian, 2003)

  • Using Xenopus laevis oocytes, we previously showed that transcriptional activation by liganded TR is coupled with increased acetylation on H3 and H4 and a robust decrease in H3-K9 methylation

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Summary

Introduction

Thyroid hormone receptors (TRs) can bind to target promoter as monomers, homodimers, or heterodimers with retinoid X receptor (RXR) (An et al, 1997). TRs can positively or negatively regulate transcription dependent on the presence or absence of hormones and the presence of a positive or negative thyroid hormone response element (TRE vs nTRE) in its target genes (O'Shea and Williams, 2002). In the absence of ligand, TR/RXR heterodimers bind to TREs and actively repress transcription. The repression by unliganded TR/RXR is largely mediated through the recruitment of corepressor proteins such as silencing mediator for retinoic acid receptor and thyroidhormone receptor (SMRT) and nuclear hormone receptor co-repressor (N-CoR) (Guenther et al, 2000; Yoon et al, 2003a).

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