RBM4a-regulated splicing cascade modulates the differentiation and metabolic activities of brown adipocytes

Jung-Chun Lin,Ying-Ju Lin,Yi-Han Lu,Yun-Ru Liu

doi:10.1038/srep20665

Jung-Chun Lin, Ying-Ju Lin + Show 2 more

Open Access

https://doi.org/10.1038/srep20665

Copy DOI

Abstract

RNA-binding motif protein 4a (RBM4a) reportedly reprograms splicing profiles of the insulin receptor (IR) and myocyte enhancer factor 2C (MEF2C) genes, facilitating the differentiation of brown adipocytes. Using an RNA-sequencing analysis, we first compared the gene expressing profiles between wild-type and RBM4a−/− brown adipocytes. The ablation of RBM4a led to increases in the PTBP1, PTBP2 (nPTB), and Nova1 proteins, whereas elevated RBM4a reduced the expression of PTBP1 and PTBP2 proteins in brown adipocytes through an alternative splicing-coupled nonsense-mediated decay mechanism. Subsequently, RBM4a indirectly shortened the half-life of the Nova1 transcript which was comparatively stable in the presence of PTBP2. RBM4a diminished the influence of PTBP2 in adipogenic development by reprogramming the splicing profiles of the FGFR2 and PKM genes. These results constitute a mechanistic understanding of the RBM4a-modulated splicing cascade during the brown adipogenesis.

Highlights

RNA-binding motif protein 4a (RBM4a) reportedly reprograms splicing profiles of the insulin receptor (IR) and myocyte enhancer factor 2C (MEF2C) genes, facilitating the differentiation of brown adipocytes
To obtain comprehensive insights into the physiological functions and regulation of the RBM4a gene during brown adipogenesis, deep RNA sequencing were performed with RNAs prepared from RBM4a−/− or the wild-type (WT) brown adipose tissues (BATs)
The transcript levels of 626 genes were relatively abundant in WT BATs compared to the RBM4a−/− counterparts, whereas 175genes exhibited relatively high transcript levels in RBM4a−/− BATs (Table 1B)

Summary

Introduction

RNA-binding motif protein 4a (RBM4a) reportedly reprograms splicing profiles of the insulin receptor (IR) and myocyte enhancer factor 2C (MEF2C) genes, facilitating the differentiation of brown adipocytes. RBM4a diminished the influence of PTBP2 in adipogenic development by reprogramming the splicing profiles of the FGFR2 and PKM genes. These results constitute a mechanistic understanding of the RBM4a-modulated splicing cascade during the brown adipogenesis. RBM4a was shown to reprogram the tissue-specific splicing profiles that facilitates the differentiation of myocytes and brown adipocytes[14,16]. Results of the deep RNA-sequencing showed the differential gene expressions in RBM4a−/− brown adipose tissues (BATs) compared to the wild type counterparts.

Methods

Results

Conclusion