A Crosstalk between the Mediator Complex and the Splicing Machinery Provides a Novel Molecular Mechanism for Co-transcriptional mRNA Processing

Alternative mRNA processing, which refers to alternative splicing (AS) and alternative polyadenylation (APA) events, affects the majority of protein-coding genes in higher species, creating functional diversity for gene products. Because different cell types or tissues often generate different mRNA isoforms, there is increasing evidence that alternative mRNA processing contributes to the important biological control in development and disease. The mRNA processing is mechanistically coupled to transcription, however, the coupling mechanism is not fully understood.

 

Transcription cofactor Mediator complex is an evolutionarily conserved multi-protein complex. In addition to its classic function in recruiting the pre-initiation complex, it can also stimulate RNA synthesis at a post-recruitment step. There has been a long thought that Mediator may be involved in mRNA processing, though little progress was made in recent years. A research team led by Dr. WANG Gang at the Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), now provides the direct evidences that Mediator indeed regulates alternative mRNA processing.

 

To explore the novel function of Mediator, HUANG Yan, YAO Xiao and their colleagues, under the supervision of Dr. WANG Gang, first purified multiple soluble Mediator subunit proteins. Then combining tandem affinity purification and Mass Spectrum techniques, they identified a number of mRNA processing factors associated with MED23 subunit. HnRNP L, a splicing factor, was found to specifically interact with MED23 using a variety of biochemical methods. With the help of Dr. HUI Jingyi’s laboratory at IBCB, they demonstrated that Mediator MED23 is able to regulate the alternative splicing of a subset of hnRNP L-targeted genes. A genome-wide exon array analysis was performed to search the MED23-hnRNP L co-regulated alternative mRNA processing events, and a positive correlated set of AS and APA events impacted by Mediator MED23 and hnRNP L was revealed. The bioinformatics data analysis was done by Dr. TIAN Bin and Dr. LI Wencheng at the University of Medicine and Dentistry of New Jersey.

 

Taken together, these findings establish a direct link between Mediator Complex and the splicing machinery, demonstrate an important function of Mediator in the regulation of alternative mRNA processing, and provide novel insights into the molecular mechanisms that couple pre-mRNA processing to transcription. A paper entitled “Mediator Complex Regulate Alternative mRNA Processing via the MED23 Subunit” was published online in Molecular Cell on Jan 19^th, 2012, and it will be in print on Feb 24^th as the featuring cover story.

 

This work was supported in parts by grants from the Chinese Academy of Sciences, the Ministry of Science and Technology of China, National Natural Science Foundation of China, and National Institutes of Health USA.

 

AUTHOR CONTACT:

WANG Gang, Ph.D.

Institute of Biochemistry and Cell Biology

Shanghai Institutes for Biological Sciences

Chinese Academy of Sciences

Shanghai 200031, China

Phone: 86-21-54921083; E-mail: gwang22@sibs.ac.cn