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© Research
Project

The chromatin-remodeling complex SWI/SNF as a modulator of alternative splicing

Starting Date
17
Jul 2015
Status
Ongoing
Members
2
Structures
1

About

We have shown that the BRM subunit of the chromatin-remodeling complex SWI/SNF, also known to be perturbed during tumorigenesis, regulates the alternative splicing of several genes, such as CD44, Bim, E-cadherin and cyclin D1 (Batsché et al. 2006). The mechanism involves formation of internal ‘roadblocks’ interfering with transcriptional elongation and affecting the phosphorylation status of RNA polymerase II.

SWI-NSF chromatin RNAPII speed Batsche
The intragenic chromatin recruitment of the catalytic subunit BRM favours a slowing down or a pausing of the RNAPII into the gene body and hence, promotes the inclusion of variant exons. Importantly, while the ATPase-dependent remodeling activity of BRM is dispensable for this effect, its chromatin interaction domain is essential. This suggests that the binding of SWI/SNF complex on the chromatin is sufficient per se to influence transcription elongation and splicing.

 

 Protein coding sequences represent a very discrete portion of the whole genome and have to be detected and reassemble by the splicing process at the exact nucleotide in mature RNA  (messenger / mRNA) prior to be translated. Moreover, alternative splicing allowing expression of variant mRNAs, estimated to affect almost all human genes, is now considered the rule rather than the exception. Many genetic disorders and cancers are caused by mutations that alter the function of alternative splicing–regulatory sequences. Alternative splicing regulation not only depends on the interaction of splicing factors with their pre-mRNA target sequences but is coupled to RNA synthesis (transcription) which take place in a chromatin context. The chromatin organizing the DNA through histone proteins is subject to numerous modifications and functions as a matrix for epigenetic information. This information involves enzymes guided to their target sites by transcription factors, but also by RNAs and RNA-binding proteins. The resulting patterns of histone modifications or chromatin remodelling in turn affects both the machineries involved in transcription and those involved in maturation of the transcripts.

We explore the crosstalk between the chromatin remodelling complex, the transcription machineries, and the alternative splicing  to gain a better understanding of transcriptional regulation in the context of chromatin.  

 

Batsché E, Yaniv M and Muchardt C (2006) Nat. Struc. Mol. Biol   13:22-9. The human SWI/SNF subunit Brm is a regulator of alternative splicing. This paper pioneered the field of the alternative splicing regulation by chromatin machineries.