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Concentration-dependent regulation by Rbfox enabled by motifs of intermediate affinity

ABSTRACT: Concentration-dependent regulation by Rbfox enabled by motifs of intermediate affinity

PROVIDER: PRJNA639556 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12017716.fastq.gz	Fastqsanger.gz
	SRR12017717.fastq.gz	Fastqsanger.gz
	SRR12017718.fastq.gz	Fastqsanger.gz
	SRR12017719.fastq.gz	Fastqsanger.gz
	SRR12017720.fastq.gz	Fastqsanger.gz

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Concentration-dependent regulation by Rbfox enabled by motifs of intermediate affinity

Project description:The Rbfox family of splicing factors regulate alternative splicing during animal development and in disease, impacting thousands of exons in the maturing brain, heart, and muscle. Rbfox proteins have long been known to bind to the RNA sequence GCAUG with high affinity, but just half of Rbfox CLIP peaks contain a GCAUG motif. We incubated recombinant RBFOX2 with over 60,000 mouse and human transcriptomic sequences to reveal significant binding to several moderate-affinity, non-GCAYG sites at a physiologically relevant range of RBFOX concentrations. We find that many of these “secondary motifs” bind Rbfox robustly in cells and that several together can exert regulation comparable to a GCAUG in a trichromatic splicing reporter assay. Furthermore, secondary motifs regulate RNA splicing in neuronal development and in neuronal subtypes where cellular Rbfox concentrations are highest, enabling a second wave of splicing changes as Rbfox levels increase.

2020-06-16 | GSE152510 | GEO

Concentration-dependent splicing is enabled by Rbfox motifs of intermediate affinity.

Project description:The Rbfox family of splicing factors regulate alternative splicing during animal development and in disease, impacting thousands of exons in the maturing brain, heart and muscle. Rbfox proteins have long been known to bind to the RNA sequence GCAUG with high affinity and specificity, but just half of Rbfox binding sites contain a GCAUG motif in vivo. We incubated recombinant RBFOX2 with over 60,000 mouse and human transcriptomic sequences to reveal substantial binding to several moderate-affinity, non-GCAYG sites at a physiologically relevant range of RBFOX2 concentrations. We find that these 'secondary motifs' bind Rbfox robustly in cells and that several together can exert regulation comparable to GCAUG in a trichromatic splicing reporter assay. Furthermore, secondary motifs regulate RNA splicing in neuronal development and in neuronal subtypes where cellular Rbfox concentrations are highest, enabling a second wave of splicing changes as Rbfox levels increase.

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Project description:Rett syndrome (RTT) is a severe neurological disorder which is mainly caused by mutations found in the X-linked gene encoding MeCP2. Despite extensive studies, the molecular functions of MeCP2 remain elusive. Here, we report that MeCP2 is a new subunit of a higher-order multiunit protein complex Rbfox/LASR and acts as a scaffold for this splicing complex. Deletion or mutation of MeCP2 leads to defects in forming MeCP2/Rbfox/LASR complex and aberrant alternative pre-mRNA splicing. Our data link RTT to an impaired function of MeCP2 in splicing control through its role in nucleating Rbfox/LASR macromolecule assembly.

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