Functional coordination of alternative splicing in the mammalian central nervous system

BACKGROUND: Alternative splicing (AS) functions to expand proteomic complexity and plays numerous important roles in gene regulation. However, the extent to which AS coordinates functions in a cell and tissue type specific manner is not known. Moreover, the sequence code that underlies cell and tissue type specific regulation of AS is poorly understood. RESULTS: Using quantitative AS microarray profiling, we have identified a large number of widely expressed mouse genes that contain single or coordinated pairs of alternative exons that are spliced in a tissue regulated fashion. The majority of these AS events display differential regulation in central nervous system (CNS) tissues. Approximately half of the corresponding genes have neural specific functions and operate in common processes and interconnected pathways. Differential regulation of AS in the CNS tissues correlates strongly with a set of mostly new motifs that are predominantly located in the intron and constitutive exon sequences neighboring CNS-regulated alternative exons. Different subsets of these motifs are correlated with either increased inclusion or increased exclusion of alternative exons in CNS tissues, relative to the other profiled tissues. CONCLUSION: Our findings provide new evidence that specific cellular processes in the mammalian CNS are coordinated at the level of AS, and that a complex splicing code underlies CNS specific AS regulation. This code appears to comprise many new motifs, some of which are located in the constitutive exons neighboring regulated alternative exons. These data provide a basis for understanding the molecular mechanisms by which the tissue specific functions of widely expressed genes are coordinated at the level of AS

Functional coordination of alternative splicing in the mammalian central nervous system

Abstract Background Alternative splicing (AS) functions to expand proteomic complexity and plays numerous important roles in gene regulation. However, the extent to which AS coordinates functions in a cell and tissue type specific manner is not known. Moreover, the sequence code that underlies cell and tissue type specific regulation of AS is poorly understood. Results Using quantitative AS microarray profiling, we have identified a large number of widely expressed mouse genes that contain single or coordinated pairs of alternative exons that are spliced in a tissue regulated fashion. The majority of these AS events display differential regulation in central nervous system (CNS) tissues. Approximately half of the corresponding genes have neural specific functions and operate in common processes and interconnected pathways. Differential regulation of AS in the CNS tissues correlates strongly with a set of mostly new motifs that are predominantly located in the intron and constitutive exon sequences neighboring CNS-regulated alternative exons. Different subsets of these motifs are correlated with either increased inclusion or increased exclusion of alternative exons in CNS tissues, relative to the other profiled tissues. Conclusion Our findings provide new evidence that specific cellular processes in the mammalian CNS are coordinated at the level of AS, and that a complex splicing code underlies CNS specific AS regulation. This code appears to comprise many new motifs, some of which are located in the constitutive exons neighboring regulated alternative exons. These data provide a basis for understanding the molecular mechanisms by which the tissue specific functions of widely expressed genes are coordinated at the level of AS

Identification of widely expressed genes with CNS specific regulation of AS

Microarray profiled genes with single or multiple alternative exons displaying differential alternative splicing (AS) in the central nervous system (CNS) were identified using statistical procedures that control for covariation in transcript levels (see Results and Materials and methods). The top 100 genes with the most significant CNS associated AS levels are hierarchically clustered on both axes, based on their overall AS level similarity across 27 profiled tissues. The corresponding transcript levels of the same genes, displayed in the same order. Color scales representing AS levels (percentage exon exclusion) and transcript levels (z-score scale) are shown below each panel. The z-score represents the number of standard deviations from the mean transcript level (center of the scale, in black) of the given event. Increasingly bright yellow represents lower transcript levels, and increasingly bright blue represents higher transcript levels. White rectangles in the AS clustergram indicate removed GenASAP (Generative Model for the Alternative Splicing Array Platform) values. These values were removed when transcript levels from the same genes (as measured using probes specific for constitutive exons on the microarray) were below the 95th percentile of the negative control probes.<p><b>Copyright information:</b></p><p>Taken from "Functional coordination of alternative splicing in the mammalian central nervous system"</p><p>http://genomebiology.com/2007/8/6/R108</p><p>Genome Biology 2007;8(6):R108-R108.</p><p>Published online 12 Jun 2007</p><p>PMCID:PMC2394768.</p><p></p

Detection of new motifs in exons and introns that correlate with CNS regulated AS events

Motifs correlating with central nervous system (CNS) associated alternative splicing (AS) levels were detected in exon sequences (C1, A, C2) and intron sequences (I1, I2) using the SeedSearcher algorithm [41]. searches for motifs were performed in the individual exon and intron sequences, and in concatenations of intron/exon sequences. Motifs enriched in these locations, as indicated by lines with arrowheads, are correlated with either increased inclusion (yellow boxes), increased exclusion (blue boxes), or a change in inclusion (black boxes), respectively.<p><b>Copyright information:</b></p><p>Taken from "Functional coordination of alternative splicing in the mammalian central nervous system"</p><p>http://genomebiology.com/2007/8/6/R108</p><p>Genome Biology 2007;8(6):R108-R108.</p><p>Published online 12 Jun 2007</p><p>PMCID:PMC2394768.</p><p></p