ABSTRACT
Splicing of precursor mRNA (pre-mRNA) is an important regulatory step in gene expression. Recent evidence points to a regulatory role of chromatin-related proteins in alternative splicing regulation. Using an unbiased approach, we have identified the acetyltransferase p300 as a key chromatin-related regulator of alternative splicing. p300 promotes genome-wide exon inclusion in both a transcription-dependent and -independent manner. Using CD44 as a paradigm, we found that p300 regulates alternative splicing by modulating the binding of splicing factors to pre-mRNA. Using a tethering strategy, we found that binding of p300 to the CD44 promoter region promotes CD44v exon inclusion independently of RNAPII transcriptional elongation rate. Promoter-bound p300 regulates alternative splicing by acetylating splicing factors, leading to exclusion of hnRNP M from CD44 pre-mRNA and activation of Sam68. p300-mediated CD44 alternative splicing reduces cell motility and promotes epithelial features. Our findings reveal a chromatin-related mechanism of alternative splicing regulation and demonstrate its impact on cellular function.
Subject(s)
Alternative Splicing , Breast Neoplasms/genetics , Chromatin/metabolism , E1A-Associated p300 Protein/metabolism , Gene Expression Regulation, Neoplastic , Hyaluronan Receptors/genetics , RNA Splicing Factors/chemistry , Acetylation , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Chromatin/genetics , E1A-Associated p300 Protein/genetics , Exons , Female , Humans , Hyaluronan Receptors/metabolism , Promoter Regions, Genetic , RNA Splicing Factors/genetics , RNA Splicing Factors/metabolism , Transcription, Genetic , Tumor Cells, CulturedABSTRACT
The anterior inferior iliac spine (AIIS) has variable morphology that correlates with hip range of motion. Subspinal impingement is an extracapsular cause for femoroacetabular impingement (FAI) and is clinically significant because it results in decreased range of motion and groin pain with flexion-based activity. In symptomatic patients with AIIS extension to or below the acetabular rim, AIIS decompression is considered part of an FAI corrective procedure. A consistent exposed bony area on the anterior and inferomedial aspect of the AIIS serves as a "safe zone" of resection allowing for decompression with preservation of the origin of the rectus femoris tendon. This surgical note describes a technique for AIIS decompression. The goal for low AIIS osteoplasty is to resect the AIIS to 2 burr widths (using a 5.5-mm burr) above the acetabular rim, achieving an 11-mm clearance, creating a type I AIIS. The resultant flat anterior acetabular surface between the most anteroinferior prominent point of the AIIS and the acetabular rim allows for free movement of the hip joint without impingement. Careful execution of AIIS decompression can alleviate clinical symptoms of FAI and restore function to the hip joint.
