Epigenetics and RNA Processing Lab

It is estimated that more than 90% of human genes undergo alternative splicing, and aberrant alternative splicing has been implicated in various diseases, including cancer. The prevalence of alternative splicing and its role in the generation of tissue-specific and developmentally regulated transcripts highlight the significance of alternative splicing in human biology, yet the regulatory mechanisms governing alternative splicing remain unclear. We have recently shown that a sequence-specific DNA binding protein CCCTC-binding factor (CTCF) regulates differential inclusion of alternate exons by promoting RNA polymerase II pause. An increased Pol II pause promoted by CTCF favors spliceosome assembly and inclusion of alternative exon. In contrast, DNA methylation inhibits CTCF binding, thereby reducing pol II pause and leading to alternate exon exclusion. Aberrant epigenetic modifications including DNA methylation and global changes in pre-mRNA alternative splicing have been individually linked to many cancers. The focus of my laboratory is to identify whether and how these variables are connected, and whether they function as drivers of tumorigenesis.