Determining the factors that control dose-dependent splicing regulation by a master regulator

  • Berglund, Andrew (Investigador principal)
  • Spitale, Robert C. (CoPI)
  • Swanson, Maurice S (CoPI)
  • Wang, Eric T. (CoPI)

Detalles del proyecto

Descripción

Many trans and cis acting factors that control alternative splicing have been identified. The explosion of next-generation sequencing approaches have identified thousands of regulated splicing events (RNA-seq), and binding sites of many proteins which regulate alternative splicing have been identified via CLIPseq. An important question remaining for the field is: What are the rules governing the behavior of alternative splicing decisions? For example, what are the RNA elements (sequence and structure) that determine if alternatively regulated exons will respond at low concentrations or at high concentrations to a splicing factor, and will the splicing responses exhibit cooperative behavior or not? Addressing these questions is important for providing a framework for understanding how changes in splicing factor concentration can lead to disease. To address these questions, we have created cellular models that allow us to precisely titrate the level of an alternative splicing regulator, the Muscleblind-like 1 (MBNL1) protein. MBNL1 has been shown to regulate thousands of alternative splicing events and is important for the development of skeletal muscle, heart and the central nervous system. This regulation is highlighted by the primary role that MBNL proteins play in the disease myotonic dystrophy (DM), in which MBNL1 and its paralogs (MBNL2 and MBNL3) are sequestered by expanded CUG or CCUG repeat RNAs, resulting in aberrant RNA processing. The mis- splicing of MBNL targets has been shown to be responsible for causing some of the symptoms associated with DM, including the hallmark symptom myotonia. .
EstadoFinalizado
Fecha de inicio/Fecha fin4/8/1730/4/21

Financiación

  • National Institute of General Medical Sciences: USD421,098.00
  • National Institute of General Medical Sciences: USD32,354.00
  • National Institute of General Medical Sciences: USD407,973.00
  • National Institute of General Medical Sciences: USD446,800.00

!!!ASJC Scopus Subject Areas

  • Investigación sobre el cáncer

Huella digital

Explore los temas de investigación que se abordan en este proyecto. Estas etiquetas se generan con base en las adjudicaciones/concesiones subyacentes. Juntos, forma una huella digital única.