Alternative mRNA splicing, splice defects and human disease
Functional analyses of the molecular basis.
| Posttranscriptional processes such as alternative splicing play an
important role in the regulatory networks of gene expression and
multiply the diversity of gene products. Most human protein-coding genes
undergo alternative RNA processing, determined by the combinatorial
control of a relatively small set of splicing regulators and regulated
in a tissue- and developmental manner. Furthermore, splicing defects
caused by mutations represent an important disease mechanism in the
human system. Many examples are known by now where specific mutations in
the splice sites or splicing-regulatory regions result in altered or
non-functional mRNAs, and eventually cause disease.
We are specifically interested in studying how CA-repeat and CA-rich elements function as splicing-regulatory elements. These are very common in the human genome and are bound by heterogeneous nuclear ribonucleoprotein L (hnRNP L). An initial example was the human eNOS gene, coding for endothelial nitric oxide synthase, where a polymorphic CA repeat sequence in intron 13 has been recognized as a risk factor for coronary heart disease, functioning as a length-dependent splicing enhancer (Hui et al., 2003; Hui et al., 2005; Hung et al., 2008; Roßbach et al., 2009). Another recent focus is the interplay between hnRNP L, an RNA-binding protein and general splicing regulator protein, and the paralogous L-like, which acts as a cell-type-specific splicing repressor in T- and B-cell lymphocytes. Our overall goal is to characterize molecular mechanisms of alternative splicing defects in disease-relevant human genes.
- Hui J, Stangl K, Lane WS, Bindereif A. 2003. HnRNP L stimulates splicing of the eNOS gene by binding to variable-length CA repeats.
Nature Struct Biol 10: 33-37.
- Hui J, Hung LH, Heiner M, Schreiner S, Neumüller N, Reither G, Haas SA, Bindereif A. 2005. Intronic CA-repeat and CA-rich elements: a new class of regulators of mammalian alternative splicing.
EMBO J 24: 1988-1998.
- Hung LH, Heiner M, Hui J, Schreiner S, Benes V, Bindereif A. 2008. Diverse roles of hnRNP L in mammalian mRNA processing: a combined microarray and RNAi analysis.
RNA 14: 284-296.
- Roßbach O, Hung LH, Schreiner S, Grishina I, Heiner M, Hui J, Bindereif A. 2009. Auto- and crossregulation of the hnRNP L proteins by alternative splicing.
Mol Cell Biol 29: 1442-1451.