We all know that movie production goes through an important step called film editing after the raw films are shot at the scenes. Similarly, in our cells, after raw message RNA (mRNA) molecules are transcribed from genomic DNA (called primary mRNA, or pre-mRNA), they are processed as meticulously as the movie master Sergei Eisenstein would to his film (see left). The final products (mature mRNAs) after RNA processing are then used as templates to make proteins to carry out various biological functions, the same way we see all movie copies in cinema.
In the Lu Lab, we develop and apply proteomic methods to study the protein masters that are responsible for all of the RNA processing steps. Problems in these proteins will lead to aberrant RNA processing in all sorts of human diseases, such as cancer and neurodegeneration.
The role of RBM17 in cancer stem cell functions
RBM17, aka SPF45, is a component of the splicing complex spliceosome. It regulates the second step of pre-mRNA splicing, through which protein-coding regions (aka exons) on the pre-mRNAs are joined together, while the non-coding stretches (aka introns) are removed. RBM17 is preferentially expressed in multiple solid tumors in the bladder, lung, colon, breast, ovary, pancreas, and prostate, compared to the respective normal tissues. Higher RBM17 levels in patients are significantly associated with worse prognosis in multiple cancers. We are working to investigate whether higher RBM17 levels support cancer stem cell self-renewal and drug resistance.
Tau regulation in neurodegeneration
The brain of a dementia patient contains many dead or dying nerve cells with internal protein tangles. The main component of these tangles is a protein called Tau (aka MAPT), which, in a healthy brain, supports vital cell transport systems inside the nerve cells. The formation of tangles in nerve cells is a common feature shared between Alzheimer's Disease (AD) and many other neurodegenerative diseases, which are collectively called tauopathies, or diseases associated with Tau.
Abnormal Tau regulation at multiple levels, including gene expression, alternative splicing, RNA degradation, and phosphorylation, contribute to the formation of neurofibrillary Tau tangles. We will apply novel proteomic methods to study proteins involved in these Tau regulation processes in human cortical neurons derived from induced pluripotent stem cells (iPSC). The identified regulators will be further tested for their pathological impacts in AD and other tauopathies.
RNA modification regulation
Chemical changes, known as RNA modifications, can occur to RNA at its base, ribose, and the phosphate backbone. In recent years, the breakthrough in RNA modification analysis on message RNA (mRNA) and long non-coding RNA (lncRNA) dramatically stimulated researchers around the world to race to identify these modifications and understand their functions in our cells. To date, certain RNA modifications are linked to development and human diseases.
In the Lu Lab, we are interested in developing new proteomic methods to discover upstream writers and erasers, as well as downstream readers, of specific RNA modifications. We aim to fully understand the regulatory mechanisms in this largely uncharted domain.