Posts classified under: Basic Science

The driving goal of my laboratory is to understand the regulatory roles and biochemical mechanisms of RNA modifying enzymes and sex-specific RNA regulation in human disease. It has been demonstrated recently that a diverse set of enzyme-mediated modifications are found internally within RNAs, which markedly influence the fate of RNAs in cells. Many enzymes responsible for regulating protein and DNA modifications are targets of current therapies. RNA epitranscriptomics, the study of RNA modifications, is the new frontier in this arena. However, there are many fundamentally important questions, such as whether RNA modifications synergistically impact gene regulation, a new research area that my lab spearheaded in the RNA modification field. Our work studies the coordination of modification across RNA species through (1) interactions of RNA modifying enzymes (indirect model) and direct interactions of mRNA, tRNA, and rRNA modifications during translation.

Furthermore, based on our observation of sex-specific RNA binding proteins, we have been investigating how sex and gender influence gene regulation at the RNA level. Sex differences are evident in human diseases. One of the significant keys to sex-biased differences lies in the sex chromosomes. Our work focuses on the functions of Y chromosome-encoded RNA binding proteins in non-reproductive organs. And the functional differences between Y chromosome-encoded RNA binding proteins and their homologous proteins on the X chromosomes.

The genome is primarily non-protein coding DNA, which is actively transcribed in a cell and tissue-specific fashion. Research has revealed that noncoding RNAs have important biological functions, regulating gene expression at the levels of transcription, RNA processing, and translation. Noncoding RNAs can promote genome rearrangement, and also instruct DNA synthesis. These RNAs also protect host genomes from foreign nucleic acids. Noncoding RNAs can have enzymatic activity (ribozymes, riboswitches), but can also function as part of a protein complex (ribosomes, microRNAs, snRNPs, snoRNPs, long noncoding RNAs). Therefore, understanding the function and mechanism of noncoding RNAs will reveal novel insights for therapeutic interventions for a variety of diseases.

There are a number of Penn research labs that are investigating the function and mechanism of various types of noncoding RNAs, in the context of health and disease. This sub-group will include labs investigating regulatory functions of RNA molecules that broadly fit into several categories: small noncoding RNAs (such as miRNAs, piRNAs) and long nocoding RNAs (transcripts > 100nt).

RNA binding proteins (RBPs) and RNA-protein complexes (RNPs): their central roles in gene expression regulation and disease applications

All RNAs exist in cells as complexes with RBPs in the form of complexes called RNPs. There are over 1,000 RBP-encoding genes in human cells and hundreds of RBPs, each with many isoform, expressed in a cell at any given time. The RBPs play key roles in the life of mRNAs, including every aspect of transcription, pre-mRNA splicing, cleavage and polyadenylation, modifications, mRNA transport, translation, and stability. Research over decades has revealed that each RBP has a distinct RNA binding specificity, mediated by RNA binding domain, and protein-protein interaction domains that mediate assembly of a unique constellation of RBPs on every RNA, thereby sculpting the RNA for processing and function by cellular machineries. Thus RNPs are the functional forms of RNAs in cells. The enormous diversity of RBPs allows cells to regulate alternative splicing, which is crucial for making a large diversity of mRNA and protein isoforms, necessary for making diverse cell types and respond to environmental changes. However, this complexity greatly increases the risk of RNP perturbations, resulting from mutations in RNAs or RBPs, which cause hundreds of human diseases. Viral mRNAs also depend on host RBPs and hijack them for essential viral functions, such as translation to produce viral proteins. Much remains to be learned about the functions, structures, and regulation of RBPs and RNPs and their roles in biology and disease, which should increase the prospects of new therapies.

The BioCiphers lab combines genomic and genetic data to computationally model RNA processing, followed by experimental verification to decipher post-transcriptional regulation, phenotypic diversity and disease.