“Understanding the role of long non-coding RNAs (lncRNA) and RNA binding proteins (RBPs) in programming lineage commitment and cellular identity”
It is hypothesised that RNA served both to store genetic information as well as to perform catalytic functions in early life forms. Later, the storage of genetic information was designated to more chemically stable DNA and catalytic function was shifted towards more versatile molecules such as proteins. In higher eukaryotes, RNA remains central in translational control and splicing but otherwise seems to be relegated as a messenger of genetic information.
In the past decade, large-scale genomic studies have challenged this dogma as the importance of RNA to a diversity of cellular processes becomes apparent. It is perceived that this developmental complexity is orchestrated more by the regulatory elements that fine tune gene expression programs that in return define phenotypic heterogeneity and diversity across species. Differences in the number of functionally-linked protein families and number of encoded proteins cannot explain the hugely expanded developmental complexity of eukaryotes compared to lower metazoan, and this gap is thought to be filled by non-coding RNA regulatory elements. It is hypothesized that long non-coding RNAs and RNA binding proteins are central to this increased complexity and help explain the functional diversity that defines higher organisms. We aim to understand the importance of these novel genetic elements in the context of human development and regeneration.
In the Kurian Lab, we determined that 50% of the transcriptome activated during human cardiovascular development is comprised of lncRNAs. Intriguingly, the majority of these spatio-temporally regulated lncRNAs are not functionally annotated. Highlighting their central role in developmental decisions, we functionally characterized three lncRNAs essential for pluripotency, mesoderm commitment and cardiovascular development respectively. Our continuing efforts will center on the following questions:
In the Kurian lab, our major questions
A. Are the cell type-specific lncRNAs and RBPs important to embryonic development?
B. How are lineage-specific lncRNAs regulated?
C. How do lncRNAs drive lineage commitment and specify cellular identities?
D. What is the role of cell type specific lncRNAs in cardiovascular diseases?
E. What is the role of lncRNAs and RBPs in cardiovascular regeneration?
F. How does lncRNAs contribute to evolution at the level of developmental and molecular complexity?
We are answering these questions using two powerful in vitro and in vivo models with an array of novel genomics and molecular tools including next-generation sequencing, Crispr/Cas9 based in vitro and in vivo loss of function, RNA immunoprecipitation coupled mass spectrometry (RIP-MS) etc.