Associated Principal Investigator, Research Group Leader, CMMC
The human body is composed of about 200 different cell types. The identity and function of these distinct cell types are precisely programmed by the regulatory networks encoded in the 3 billion base pairs of DNA that constitute the human genome. While 60% of our genome is transcribed, less than 2% of it is translated to proteins. In contrast to previous assumptions, this suggests that a significant majority of the regulatory information from the genome functions as RNAs, termed non-coding RNAs. Emerging evidences suggest that a substantial portion of these non-coding transcripts control myriad biological processes ranging from development to disease, establishing the vital role played by these RNA regulatory elements. The Kurian lab investigates how RNA regulatory elements program cellular identities during embryonic development, aging, and organ regeneration.
Our research: Dr. Leo Kurian and his research team work to determine the physiological roles and molecular mechanisms by which lineage/tissue-specific long non-coding RNAs (lncRNAs) and RNA binding proteins (RBPs) modulate cardiac development, aging, and regeneration. Cardiovascular diseases (CVDs) remain the leading cause of death worldwide despite improved prognosis and etiological understanding. In addition, congenital cardiac disorders affect 0.8% of live births globally. Due to the prevalence of cardiovascular disease it is crucial to gain in-depth understanding of the genetic networks driving cardiac development and function, in order to devise strategies to combat CVDs and engineer regenerative strategies.
Our goals: The team’s long term goal is to determine how RNA regulatory networks program and reprogram specific cellular identities. The focus is currently on the following questions:
Our successes: One of the major classes of non-coding transcripts is regulatory RNAs that are greater than 200 bases, termed long non-coding RNAs (lncRNAs). According to current estimates, the human genome codes for around 58000 lncRNAs. Despite these exciting discoveries, the lncRNAs explored. The functional significance of these transcripts has been called into question, underlining the importance of a fundamental understanding of lncRNAs in gene regulation. Encouraged by the cell type-/tissue-specific expression pattern, and combining state-of-the-art transcriptomics with in vitro and in vivo developmental models, Dr. Kurian and his team recently identified and characterized the functions of three novel lncRNAs essential for early embryonic development. They also demonstrated that these three lncRNAs are functionally conserved across vertebrate evolution.
Additionally, they determined a novel post-transcriptional mechanism dictating cellular homeostasis (Nature, 2011b) and developed an in-vitro model that molecularly and functionally recapitulates human embryonic cardiovascular development (Nature 2011a, Nature Methods, 2013). Lastly, they identified a cohort of lncRNAs and novel regulatory networks choreographing human cardiovascular lineage commitment and regeneration (Genes and Development 2013, Circulation 2015, Cell Stem Cell 2014)
Our methods/techniques: Cardiovascular diseases are the primary cause of age-related morbidity and death in developed countries. One of the main reasons for this is the limited regenerative potential of adult mammalian heart. Researchers in the Kurian lab employ a holistic approach using human pluripotent stem cell-based differentiation models, mouse and zebrafish, combined with state-of-the-art systems biology approaches to decipher the molecular basis of vertebrate cardiac development, aging, and regeneration.
Figure 1: Schematic representation of human embryonic cardiac development.
Figure 2: Directed Differentiation of human pluripotent stem cells to cardiomyocytes.
Figure 3: Network depicting novel lncRNAs in correlation with key developmental regulators.
Figure 4: Regenerating zebrafish heart after 7 days post injury undergoing controlled in vivo reprogramming.