Associated Principal Investigator, Research Group Leader, CMMC
Dr. Leo Kurian
Zentrum fur Molekulare Medizin Köln (ZMMK)
In humans, ~30% of the developing embryos terminate before implantation, and about 25% fail during the transition from gastrulation to organogenesis, when cell fate and identity are set. The failure to specify cell fate and identity in a timely and robust manner results in developmental abnormalities and diseases. For example, 1 out of 100 children are born with congenital cardiac diseases, for the majority of which the causes are unknown. The Kurian lab investigates the regulatory principles that govern cell fate and identity during human cardiac development, homeostasis, and pathomechanisms of cardiac aging.
Our research: The heart is the first organ to form and function during embryogenesis. The development of the heart is carefully choreographed by a series of precisely controlled cell fate decisions, which enables cardiac morphogenesis. A systematic understanding of molecular regulation of cardiac fate and identity is essential not only to understand the principles of self-organization of the human heart, but also to develop therapeutic interventions for congenital and adult-onset cardiac disease. The current understanding of the molecular regulation of cell fate and identity is mainly based on morphogen-mediated signal transduction, epigenetic, and transcriptional mechanisms. However, RNA is the primary language of communication from the genome, and it is distinctly regulated at each stage of its life cycle. We are only beginning to understand the RNA regulatory principles that govern cell fate decisions and cellular identity. The Kurian lab is focused on understanding the RNA-centric processes (controlled by RNA binding proteins, non-coding RNAs, and regulatory motifs embedded in primary transcripts and mRNAs) and their regulatory logic that program cardiac cell fate and identity during human embryogenesis. In parallel, they study how the breakdown of RNA regulatory processes causes congenital and age-associated cardiac diseases. In close collaboration with the industry, they are developing personalized, non-immunogenic RNA therapeutics for congenital cardiac diseases.
Our successes: In the context of embryonic development, the Kurian lab discovered and characterized a new class of long non-coding RNAs (lncRNAs) which we termed YYLNCRNAs. Their proof of principle study using one of the YYLNCRNAs, YYLNCT, revealed the crucial role of YYLNCRNAs in controlling developmental cell fate decisions. In addition, the studies from the Kurian lab revealed a mechanism by which de novo DNA methylation is controlled via lncRNAs during early embryonic cell fate decisions (Frank et al. Cell Stem Cell. 2019). In the context of aging, Kurian lab and colleagues discovered that the accumulation of the metabolite sphinganine is a hallmark of cardiac aging and age-associated deterioration of cardiac function. Sphinganine derivatives are potent HDAC inhibitors. Aging leads to the accumulation of sphinganine derivatives in the heart, causing histone hyperacetylation and loss of transcriptional fidelity leading to genome instability resulting in the progressive weakening of cardiac function (Ahuja et al. EMBO Reports 2019 ). Recently, the work from the Kurian lab revealed how proteins recruited to ribosomal complexes (translation specialization factors) control selective mRNA translation during embryonic development. Translational specialization factors selectively program the translation of mRNAs encoding key developmental regulators that are essential to initiate future cell fate choices, akin to how pioneering transcription factors program specific transcriptional networks allowing cell fate decisions. This study revealed a pivotal role for translational specialization in sculpting cellular identity during early developmental lineage decisions, and proposes that ribosomes act as a unifying hub for cellular decision-making rather than a constitutive protein synthesis factory (BioRxiv 2021.04.12.439420).
Our goals: The long-term mission of the Kurian Lab is to gain a systems-level understanding of the RNA regulatory principles that shape the self-organization and homeostasis of tissue and organs in humans in order to develop therapeutic solutions for tissue/organ regeneration.
The key questions they address are:
Our methods/techniques: The Kurian lab employs pluripotent stem cells and cell fate engineering (2D differentiation and organoid models) in combination with systems biology and genome editing approaches to reconstruct and investigate human cardiac development and disease.
Figure 1 Overarching research theme: The RNA regulatory principles of cardiac identity in embryogenesis, homeostasis, and aging in humans.
Figure 2 Human cardiac organoids showing morphogenesis defect due to the loss of an embryonic translation specialization factor (Deniz Bartsch, Kurian lab)
Figure 3 Loss of a cardiac pre-mRNA splicing factor prevents sarcomerogenesis (white arrows) in human cardiomyocytes (Wenjie Yao (now: lead for single-cell genomics, Bayer Pharmaceuticals, Berkley) & Deniz Bartsch, Kurian lab)
Figure 4 DNA damage (green dots) in human hearts increases with age (Gaurav Ahuja (now: Associate Professor, IIIT Delhi), Kurian lab)