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. In addition, these molecules are regulated by RNA binding proteins at the functional level. We investigate how RNA regulatory elements program cellular identities during cardiac development, aging, and regeneration.
A complete functional regeneration of the adult mammalian heart remains to be achieved despite meticulous investigation over the past 150 years. In pursuit of this, the heart has been clipped, contused, pierced, frozen, injected with toxins, infected and infarcted in organisms ranging from invertebrates to pigs. Yet our understanding of cardiac regeneration is limited. The fact that cardiovascular disorders (CVDs) are one of the prominent causes of death worldwide, mainly due to the inability of the mammalian heart to regenerate, makes this more than an academic curiosity. A cardiac episode like myocardial infarction can wipe-out up to 25% of the cardiomyocytes in a matter of few hours. Aging as well as adult onset conditions like hypertension or valvular heart diseases lead to a significant loss of cardiomyocytes over the years, thereby weakening the heart. Despite numerous drugs and mechanical devices that can improve cardiac function transiently, we are far from simulating a complete functional cardiac regeneration upon injury in mammals. Surprisingly, lower order vertebrates like zebrafish are able to elicit a robust regenerative response, enabling complete injury recovery upon cardiac damage. To achieve complete regeneration, cardiac tissue architecture and function need to be restored by sequential events including dedifferentiation, proliferation and re-differentiation of cardiomyocytes. This process is basically a controlled cellular reprogramming process, recapitulating early stages of cardiac development. Importantly, recent evidence indicates that the mammalian heart does possess a limited regenerative ability confined to the neonatal stages, suggesting the mechanisms driving cardiac regeneration are essentially conserved, but progressively inactivated upon birth. While appreciating the physiological differences in cardiomyocytes in regeneration-permissive and non-permissive states, it is conceivable that even a partial regenerative response upon injury/ aging would alleviate the tremendous burden that CVDs impose on patient mortality and morbidity and in turn on public health care. In order to device novel strategies for cardiac regeneration, in our lab we focus our efforts on
I) Identifying key molecular regulators of cardiac lineage commitment events during development
II) Understanding mechanisms of controlled reprogramming events that regulate cardiac regeneration
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, we recently identified and characterized the functions of three novel lncRNAs essential for early embryonic development. Importantly, we demonstrated that these three lncRNAs are functionally conserved across vertebrate evolution.
Heart failure is a leading cause of mortality and morbidity in the developed world, partly because of the minimal regenerative ability of the mammalian heart. However, several fish and amphibians do possess dramatic ability to regenerate damaged organs, including heart. We use a combinatorial approach including regeneration competent models, state-of-the art stem cell-based models and systems biology approaches to understand the hidden regulatory layers enabling organ/ tissue regeneration.
Cardiac failure is a burgeoning public health issue predicted to reach epidemic proportion as the current population ages. Compounding reason for this is the inability of the adult mammalian heart to elicit effective regeneration. In our lab we intent to comprehend the molecular basis of cardiac development and regeneration, widening the array of therapeutic opportunities.
1. Kurian L, Aguirre A, Sancho-Martinez I, Benner C, Hishida T, Nguyen TB, Reddy P, Nivet E, Nelles DA, Rodriguez Esteban C, Campistol JM, Yeo GW, Izpisua Belmonte JC (2015). Identification of novel long noncoding RNAs underlying vertebrate cardiovascular development. Circulation. 7;131(14):1278-90.
2. Kurian L, Sancho-Martinez I, Nivet E, Aguirre A, Moon K, Pendaries C, Volle-Challier C, Bono F, Pulecio J, Xia Y, Li M, Ruiz S, Dubova I, Rodriguez C, Thiagarajan RD, Gage FH, Loring JF, Laurent LC, Izpisua Belmonte JC. (2013). Conversion of human fibroblasts to angioblast-like progenitor cells. Nature Methods. 10(1):77-83.
3. Aguirre A, Montserrat N, Zacchigna S, Nivet E, Hishida T, Kurian L, Ocampo A, Vazquez-Ferrer E, Moresco JJ, Yates JR 3rd, Sancho-Martinez I, Giacca M, Izpisua Belmonte JC (2014) In vivo activation of a conserved microRNA program induces mammalian heart regeneration. Cell Stem Cell 6;15(5):589-604
4. Pulecio J, Nivet E, Sancho-Martinez I, Vitaloni M, Guenechea G, Xia Y, Kurian L, Dubova I, Bueren J, Laricchia-Robbio L, Izpisua Belmonte JC (2014). Conversion of human fibroblasts into monocyte-like progenitor cells. Stem Cells. 32(11):2923-38
5. Rangaraju S , Solis GM , Thompson RC , Rafael AG , Kurian L, Encalada S , Niculescu AB, Salomon DR (2015). Suppression of Transcriptional Drift Extends C. elegans Lifespan by Postponing the Onset of Mortality. eLife 2015 Dec 1;4:e08833
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Institute for Neurophysiology / RG location - CMMC Building
Principal Investigator - A 07
CMMC - assoc. Junior Research Group 01show more…
Stefan Frank (Post-Doc)
Gaurav Ahuja (Post-Doc)
Deniz Bartsch (Doctoral Student)
Wenjie Yao (Doctoral Student)
Natalia Emilse Vargas Avila (MD Student)
Cristina Stoia (Master Student)
Marie Gramm (Bachelor Student)
Nicole Russ (Technician)