Role of Elk1 in congenital and late onset cardiac disease: at the heart of the matter
- *Australian Regenerative Medicine Institute, Monash University, Melbourne.
- Victor Chang Cardiac Research Institute, Sydney, Australia.
- Department of Physiology, Anatomy and Microbiology, LaTrobe University, Melbourne.
- Garvan Institute of Medical Research, Sydney, Australia.
Elk1 is an ETS Class I, TCF subfamily transcription factor known as a well- established downstream effector of the MAPK pathway and has been implicated in the causation of a variety of cancers. Recent in vitro evidence places Elk1 in the context of the cardiogenic transcription factor network, although its in vivo role in cardiogenesis remains unexplored. We provide the first in vivo evidence of the role of Elk1 in cardiogenesis using a zebrafish mutant with disrupted DNA binding domain (elk1-543/-543) and cardiac defects including valve displacement and elongation with hypertrophic/hyperplastic changes in the ventricular myocardium. elk1-543/-543 are predisposed to early embryonic death, with high incidence of heart looping defects and accelerated growth among survivors. RNA-sequencing (RNA-seq) at larval stage provides insights into the basis of heart defects, indicating up-regulation of MAPK pathway genes and down-regulation of trim63a, encoding a homeostatic protein involved in reducing muscle mass, dys-regulation of which is associated with Hypertrophic Cardiomyopathy (HCM) in humans. MAPK pathway up-regulation is commonly associated with HCM although the fundamental basis of this relationship is not completely understood. We provide mechanistic insight, suggesting MAPK perturbations could converge via the TCFs at a predicted trim63a enhancer, down-regulating trim63a to mediate HCM. Early developmental RNA-seq indicates loss of Elk1 function is associated with down-regulation of tumor suppressor genes. We hypothesize this promotes embryonic survival via non-optimal pathways, and underlies observed defects. The sum of changes in elk1 -543/-543 mimic a group of congenital syndromes known as “RASopathies" in humans. Our data provides important insights into the time line of molecular events underlying RASopathies/MAPK pathway defects and their relationship to molecules imperative in heart patterning and homeostasis.