Oral Presentation ANZSCDB National Scientific Meeting 2019

Elk1 in Congential and Late Onset Cardiac Disease: at the Heart of the Matter (67367)

Jeannette JCH Hallab 1 , Gonzalo GDM Del Monte Nieto 2 , Inken IH Huttner 3 , Celine CS Santiago 3 , Akriti AV Varshney 1 , Lee LM Miles 4 , Daniel DH Hesselson 5 , Sebastian SD Dworkin 4 , Kazu KK Kikuchi 3 , Diane DF Fatkin 3 , Richard RPH Harvey 2 , Mirana MR Ramialison 1
  1. Australian Regenerative Medicine Institute, Monash Uni, Clayton, VIC, Australia
  2. Stem Cell and Developmental Biology Division, The Victor Chang Cardiac Research Institute, Sydney, NSW, Australia
  3. The Victor Chang Cardiac Research Institute, Sydney
  4. La Trobe University, Melbourne
  5. The Garvan Insitute for Medical Research, Sydney, NSW

Elk1 is an ETS Class I, TCF subfamily transcription factor known as a well- established downstream effector of the MAPK pathway and 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 congenital defects affecting the Atrio Ventricular Canal (AVC) with variable effects on valve leaflet morphology including elongation, shortening, displacement and thickening, with dysmorphic annuli characteristic of Congenital Heart Disease (CHD). elk1-543/-543 are predisposed to early embryonic death, with high incidence of embryonic heart and growth defects among survivors. RNA-seq at 6dpf 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 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 and has generated fundamental mechanistic insights into the genetic basis of CHD. 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.