학술논문
Loss of Rearranged L-Myc Fusion (RLF) results in defects in heart development in the mouse.
Document Type
Academic Journal
Author
Bourke LM; Epigenetics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia; School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4006, Australia.; Del Monte-Nieto G; The Victor Chang Cardiac Research Institute, Sydney, NSW 200, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington 2052, Australia.; Outhwaite JE; School of Biomedical Sciences, Faculty of Medicine and Biomedical Sciences, The University of Queensland, St. Lucia, Queensland 4072, Australia.; Bharti V; Epigenetics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.; Pollock PM; School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4006, Australia.; Simmons DG; School of Biomedical Sciences, Faculty of Medicine and Biomedical Sciences, The University of Queensland, St. Lucia, Queensland 4072, Australia.; Adam A; The Victor Chang Cardiac Research Institute, Sydney, NSW 200, Australia.; Hur SS; The Victor Chang Cardiac Research Institute, Sydney, NSW 200, Australia.; Maghzal GJ; The Victor Chang Cardiac Research Institute, Sydney, NSW 200, Australia.; Whitelaw E; Department of Genetics, La Trobe Institute for Molecular Science, Department of Genetics, La Trobe University, Bundoora, Victoria 3086, Australia.; Stocker R; The Victor Chang Cardiac Research Institute, Sydney, NSW 200, Australia; School of Medical Sciences, University of New South Wales, Kensington 2052, Australia.; Suter CM; The Victor Chang Cardiac Research Institute, Sydney, NSW 200, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington 2052, Australia.; Harvey RP; The Victor Chang Cardiac Research Institute, Sydney, NSW 200, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington 2052, Australia; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington 2052, Australia. Electronic address: r.harvey@victorchang.edu.au.; Harten SK; Epigenetics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. Electronic address: sarah.harten@qimrberghofer.edu.au.
Source
Publisher: Elsevier Country of Publication: England NLM ID: 0401650 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0436 (Electronic) Linking ISSN: 03014681 NLM ISO Abbreviation: Differentiation Subsets: MEDLINE
Subject
Language
English
Abstract
Recently we reported that Rearranged L-Myc Fusion, RLF, acts as an epigenetic modifier maintaining low levels of DNA methylation at CpG island shores and enhancers across the genome. Here we focus on the phenotype of Rlf null mutant mice generated via an ENU mutagenesis screen, to identify genes required for epigenetic regulation. RLF is expressed in a range of fetal mouse tissues, including the fetal heart. Comprehensive timed-mating studies are consistent with our previously reported findings that Rlf homozygous mutant mice rarely survive to adulthood, with the majority dying shortly after birth. Histological analysis of two independent Rlf ENU mutant lines at E11.5-E14.5 showed heart defects resembling those present in humans with Left Ventricular Non-Compaction (LVNC). In situ hybridisation analysis localized expression of Rlf to the endocardium and epicardium of embryonic and postnatal hearts, and transiently to cardiomyocytes during heart looping and early chamber formation stages. RNA-seq analysis of Rlf mutant hearts highlighted defective NOTCH pathway signalling, recently describe as one cause of LVNC. This study provides the first evidence that RLF is required for normal heart development in the mouse. The heart morphological defects present at high penetrance in Rlf mutants are consistent with features of LVNC in humans, and molecular analysis identified attenuated JAGGED 1 expression and NOTCH signalling as likely contributors to these defects. Our study highlights the importance of RLF-dependent epigenetic modifications to DNA for maintaining correct gene regulatory network and intercellular signalling interactions during heart chamber and septal development. Further investigations are needed to define the biochemical role of RLF in the developing heart, and whether RLF mutations are a cause of heart defects in humans.
(Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)
(Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)