Title: Genome-wide Computational Analysis Reveals Cardiomyocyte-specific Transcriptional Cis-regulatory Motifs That Enable Efficient Cardiac Gene Therapy
Authors: Rincon, Melvin Y ×
Sarcar, Shilpita
Danso-Abeam, Dina
Keyaerts, Marleen
Matrai, Janka
Samara-Kuko, Ermira
Acosta-Sanchez, Abel
Athanasopoulos, Takis
Dickson, George
Lahoutte, Tony
De Bleser, Pieter
Vandendriessche, Thierry
Chuah, Marinee #
Issue Date: Jan-2015
Publisher: Academic Press
Series Title: Molecular Therapy vol:23 issue:1 pages:43-52
Article number: 10.1038/mt.2014.178
Abstract: Gene therapy is a promising emerging therapeutic modality for the treatment of cardiovascular diseases and hereditary diseases that afflict the heart. Hence, there is a need to develop robust cardiac-specific expression modules that allow for stable expression of the gene of interest in cardiomyocytes. We therefore explored a new approach based on a genome-wide bioinformatics strategy that revealed novel cardiac-specific cis-acting regulatory modules (CS-CRMs). These transcriptional modules contained evolutionary-conserved clusters of putative transcription factor binding sites that correspond to a "molecular signature" associated with robust gene expression in the heart. We then validated these CS-CRMs in vivo using an adeno-associated viral vector serotype 9 that drives a reporter gene from a quintessential cardiac-specific α-myosin heavy chain promoter. Most de novo designed CS-CRMs resulted in a >10-fold increase in cardiac gene expression. The most robust CRMs enhanced cardiac-specific transcription 70- to 100-fold. Expression was sustained and restricted to cardiomyocytes. We then combined the most potent CS-CRM4 with a synthetic heart and muscle-specific promoter (SPc5-12) and obtained a significant 20-fold increase in cardiac gene expression compared to the cytomegalovirus promoter. This study underscores the potential of rational vector design to improve the robustness of cardiac gene therapy.
ISSN: 1525-0016
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular and Vascular Biology
× corresponding author
# (joint) last author

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