Emerging Field of Cardiomics: High-Throughput Investigations into Transcriptional Regulation of Cardiovascular Development and Disease

Abstract

Congenital heart defects remain a leading cause of infant mortality in the western world, despite decades of research focusing on cardiovascular development and disease,. With the recent emergence of several high-throughput technologies including RNA sequencing, chromatin immunoprecipitation-coupled sequencing, mass spectrometry-based proteomics analyses, and the numerous variations of these strategies, investigations into cardiac development have been transformed from candidate-based studies into whole-genome, -transcriptome, and -proteome undertakings. In this review, we discuss several reports that have emerged from our lab and others over the last five years that emphasize the versatility of large dataset-based investigations of cardiogenic transcription factors, from phenotypic validations and new gene implications to the identification of novel roles of well-studied transcriptional regulators. Broadening the understanding of cardiac development and diseaseA growing body of work has indicated an association between mutations in several transcription factors (TFs) and congenital heart disease (CHD) (Bruneau, 2013; Prendiville et al., 2014), highlighting the need to elucidate the transcriptional regulation of various aspects of cardiovascular development. High-throughput technologies have dramatically broadened the capacity in which to study regulators of gene networks (see Figure 1 for an overview of the main high-throughput technologies discussed here). High-throughput sequencing of a cell's transcriptional profile (RNA-seq) allows for comparison of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.

CHD4 and the NuRD complex directly control cardiac sarcomere formation

“…To explore the molecular mechanism by which CHD4 functions, we performed transcriptomic analysis (RNA-seq) on E9.5 and E10.5 hearts to reflect states before and at the early stage of the observed cardiac defects in Chd4 null hearts ( 35 ). Comparing transcript abundances in the presence ( Chd4 flox/flox ) or absence ( Chd4 Δ flox/ Δ flox ) of CHD4 revealed 1,285 differentially expressed genes at E9.5 and 1,318 differentially expressed genes at E10.5 [adjusted P value <0.05, log 2 (fold change) ≥ ±0.5] ( SI Appendix , Fig.…”

miRNA‐124‐3p/neuropilin‐1(NRP‐1) axis plays an important role in mediating glioblastoma growth and angiogenesis

“…It is well acknowledged that high‐throughput technology could be used to identify complex molecular processes of diseases. Over the last two decades, many mRNA and miRNA expression studies have been performed by using microarray or high‐throughput sequencing . And the differentially expressed miRNAs were identified by comparing to normal tissues.…”

The contribution of non-coding regulatory elements to cardiovascular disease

“…In this regard, recent work has begun dissecting genome-wide changes in epigenetic marks, transcription factor binding and chromatin accessibility during cardiac development and in response to stress (reviewed in [ 85 ]). Applying functional genomics to null mouse models for the cardiogenic transcription factors NKX2–5 and TBX5, Luna-Zurita et al [ 86 ] documented extensive cooperativity between these transcription factors and GATA4, which could often be explained by specific binding motif arrangements.…”