Sequential Binding of MEIS1 and NKX2-5 on the Popdc2 Gene: A Mechanism for Spatiotemporal Regulation of Enhancers during Cardiogenesis.

Laurent Dupays,Sophie Wood,Surendra Kotecha,Robert Wilson,Timothy Mohun,Catherine Shang,Norma Towers

doi:10.1016/j.celrep.2015.08.065

Abstract

SummaryThe homeobox transcription factors NKX2-5 and MEIS1 are essential for vertebrate heart development and normal physiology of the adult heart. We show that, during cardiac differentiation, the two transcription factors have partially overlapping expression patterns, with the result that as cardiac progenitors from the anterior heart field differentiate and migrate into the cardiac outflow tract, they sequentially experience high levels of MEIS1 and then increasing levels of NKX2-5. Using the Popdc2 gene as an example, we also show that a significant proportion of target genes for NKX2-5 contain a binding motif recognized by NKX2-5, which overlaps with a binding site for MEIS1. Binding of the two factors to such overlapping sites is mutually exclusive, and this provides a simple regulatory mechanism for spatial and temporal synchronization of a common pool of targets between NKX2-5 and MEIS1.

Highlights

Congenital heart disease affects up to 1% of all live births in the west and constitutes a major public health burden (Hoffman and Kaplan, 2002)
chromatin immunoprecipitation (ChIP)-Seq Analysis in the Embryonic Heart Identifies Putative Direct Targets of NKX2-5 with a Critical Role in Heart Structure and Function We performed ChIP with embryonic day (E)11.5 mouse embryo hearts using an NKX2-5 antibody followed by massive, parallel sequencing (ChIP-seq) to identify 2,610 regions enriched for that factor (Data S1)
Bioinformatic analysis identified 3,313 genes flanking the NKX2-5-binding loci, and we performed a computational analysis for enrichment of gene ontology (GO) terms associated with those genes

Summary

Introduction

Congenital heart disease affects up to 1% of all live births in the west and constitutes a major public health burden (Hoffman and Kaplan, 2002). Numerous transcription factors have been shown to play a decisive role in vertebrate heart formation (reviewed in Bruneau, 2008). Identifying the targets of these factors and their regulatory interactions will be a major step toward understanding the broader cardiac developmental program. NKX2-5 is one of the earliest transcription factors expressed in the cardiac lineage, and genetic studies have demonstrated that, from flies to man, the protein has an essential function in heart development (Biben et al, 2000; Tanaka et al, 1999). Mutations in the NKX2-5 gene cause congenital heart disease; haploinsufficiency results in a spectrum of congenital heart disease of varying phenotypic penetrance, which is mirrored in mouse models (reviewed in Akazawa and Komuro, 2005)

Results

Discussion

Conclusion