Transcriptional Regulation of RUNX1: An Informatics Analysis.

Amarni L Thomas,William Schierding,Justin M O'Sullivan,Jisha Antony,Julia A Horsfield,Judith Marsman

doi:10.3390/genes12081175

Abstract

The RUNX1/AML1 gene encodes a developmental transcription factor that is an important regulator of haematopoiesis in vertebrates. Genetic disruptions to the RUNX1 gene are frequently associated with acute myeloid leukaemia. Gene regulatory elements (REs), such as enhancers located in non-coding DNA, are likely to be important for Runx1 transcription. Non-coding elements that modulate Runx1 expression have been investigated over several decades, but how and when these REs function remains poorly understood. Here we used bioinformatic methods and functional data to characterise the regulatory landscape of vertebrate Runx1. We identified REs that are conserved between human and mouse, many of which produce enhancer RNAs in diverse tissues. Genome-wide association studies detected single nucleotide polymorphisms in REs, some of which correlate with gene expression quantitative trait loci in tissues in which the RE is active. Our analyses also suggest that REs can be variant in haematological malignancies. In summary, our analysis identifies features of the RUNX1 regulatory landscape that are likely to be important for the regulation of this gene in normal and malignant haematopoiesis.

Highlights

Accurate spatiotemporal and quantitative gene expression is crucial for normal development and, in many cases, is achieved by the interaction of promoters with cis-regulatory elements (REs)
Several studies have focused on a strong Runx1 enhancer in mice: Runx1 +23/+24/eR1/RE1 [19,20,21]
The inconsistency of enhancer naming between groups is because Ng et al (2010) uses the transcriptional start site (TSS), +1 as the reference point [21], whilst the other groups refer to this enhancer being 23.5 kb downstream from the ATG of exon 1. +23/+24 is referred to as eR1, and RE1

Summary

Introduction

Accurate spatiotemporal and quantitative gene expression is crucial for normal development and, in many cases, is achieved by the interaction of promoters with cis-regulatory elements (REs). REs, such as enhancers, are able to control the expression of genes by long-range chromatin interactions [1,2]. Clusters of conserved REs surround some highly conserved developmental genes. REs often regulate the closest gene, they can control expression of genes further afield [6,7,8]. Long-range chromatin interactions between promoters and REs can be mediated by scaffolding proteins and transcription factors (TFs) to regulate gene expression [10]. These factors include those responsible for the three-dimensional organisation of chromatin, such as cohesin and CTCF [10,11]

Methods

Results

Discussion

Conclusion