Interplay between Transcription Factors and the Epigenome: Insight from the Role of RUNX1 in Leukemia

Abstract

The genome has the ability to respond in a precise and co-ordinated manner to cellular signals. It achieves this through the concerted actions of transcription factors and the chromatin platform, which are targets of the signaling pathways. Our understanding of the molecular mechanisms through which transcription factors and the chromatin landscape each control gene activity has expanded dramatically over recent years, and attention has now turned to understanding the complex, multifaceted interplay between these regulatory layers in normal and disease states. It has become apparent that transcription factors as well as the components and modifiers of the epigenetic machinery are frequent targets of genomic alterations in cancer cells. Through the study of these factors, we can gain unique insight into the dynamic interplay between transcription factors and the epigenome, and how their dysregulation leads to aberrant gene expression programs in cancer. Here, we will highlight how these factors normally co-operate to establish and maintain the transcriptional and epigenetic landscape of cells, and how this is reprogramed in cancer, focusing on the RUNX1 transcription factor and oncogenic derivative RUNX1-ETO in leukemia as paradigms of transcriptional and epigenetic reprograming.

Keywords: RUNX1; cancer; chromatin; epigenetic mechanisms; epigenome.

Figure 1

RUNX1 regulates gene expression at both the transcriptional and epigenetic level. RUNX1 binding to promoters and enhancers is regulated by the chromatin structure encompassing its binding sites (TGTGGNNN, as indicated), with condensed chromatin (nucleosomes, large blue circles) acting as a barrier to RUNX1 binding. DNA methylation (small black circles) may further inhibit RUNX1 binding. RUNX1 binds in a complex with other transcriptional regulators and coactivators/corepressors (represented by purple, red and green circles) at regions of open chromatin (nucleosome-depleted regions), which can impact gene expression through interactions with the transcription machinery or by modifying chromatin structure and composition. At enhancers, RUNX1 binding is accompanied by active histone marks, histone 3 lysine 27 acetylation (27ac), and histone 3 lysine 4 monomethylation (4me1) while at promoters, RUNX1 binding is associated with histone 3 lysine 3 trimethylation (4me3), histone 3 acetylation (of lysine 9 and 14; H3ac), and histone 3 lysine 27 acetylation (27ac). These active gene regulatory elements may interact through DNA loops (purple bidirectional arrow) and are devoid of DNA methylation (small white circles). Arrow, transcriptional start site (TSS).

Figure 2

RUNX1 and RUNX1–ETO regulate gene expression by recruiting transcriptional cofactors and epigenetic modifiers. (A) RUNX1 can act as a transcriptional activator or repressor dependent on the balance of coactivators/corepressors associated with it at a particular time. RUNX1 can recruit coactivators [for example, p300 histone acetyltransferase (p300) and protein arginine methyltransferase (PRMT1)] and epigenetic modifiers, which enhance RUNX1 activity through post-translational modification (shown as acetylation (ac) and methylation (me) of the RUNX1 protein) and impart activating modifications to chromatin [for example, histone 3 acetylation of lysine 9 and 14 (H3ac)]. RUNX1 can also recruit corepressors and epigenetic modifiers [for example, PRMT6 and PRMT4 as well as histone deacetylases (HDAC)], which inhibit RUNX1 activity through post-translational modification (removal of acetylation marks from RUNX1 and chromatin) and establish repressive chromatin modifications (for example, histone 3 lysine 27 trimethylation, 27me3). Various continuums of the two extremes that are shown no doubt exist. (B) RUNX1–ETO binds to RUNX1 target genes and primarily acts as a transcriptional repressor through the assembly of repressive transcriptional and epigenetic complexes. While many of the molecules that associate with RUNX1–ETO are shown [for example, DNA methyltranferases (DNMT), nuclear receptor corepressor (NCoR), mSin3A corepressor complex (mSin3a), p300, and HDAC], they do not necessarily all complex with RUNX1–ETO at a given time. In keeping with the primarily repressive function of RUNX1–ETO, its binding is generally associated with repressive histone modifications (for example, histone 3 lysine 27 trimethylation (27me3) and histone 3 lysine 9 trimethylation (9me3).