Gene regulation is a complex system that must be tightly regulated for cell function and survival. Understanding this regulation is relevant to all cellular processes – to both malignancies and to understanding normal cell function. One part of this complex web are the post-translational modifications present on DNA-interacting proteins, including methylation, acetylation and phosphorylation. The suites of enzymes required to add or subtract these chemical groups, the substrate proteins and those that “read” these signals demonstrate a large amount of this complexity in gene regulation.
BET proteins are notable “readers” of acetylated lysine residues in DNA-interacting proteins. BETs have two bromodomains that provide hydrophobic cavities for acetyl-lysine residues, an extra-terminal domain that is able to signal to other proteins, such as chromatin regulators, and some of this group have C-terminal domains that are able to interact with P-TEFb and RNA polymerase II. As such, BETs are able to transduce the acetylation of these DNA-interacting proteins into changes of gene expression.
Classically, BETs are known for their interactions with acetyl-lysines in histones, but their ability to also recognise acetylation in transcription factors is becoming increasingly appreciated. Transcription factors are proteins that bind specific DNA sequences to either up or down regulate their target genes. It has previously been shown that transcription factor GATA1 can be diacetylated and thus interact with BET protein BRD3, and that RelA, subunit of NF-kB, can be mono-acetylated and interact with BRD4, suggesting multiple mechanisms of recognition by BETs. Previous work in the Mackay lab has shown that isolated bromodomains of BETs can interact with acetylated peptides of transcription factors, E2F1 and MyoD1. This work suggests that there is a wide and complex interaction network between acetylated transcription factors and the BET proteins.
This presentation describes the fundamental work and proposed direction of my PhD project in the Mackay lab, in which I aim to further explore the interaction of BET proteins with acetylated, full-length transcription factors.