Precise dynamic control of the polycomb-trithorax axis is crucial for normal development and cellular differentiation. The fundamental importance of this regulation is highlighted by the remarkably high frequency with which polycomb and trithorax proteins are mutated or dysregulated in cancer. Critical genes primed for tissue specific expression may be marked concurrently by activating H3K4me3 and repressive H3K27me3 histone modifications, termed ‘bivalent’. These bivalent chromatin domains maintain genes in a transcriptionally inert but poised state, enabling rapid transcriptional activation or progression to stable repression. Understanding the key mechanisms and critical cellular components that regulate maintenance of bivalency is of great importance in order to provide insight into how these processes become corrupted in cancer.
By coupling a cell surface readout of bivalent gene expression with whole genome CRISPR/Cas9 screens we have identified specific roles for components of the PRC2.1 and PRC1.1 polycomb complexes, along with Menin containing MLL1/2-COMPASS-like complex components, in maintaining bivalency. Unexpectedly, genetic loss or pharmacological inhibition of Menin phenocopies the effects of impaired polycomb, resulting in derepression of bivalent genes in both cancer cells and human pluripotent and embryonic stem cells. This is in contrast to the current paradigm whereby disruption of COMPASS and polycomb complexes is expected to have opposing effects on bivalent gene regulation. I will discuss our ongoing work, which has identified an essential Menin-independent role of MLL1/2 in bivalent gene activation and revealed how specific transcription factors can overcome this dependence. Functionally, combined pharmacological inhibition of Menin-MLL and Polycomb potentiates derepression of key bivalent genes to augment tumour cell killing and anti-tumour immune responses.
Our findings provide new insights into the regulation of bivalency and reveal a functional partitioning of COMPASS complex components, yielding novel therapeutic opportunities that can be leveraged through the inhibition of Menin.