MYC and MAX drive the reactivation of the genome after mitosis

Abstract

Shortly after cell division, a robust wave of hyper-transcription reactivates the genome.1-3This phenomenon is particularly pronounced in pluripotent cells,4which necessitate rapid transcriptome reactivation to maintain their undifferentiated state and prevent premature differentiation. While recent work has illuminated how specific groups of genes are reactivated,4-8the mechanisms enabling the global, efficient and accurate post-mitotic reactivation of the genome remain unknown. Here we elucidate the direct involvement of the MYC/MAX transcription factors in the post-mitotic reactivation of pluripotent mouse embryonic stem cells. While MYC undergoes extensive phosphorylation and largely dissociates from its DNA binding sites during mitosis, we report that MAX remains bound to its targets, preferentially at promoters, and facilitates early recruitment of MYC following mitosis. Through the application of MYC/MAX heterodimerization inhibitors, we demonstrate their indispensable role in sustaining hyper-transcription in ES cells, including during the critical transition from mitosis to G1 phase. Our findings uncover a novel role for MAX in mitotic bookmarking, highlighting its pivotal role in post-mitotic MYC recruitment and the re-establishment of high global transcription levels. These findings hold significant implications for medically relevant contexts, particularly when cell proliferation is of paramount importance.9We anticipate that the study of mitotic bookmarking by MYC and MAX and of the effects of anti-cancer drugs targeting MYC/MAX interactions in such process10-12will be relevant for our understanding of cancer and its potential treatments.

A dynamic role for transcription factors in restoring transcription through mitosis

“…This approach has been used to detect site-specific binding of Esrrb, Oct4, Nanog, MYC, and MAX in mitosis. For both Esrrb and MAX, the number of bound sites is reduced in mitosis, representing 29.9% and 11.8%, respectively, of their interphase-bound sites, whereas MYC, Oct4, and Nanog showed near complete loss of binding in mitosis [ 8 , 40 ]. Although dual cross-linking allows the detection of site-specific binding in mitosis by some TFs, it remains to be determined how closely the dual cross-linking represents the native conditions of the mitotic cell.…”

“…For certain TFs, a clear link between mitotic binding and gene reactivation has been established. For instance, MAX binding during mitosis leads to recruitment of MYC immediately following mitosis, allowing for rapid re-expression of target genes [ 40 ], and rapid degradation of Sox2 and Oct4 during mitosis impairs pluripotency maintenance [ 14 , 67 ]. Given that most TFs interact with mitotic chromosomes in a variety of ways, it remains to be seen whether an overarching model for how TFs promote transcriptional memory can be discerned.…”