Roles for MYC in the Establishment and Maintenance of Pluripotency

Abstract

MYC and MYCN have been directly implicated in the transcriptional regulation of several thousand genes in pluripotent stem cells and possibly contribute to the activity of all transcribed genes. Control of transcription by a pause-release mechanism, recruitment of positive and negative epigenetic regulators, and a general role in transcriptional amplification have all been implicated as part of the broad, overarching mechanism by which MYC controls stem cell biology. As would be anticipated from the regulation of so many genes, MYC is involved in a wide range of cellular processes including cell-cycle control, metabolism, signal transduction, self-renewal, maintenance of pluripotency, and control of cell fate decisions. MYC transcription factors also have clear roles in cell reprogramming and establishment of the pluripotent state. The mechanism by which MYC accomplishes this is now being explored and promises to uncover unexpected facets of general MYC regulation that are likely to be applicable to cancer biology. In this work we review our current understanding of how MYC contributes to the maintenance and establishment of pluripotent cells and how it contributes to early embryonic development. W ell before MYC was implicated in the establishment and maintenance of pluripotency, it was known as a potent oncogene with roles in transcriptional regulation of metabolism, differentiation, cell lifespan, cell cycle, and cell size control. These functions are all generally relevant to the maintenance and establishment of pluripotent stem cells. Despite this, however, defining the precise mechanism by which MYC functions has been problematic and has led to much confusion. The following discussion will focus on our current understanding of how MYC functions in early embryonic development, maintenance of stem cell identity, and in somatic cell reprogramming. MYC AND MYCN ARE FUNCTIONALLY REDUNDANT IN EARLY EMBRYONIC DEVELOPMENTThe MYC family of basic helix-loop-helix leucine zipper transcription factors consists of MYC, MYCN, and MYCL. DNA binding of MYC family members usually requires heterodimerization with MAX (Myc-associated factor X) through their respective leucine zipper do-

Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma

“…50 This observation points to other meaningful links between Myc and SUMOylation, where the concordant expression of c-Myc and SUMO regulators in B-cell subsets suggests developmental roles of the Myc-SUMOylation circuit, which could also include roles in stem cells where Myc plays key roles in self renewal. 51,52 While Myc oncoproteins are targets of SUMOylation that bear a highly conserved SUMOylation site, extensive studies of mutant Myc that cannot be SUMOylated did not show any effects on cell growth, cell-cycle control, or apoptosis. 53 We conclude that while Myc drives the hyper-SUMOylation phenotype, and thus facilitates its own SUMO modification in a feedforward loop, the therapeutic outcome of SUMOi is unlikely caused by inhibition of Myc SUMOylation.…”

Origins, genetic landscape, and emerging therapies of small cell lung cancer

“…The exact mechanism of MYC-mediated transformation in SCLC cells is not completely understood. MYC has been implicated in the control of pluripotency, self-renewal, and epithelial-to-mesenchymal transition, processes that are strongly implicated in cellular transformation (Chappell and Dalton 2013). Analysis of mouse models of SCLC with targeted MYC overexpression can help to dissect its function further.…”

Role of MYC in Medulloblastoma

“…The amplification of MYC and MYCN is mutually exclusive with these recurrent mutations in epigenetic regulators raising the possibility that MYC and MYCN amplification could affect epigenetic marks that promote maintenance of the undifferentiated state (Fig. 3A) (see Chappell and Dalton 2013).…”