The Eisenman laboratory is interested in how cell proliferation, growth, and differentiation are regulated through the actions of transcriptional networks, and how this regulation is subverted during tumor progression. The laboratory employs the tools of molecular biology as well as mammalian and Drosophila genetics to study basic mechanisms underlying normal and neoplastic cellular functions.

We have focused on a transcription factor network - the Max network- whose interacting components together comprise a transcriptional switching system that has been highly conserved throughout evolution. One of the components of the network is the Myc oncoprotein, the product of an oncogene profoundly involved in the genesis of many different tumors, but also normally involved in cell proliferation, differentiation, and death. Myc interacts in a specific manner with its dimerization partner, Max, permitting the Myc-Max heterodimer to bind DNA and regulate gene expression.

Importantly, Max not only interacts with Myc family proteins but also dimerizes with other bHLHZ proteins including the Mxd (formerly known as Mad) family, Mnt, and Mga.  These proteins act as transcriptional repressors. Mad and Mnt proteins repress by interacting with the mSin3-histone deacetylase corepressor complex. This co-repressor complex, which is brought to specific sites in chromatin through its binding with Mxd:Max heterodimers, causes deacetylation of the N-terminal tails of nucleosomal histones. This in turn is believed to lead to formation of a repressive chromatin structure. Because Mxd proteins are expressed during terminal differentiation of many cell types the Mad proteins provide a link between transcriptional repression, chromatin structure, and terminal differentiation. Recent evidence suggests that Myc-Max and Mxd-Max as well as Mnt-Max dimers bind a common set of target genes suggesting that the balance between the activating factors and the repressing factors is likely to control major aspects of cell behavior through modification of chromatin structure. We have called this interacting group of transcription factors the Max network.

Our current work involves investigating three broad aspects of the Max network. First we are studying the role of the component proteins in development and in cancer by creating transgenic overexpressing mice as well as targeted deletions of different Myc and Mad family genes. Second we are using the mouse models to probe the molecular mechanisms underlying Max network functions and to identify genes regulated by the network. Third, because we have identified all the Max network proteins in Drosophila we are employing the powerful tools of fruit fly genetics to identify genes that are regulated by the network as well as to analyze the effects of loss of function mutations on embryonic development. We have demonstrated that Myc in both mammalian and Drosophila cells regulates cell growth (i.e. increase in cell mass) through its ability to bind to a large number of target genes and to induce a widespread changes in histone modifications. Indeed Myc regulates gene expression mediated by all three RNA polymerases. A major focus has been on understanding the biological roles of Max network proteins and to link their physiological effects to the nature and number of their genomic binding sites and gene targets. This work has lead to the notion that Myc/Max/Mad binding is widespread and is likely to have a broad influence on chromatin structure.

Another major research focus in the laboratory involves gaining a deeper understanding of the mechanisms through which Myc/Max/Mxd proteins influence cell differentiation and the induction of pluripotency. We have been examining two mechanisms through which Myc influences differentiation pathways. First, the regulation by c-Myc of a specific set of microRNAs that attenuate differentiation in murine embryonic stem cells and may therefore be involved in maintenance of stem cell self-renewal and pluripotency. Second, the identification of a cytoplasmic form of Myc protein that modifies tubulin and facilitates differentiation. In addition, the lab is conducting screens for genes that modulate Myc’s ability to suppress differentiation in mammalian cells as well as for novel genes that influence the balance between cell division and differentiation in the Drosophila brain. Finally,  several projects in the lab are directed towards understanding the regulation of Myc protein degradation in both Drosophila and mammalian systems.