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 module - the Myc 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 protein. Myc family proteins are essential for normal cellular functions but when deregulated are profoundly involved in the genesis of many different types of tumors.
Myc interacts in a specific manner with its dimerization partner, Max, permitting the Myc-Max heterodimer to bind DNA and regulate gene expression. Myc-Max dimers recruit histone acetyltransferases and other factors that mediate increased DNA accessibility in chromatin and act to augment gene expression.
Importantly, Max not only interacts with Myc family proteins but also dimerizes with other bHLHZ class proteins including the Mxd family. Mxd proteins act as transcriptional repressors by interacting with the mSin3-histone deacetylase corepressor complex. This co-repressor complex, which is recruited to specific sites in chromatin through its binding with Mxd:Max heterodimers, causes deacetylation of the N-terminal tails of nucleosomal histones leading to formation of a repressive chromatin structure. Because Mxd proteins are expressed during terminal differentiation of many cell types they provide a link between transcriptional repression, chromatin structure, and terminal differentiation. Evidence indicates that Myc-Max and Mxd-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.
A more extended form of the network has also been uncovered. A Max-like protein known as Mlx dimerizes with a subset of the Mxd proteins as well as two Myc-like proteins: Mondo A and ChREBP. These Mlx:MondoA heterodimers are profoundly involved in transcriptional regulation of cellular metabolism in response to changes in nutrient availability.