Growth Factor Signaling-Mediated Control of Enhancer Specification

Abstract

A central challenge in modern developmental biology has been to understand how a single fertilized egg can give rise to a complex multicellular organism, in particular mammals. This process requires the specification of an amazing diversity of cell lineages that arises due to differential gene expression controlled by enhancer elements within the genome. However, it is unclear how extrinsic factors such as direct cell-cell interactions and soluble growth factors collaborate with cell type-specific transcription factors to promote enhancer specification so that the intrinsic process of cell differentiation is orchestrated by signals in the cell's environment. Growth factors activate the Ras/MAPK pathway and induce transcription of early response gene transcription factors (ERG TFs) in multiple cell types, leading to activation of cell type-specific late-response genes (LRGs) that mediate the cell’s response to external stimuli. We find that the ERG TFs AP-1 downstream of Ras/MAPK pathway activation are required to determine which enhancers are chosen in a given cell during development and likely also in cells of the mature organism. AP-1 recruits the SWI/SNF complex to enhancers, thus promoting nucleosome remodeling, and functions synergistically with cell type-specific transcription factors to specify the appropriate enhancers. These findings implicate the SWI/SNF complex as a co-factor for AP-1 during enhancer specification, provide insight into the function of the SWI/SNF complex in cancer and intellectual disability, and describe a fundamental biological mechanism that is central to the differentiation of virtually all mammalian cells.