AP1 Keeps Chromatin Poised for Action
The basal chromatin state is regulated by multiple factors in different cell types. In mammary cells, activator protein 1 (AP1) is a key factor that opens chromatin to direct glucocorticoid receptor binding to select sites upon hormone (dexamethasone – dex) activation. In other cell-types, other factors (Factor X, Y) act to regulate the receptor action to drive gene expression appropriate for that cell.
The human genome harbors gene-encoding DNA, the blueprint for building proteins that regulate cellular function. Embedded across the genome, in non-coding regions, are DNA elements to which regulatory factors bind. The interaction of regulatory factors with DNA at these sites modifies gene expression to modulate cell activity. In cells, DNA exists in a complex with proteins called chromatin that compacts the DNA in the nucleus, strongly restricting access to DNA sequences. As a result, regulatory factors only interact with a small subset of their potential binding elements in a given cell to regulate genes. How factors recognize and select sites in chromatin across the genome is not well understood -- but several discoveries in CCR’s Laboratory of Receptor Biology and Gene Expression (LRBGE) have shed light on the mechanisms that direct factors to DNA.
Recently, Simon Biddie, working on his Ph.D. with Gordon Hager, Ph.D., Chief of the LRBGE, published findings in Molecular Cell showing that regulatory factors bound to DNA direct a steroid-responsive transcription factor, the glucocorticoid receptor (GR), to select sites across the genome. They have identified activator protein 1 (AP1) transcription factor as a major effector of this GR action, which is a key factor involved in inflammation, metabolism, and cancer.
Studying GR interactions with chromatin, Biddie and colleagues mapped receptor interactions with DNA by chromatin immunoprecipitation and with high-throughput sequencing. Using the enzyme DNase1, they identified open chromatin sites and found that the interaction of key transcription factors occurs at these open sites. These localized regions are maintained by the AP1 transcription factor that keeps chromatin poised for action.
Importantly, the CCR scientists showed that the basal state of chromatin is actively maintained by regulatory factors such as AP1. This basal occupation of key transcription factors primes chromatin for the recruitment of other regulatory factors. This discovery is important as chromatin priming by regulatory factors enables the selective binding of receptor to drive appropriate gene expression. The findings indicate that properties that regulate cellular chromatin states can modify receptor action and transcription. Importantly, different factors act to modulate chromatin in different cell types (see Figure), thus conferring a major component of cell selective receptor action. These mechanisms are likely to extend to other nuclear receptors and inducible transcription factors that are often are involved in diseases such as inflammation and cancer.Summary Posted: Fri, 07/01/2011
http://www.sciencedirect.com/science/article/pii/S1097276511004606/ Reviewed by Donna Kerrigan