Abstract A23: Epigenetic Cis-regulatory interactions in HIF1a-activated melanocytes

Abstract

Melanoma tumors are heterogeneous lesions that progress through distinct cellular phenotypes exhibiting either highly proliferative or invasive cell state gene expression signatures (SOX10+ vs. TGFB+ pathways, respectively) as disease progression occurs. It is appreciated that even within a single tumor, individual cells respond to hypoxic conditions through Hypoxia Inducible Factor 1a (HIF1a) activation, leading to gene expression that promotes invasive cell properties. Regulation of gene expression integrates the binding of intrinsic cell lineage factors and general transcription machinery to key cis-regulatory DNA sequences that are epigenetically defined. In order to identify the cis-regulatory sequences that are utilized in a cell's response to HIF1a activation, we have established an integrated regulatory dataset from melan-Ink4a-ARF-/- immortalized mouse melanocytes. This dataset includes Dnase1 HS regions, enhancer regions marked by H3K4me1 and EP300 co-binding, ChIP-Seq for the transcription factors HIF1a and SOX10, and RNA-SEQ datasets under proliferative and HIF1a-activated growth conditions. We are evaluating HIF1a binding regions in order to identify the cis-regulatory sequences utilized to regulate gene expression, identify the key factors engaged at these sites, and assess the role that DNA variation has in modulating factor binding and gene transcription in the switch from proliferative to hypoxic cell signaling conditions. By identifying the epigenetic cis-regulatory interactions that occur as a result of HIF1a activation, we hypothesize that we will highlight pathways important for melanoma progression that may be relevant to future therapeutics. Citation Format: Stacie Loftus, Julie Cronin, Temesgen Fufa, Andrew McCallion, Gregory Crawford, William Pavan. Epigenetic Cis-regulatory interactions in HIF1a-activated melanocytes. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A23.