Functionally Characterizing the Enhancer Cistrome in Advanced Human Kidney Cancer
Abstract
The study of epigenetics addresses the following question: If all of the cells in an individual carry roughly the same DNA sequence, how is it that a cell from one part of the body, say a skin cell, looks different and performs functions distinct from another cell, such as a liver cell? Epigenetics, which literally means on top of genetics, refers to the machinery that determines which genes are turned on or off. This gene regulation is not due to alterations in the underlying DNA sequence. The estimated 200 different cell types that exist in a human being can be distinguished by the repertoire of genes that are expressed in a given cell type; in the example above, a skin cell expresses a different set of genes than a liver cell, due in large part to the difference in epigenetic programs. The mechanism by which genes are turned on is driven by proteins called transcription factors (TFs) binding to certain locations in the human genome called regulatory elements. TFs recognize and bind to specific regulatory elements (i.e., stretches of specific DNA sequences) and this interaction can result in a gene being turned on. These regulatory elements are proving to be important in cancer biology. Regulatory elements are located throughout the 98% of the human genome that does not code for genes. Due to the lack of tools available for studying the noncoding region, until recently it was difficult to identify, to functionally characterize, and to therapeutically target these non-genic genomic regions. Advances from our (and other) laboratories, however, are enabling the systematic identification and testing of relevant regulatory elements as well as the ability to target their associated TFs, which were once considered undruggable. The ultimate goals of our proposal are to identify and characterize critical regulatory elements that contribute to advanced kidney cancer. Aim 1 will utilize a method called chromatin immunoprecipitation followed by sequencing (ChIP-seq) in clinically relevant patient samples to characterize the regulatory landscape during progression to metastatic disease. We will also use a novel technique called HiChIP to create a 3D model of the kidney cancer genome to determine which regions communicate with each other. Gene regulation often occurs when distal enhancers come into contact with target genes in 3D space. Finally, using an innovative technology termed genome editing, Aim 2 will identify candidate regulatory elements that are functionally relevant for mediating resistance to therapy. We have assembled a team with the appropriate expertise necessary to complete this work. By focusing on epigenetics and the non-coding portions of the genome, our proposal takes a decidedly innovative approach to identifying functionally important gene regulatory elements. These regions have been understudied compared with the protein coding genome. We have designed our proposal to benefit patients with advanced kidney cancer. The study will open new areas for drug target discovery. We believe that our approach paves the way for systematically studying cancer and identifying targets through an epigenetic perspective.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910554
Entities
People
- Mark Pomerantz
Organizations
- Dana–Farber Cancer Institute
- United States Army