Decoding Cancer Through Epigenetics

Why chromatin & epigenetics

“Cancer is a disease of the chromatin, because the genetic contributions to phenotypes are entrusted to the chromatin.”

A human consists of trillions of cells with different functions to form different tissues & organs. While genetic differences account for the phenotypic traits unique to individuals, cells from different tissues & organs isolated from one individual each carry a copy of the same genome, a sequence of 6 billion DNA base pairs. Cells across tissues & organs appear and function very differently from one another because each uses different sections of the 6 billion DNA base pairs they carry.

In cells, DNA is packaged with proteins to form chromatin. Chromatin ranges from being “compacted” to “accessible”, the latter associated with sections of the genome driving cell identity. Tissues & organs develop from gradual changes in chromatin accessibility occurring over different DNA base pairs in a stem cell that differentiates into one of many mature cell types. While some DNA base pairs fall in compacted chromatin, others will lie in accessible chromatin to serve as templates for biological functions. Along the way, changes to chromatin accessibility are bookmarked with hundreds of different chemical modifications, such as DNA methylation. These chemical modifications are commonly referred to as “epigenetic” marks. Different combinations of these epigenetic marks over sections of DNA define epigenetic states. Epigenetic states differ across accessible and compacted chromatin and provide information complementary to DNA sequences. DNA base pairs that transition between chromatin accessibility or epigenetic states over development correspond to chromatin variants. Identifying chromatin variants specific to a cell type can therefore identify the genetic basis of a cell’s phenotype.

Cancer is a disease of the chromatin because it arises when a patient’s normal cell acquires the wrong chromatin variants, such as when a normal cell loses control over which sections of the genome are in accessible versus compacted chromatin. Such chromatin variants can originate from inherited or acquired genetic variants, including risk-associated single nucleotide polymorphism (SNPs) or somatic mutations respectively. They can also originate from environmental stresses, such as metabolic stress. Cancer-specific chromatin variants reveal which misused DNA sequences contribute to oncogenesis. Understanding the nature of DNA sequences found in cancer-specific chromatin variants reveals genetic dependencies to oncogenesis and by extension the Achilles heel of cancer needed to guide precise treatment decisions. This is why our research is focused on chromatin and the epigenetics of cancer.