The epigenome could hold the key to identifying novel biomarkers and drug targets to advance precision medicine. The epigenome comprises a complex molecular code that regulates chromatin structure and function to control gene expression. As such, studying the epigenome could serve as an important molecular tool to help us understand changes in gene expression resulting from genetic variants, the environment, and therapeutics.
To that end, chromatin modifications, including DNA methylation and histone post-translational modifications (PTMs), have provided remarkable insight into gene regulatory programs and are becoming an essential aspect of precision medicine research.
Historically, mapping DNA methylation has been the preferred approach for epigenomic precision medicine research. This established repressive chromatin mark has multiple options for detection: methylation-sensitive PCR & restriction enzymes, antibody-based methods (e.g. MeDIP), or bisulfite conversion followed by sequencing (BS-seq/WGBS) (36,37). The integration of DNA methylation into diagnostics has resulted in exciting advances:
Case Study 5: Classification and treatment selection for central nervous system (CNS) tumors
Many primary CNS tumors are difficult to classify by conventional histological methods (38). For example, CNS neuroectodermal tumors are a broad class histologically characterized by small, poorly differentiated neurons and glia. In one study, the integration of DNA methylation profiling reclassified over 75% of tumors to more specific subtypes such as medulloblastomas, high-grade gliomas, ependymomas, and pineal tumors (39). In other primary CNS tumors, such as glioblastoma, the methylation of select promoters (e.g. MGMT) promotes sensitivity to treatments, such as temozolomide, guiding therapeutic selection (40).
Case Study 6: Non-invasive in vitro diagnostic development
DNA methylation was detected on circulating cell-free nucleosomes in patient plasma/serum in early studies and has been observed in several proof-of-concept clinical studies, such as lung, breast, and colorectal cancers (37,41-43). This paved the way for development of FDA-approved in vitro diagnostic tests from easily obtained samples, such as stool or blood for Cologuard® and Epi proColon®, respectively, as well as several promising liquid biopsy tests, including GRAIL’s Galleri™ to detect cancer regardless of its type (44-46).
However, due to the inability to provide granular details about distinct chromatin compartments, particularly tissue/cell-specific enhancer activity, DNA methylation is not sufficient for some applications. Furthermore, DNA methylation is not always a repressive mark (47), meaning its impact on gene expression can be ambiguous. While DNA methylation has proven that deciphering the epigenome can inform precision medicine approaches, it is only the tip of the iceberg in terms of unraveling epigenomics and gene expression-modifying mechanisms on chromatin.
Histone post-translational modifications
The remarkable chemical and protein diversity on chromatin is brimming with potential precision medicine markers. Specifically, histone PTMs and chromatin-bound proteins (such as transcription factors) exert powerful and dynamic influences on gene expression. To date, over 100 unique histone PTMs or combinations thereof have been linked to human disease, including multiple cancers (48-53), and global alterations to histone PTM patterns have been found to be predictive of disease state, recurrence, and patient response (54-56).
Unlike DNA methylation or even chromatin accessibility assays (e.g. ATAC-seq), histone PTMs provide insight into distinct, specific genomic features. The development of genome-wide chromatin mapping tools helped assign histone PTMs to specific genomic compartments (Figure 2), such as active enhancers (H3K27ac), active promoters (H3K4me3), active gene bodies (H3K36me3), and even repressed genes (H3K9me2/3, H3K27me3). Therefore, studying histone PTMs can illuminate the diversity of the gene regulatory landscape – including what a cell is primed to do. A classic example is the bivalent H3K4me3/H3K27me3 mark, which denotes enhancers and promoters that are “poised” for activation in undifferentiated stem/progenitor cells57. Notably, altered expression of bivalent genes is frequently observed in cancer58, where they can be associated with more severe progression (59) and/or drug resistance (60).