In a landmark study published in Nature, researchers have constructed a comprehensive “pan-cancer” atlas of single nucleus ATAC-seq and RNA-seq datasets to delineate mechanistic insights into the interplay between epigenetic alterations and gene regulation across 11 diverse cancer types. This groundbreaking work sheds light on the pivotal role of epigenetic drivers in orchestrating tumor initiation, progression, and metastasis, paving the way for novel therapeutic strategies and personalized medicine approaches.
The epigenetic drivers of cancer
The term “epigenetics” was first coined in 1942 by Waddington to describe alterations in an organism’s phenotype that occur independently of changes in the DNA sequence. Epigenetics gained significance following the discovery of the histone code, which, along with DNA methylation, regulates gene expression by modifying chromatin structure. Chromatin, composed of DNA, proteins, and RNA, serves to compact genetic material, prevent DNA damage, and regulate gene expression and replication. Histones, which are the primary protein components of chromatin, aid in DNA compaction through interactions between their positively charged tails and the negatively charged DNA backbone. DNA methylation, which is a chemical modification of cytosine nucleotides that has been traditionally thought to repress gene transcription, is now recognized to play a broader role in modulating gene expression patterns, impacting various cellular processes such as signaling cascades and cellular reprogramming. Technological advancements in next-generation sequencing and biochemical techniques like chromatin immunoprecipitation (ChIP-seq), assay of transpose accessible chromatin (ATAC-seq) and bisulfite (BS-seq) sequencing have enabled high-resolution analysis of the epigenome, facilitating epigenetic profiling in both normal and abnormal cells or tissues, such as tumors. Interestingly, although the genetic components of oncogenesis have been thoroughly investigated, the epigenetic drivers are unclear.
In a recent Nature publication, Terekhanova et al. (2024) employ single-nucleus chromatin accessibility profiling (snATAC-seq) and RNA sequencing (snRNA-seq) to map the dynamic interplay between chromatin landscapes and transcriptional machinery across various cancer stages.
Understanding the interplay between epigenetics and gene expression during cancer progression
The interplay between chromatin accessibility, gene regulation, and cellular identity is critical to tumorigenesis. Alterations in chromatin accessibility have been implicated in driving cancer initiation, progression, and metastasis. In this study, Terekhanova et al. (2024) constructed a comprehensive pan-cancer epigenetic and transcriptomic atlas using single cell chromatin accessibility data obtained through the snATAC-seq. In snATAC-seq, individual cell nuclei are isolated from a heterogeneous sample followed by tagmentation using the Tn5 transposase enzyme, which selectively binds to regions of open chromatin and inserts sequencing adapters into these accessible regions. This results in the fragmentation of chromatin and the tagging of accessible regions for downstream high throughput sequencing. The dataset comprised 225 samples, with matched snRNA-seq data from 206 samples. Analyzing over 1 million cells from each platform, the study enriched accessible chromatin regions, transcription factor motifs, and regulons to identify epigenetic drivers associated with cancer transitions.
The study identified a spectrum of epigenetic drivers, with some appearing across multiple cancers, such as regulatory regions of ABCC1 and the FOX-family of motifs. Others were specific to certain cancers, such as regulatory regions of FGF19, and the PBX3 motif. Among the pathways influenced by epigenetic alterations, TP53, hypoxia, and TNF signaling were linked to cancer initiation, while estrogen response, epithelial–mesenchymal transition (EMT), and apical junction pathways were associated with metastatic transition. Additionally, the study uncovered a significant correlation between enhancer accessibility and gene expression and identified cooperation between epigenetic and genetic drivers.
To further the exploration of epigenetic drivers of cancer, the authors developed an elegant integrated multi-omic single cell atlas consisting of snRNA-seq and matching snATAC-seq datasets. The extensive sample size and diverse representation of cancer types and stages provides a robust cohort for examining the interplay between chromatin accessibility, gene expression, and cancer progression. By deciphering the epigenetic landscape underlying oncogenic transitions, researchers aim to pave the way for the development of targeted therapeutic strategies tailored to combat multiple stages of cancer progression.
Implications for the Pharmaceutical industry
This study offers a significant opportunity for the pharmaceutical industry to investigate new therapeutic venues. An understanding of epigenetic drivers across various cancer types and stages provides an opportunity for the discovery of novel biomarkers for early cancer detection and therapeutic targets. Moreover, the identification of epigenetic signatures indicative of patient response to existing therapies holds immense potential for personalized medicine. By stratifying patients based on their epigenetic profiles, clinicians can optimize treatment strategies, ensuring that individuals receive therapies that are likely to benefit them. This predictive biomarker approach not only enhances treatment outcomes but also minimizes adverse effects, thereby increasing patient well-being and therapeutic success. Additionally, the comprehensive single cell atlas serves as a valuable resource for drug discovery endeavors. By pinpointing novel drug targets and validating potential therapeutic candidates, this resource accelerates the drug development process, expediting the translation of scientific insights into effective cancer treatments.
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Haider M. Hassan, Data Scientist, Bridge Informatics
Haider is one of our premier data scientists. He provides bioinformatic services to clients, including high throughput sequencing, data pre-processing, analysis, and custom pipeline development. Drawing on his rich experience with a variety of high-throughput sequencing technologies, Haider analyzes transcriptional (spatial and single-cell), epigenetic, and genetic landscapes.
Before joining Bridge Informatics, Haider was a Postdoctoral Associate at the London Regional Cancer Centre in Ontario, Canada. During his postdoc, he investigated the epigenetics of late-onset liver cancer using murine and human models. Haider holds a Ph.D. in biochemistry from Western University, where he studied the molecular mechanisms behind oncogenesis. Haider still lives in Ontario and enjoys spending his spare time visiting local parks. If you’re interested in reaching out, please email [email protected] or [email protected]