Principal Investigator
Epigenetic alterations and genome instability are hallmarks of aging and cancer. Our lab explores the existence and significance of age and cancer-related epigenome structural alterations and its interconnection with genome instability.
The genomic structure may significantly change with age, which for mammals may create a predisposition to disease development. We discovered substantial guanine quadruplex DNA secondary structure (G4) formation in regulatory regions of cancer genomes, marking amplified genes that are also highly expressed. We are now addressing the physiological causes and consequences of G4-linked genome instability, as well as its diagnostic and therapeutic potential.
Never stop questioning – Albert Einstein
Our lab aims to address four conceptual questions:
DNA and its role in genome biology has long been recognized as double-helical B-DNA structure, encoding the genetic information. However, other DNA structure function relationships may exist beyond coding and the double-helix. Dr. Robert Hänsel-Hertsch and co-workers discovered stable guanine-based G-quadruplex (G4) DNA secondary structure formation in the nucleus of living cells using in-cell NMR spectroscopy. Intrigued by the potential relevance for genome biology, they revealed the first maps of DNA G-quadruplex secondary structures in in situ preserved chromatin by developing a massive parallel sequencing technology. Their key findings established G4 enrichment in active promoters linked with elevated transcription and a rational to diagnose and target cancer cells with prevalent endogenous G4 DNA structure formation (see figure). G4s have been connected with genome instability since the absence or removal of G4-resolving helicases leads to mutations in genomic regions enriched for G4-motifs. Importantly, small molecule mediated stabilization of endogenous G4s results in DNA double-strand breakage (DSB), suggesting a direct link between G4s and DSBs.
By developing and applying an enhanced massive parallel sequencing technology to map endogenous DSBs, Dr. Robert Hänsel-Hertsch and co-workers revealed an association between transcription-dependent DSBs and G4 structure formation (see figure). Cancer in comparison to physiological genomes adopt substantially more DNA G4s, but the locations of these structures and their relationship to cancer biology have remained elusive. To address these questions, Dr. Robert Hänsel-Hertsch and colleagues recently developed a quantitative massive parallel sequencing technology that detected differentially enriched G4 DNA-structural regions (∆G4Rs) in in situ preserved chromatin from 22 breast cancer patient-derived tumour xenograft models. This very recent study showed that ∆G4Rs report on the genomic, transcriptomic, and regulatory architecture of cancer tissue states (see figure). Dr. Robert Hänsel-Hertsch and colleagues further uncovered increased breast cancer heterogeneity and prevalent association between promoters of gene drivers of triple-negative breast cancer and ∆G4Rs.
Our lab aims to address conceptual questions: are epigenome structural alterations passengers or drivers of mammalian aging and disease? Are defined epigenome states of diagnostic and therapeutic value?
1. Existence of epigenome structural alterations that promote genomic instability during normal and rapid tissue aging. We are investigating age-related epigenome alterations in tissues of different but closely-related rodents, extremely long-lived rodents and human stem-cell models.
2. Epigenome structural alterations predisposing to cancer development and/or drug resistance. Precision medicine aims to characterise tumour heterogeneity and identify cancer-specific molecular vulnerabilities. Our lab aims to uncover epigenome alterations that critically drive cancer and resistance mechanisms using quantitative bulk and single-cell genomics to better stratify patients, reflecting on personalised genome architecture, transcription factor regulation and activity, as well as cancer subtypes suitable for drug treatment.
Principal Investigator