Associated Principal Investigator, ZMMK
Epigenetic alterations and genome instability are hallmarks of aging and cancer but their molecular interdependency remains largely unknown. For example, gene activity and their regulation change with age, however, underlying relationships with epigenome structural alterations and genome instability, and their impact on ageing and related disease development remain to be determined.
Our research: Dr. Robert Hänsel-Hertsch and his team explores the existence and significance of age-related epigenome structural alterations and its impact on genome instability and disease development. Hence, the structure of the genome may significantly change with age and predispose mammals to disease development, such as cancer or degenerative diseases. Additionally, we are exploring whether defined age- or cancer-related epigenome structural and stability alterations are of diagnostic and therapeutic value.
Our goals: Our lab aims to address four conceptual questions:
Our successes: 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 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 (Fig. 1). 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 (Fig. 1). 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 (Fig. 1). 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 methods/techniques: Massive parallel sequencing, ChIP-seq, DSBCapture, functional genomics, microscopy, stem cell culture, mouse models, tissue culture, molecular biology, biochemistry, cell biology.
Figure 1: G-quadruplex (G4) DNA secondary structures mark highly expressed and amplified oncogene promoter DNA regions that are hotspots of endogenous double-stand break formation and transcription factor occupancy. G4s are prevalent in nucleosome-depleted regions (NDRs).