Prof. Dr. Leonie Helen Ringrose

Prof. Ringrose erforscht die epigenetische Genregulation durch Polycomb- und Trithorax-Proteinkomplexe, die Genexpression über viele Zellgenerationen stabil aufrechterhalten. Sie untersucht, wie diese Proteine spezifische DNA-Elemente (PRE/TREs) erkennen und wie nicht-kodierende RNAs sowie alternative DNA-Strukturen (Z-DNA) als epigenetische Gedächtnis-Träger fungieren. Ihr aktueller Fokus liegt auf der mathematischen Modellierung epigenetischer Prozesse — sie leitet das europäische Netzwerk PEP-NET, das theoretische und experimentelle Epigenetik verbindet. Für Industrie und öffentliche Hand relevant: Besseres Verständnis von Genregulation ermöglicht präzisere Ansätze in der Biotechnologie, Zelltherapie und möglicherweise der Krebsforschung.

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• Dynamik der Zellschicksalsentscheidungen nach Brustkrebs-Strahlentherapie

  Quelle ↗

  Most breast cancer patients receive adjuvant radiation therapy. Despite its success, still many patients gain little or no benefit from this treatment, as evidenced from the elevated rates of recurrence, distant metastatic spread, and breast cancer deaths. Currently there are no robust biomarkers to predict the outcome of radiotherapy. Variability in response to radiation might be due to the heterogeneity of breast cancers cells; cells show wide ranges of radioresistance and capability to adapt to changing environments. Our ultimate aim is to develop tumor subtype-specific radiation strategies that maximize the damage in cancerous cells while minimizing the damage to normal cells. Recent studies have shown that radiotherapy is particularly effective for classical breast cancers subtypes luminal A and HER2. This suggests a potential connection between breast cancer subtype and radio-sensitivity. We will study how single genetic modifications frequently found in breast cancer subtypes determine changes in the cellular fate. Current therapies only use three classical markers to distinguish tumor subtypes, and follow a standardized protocol of daily radiation doses, given over 5 to 6 weeks. Upon DNA damage cells initiate diverse cellular programs ranging from DNA repair and transient cell cycle arrest to terminal fates such as cell death and senescence. The connection between breast cancer subtypes, with their associated genetic portraits, to each of these alternative cellular outcomes remains largely unknown. In addition, the optimal radiation frequency for destroying various breast cancer subtypes has never been explored experimentally. In Aim 1 we will combine experimental approach at the single-cell level together with computational tools to quantitatively investigate the temporal response and fate of a collection of cells upon different frequencies of radiation. We will study the response of a collection of cells carrying single somatic modifications frequently found in breast cancer. In our second aim we will determine how cycling cell-intrinsic factors affect cellular outcomes. We will track internal cellular states of a subset of lines selected from Aim 1, and follow their dynamics in response to radiation with the goal of determining why different cells carrying different modifications show different outcomes in response to a similar treatment. This will help to identify the optimal cellular state for treatment. In Aim 3 we will use a mouse xenograft model to validate the optimal frequency and initial cellular state for destroying breast tumors in-vivo. We will implement computational tools for automatized single-cell tracking, statistical analysis of the single-cell data, and develop simple mathematical models to correlate cellular states with cell-fate in response to various radiation frequencies. This interdisciplinary study will identify optimal timings for radiation tailored to specific mutations frequently found in breast cancer.

• The quest for mammalian Polycomb response elements: are we there yet?

  2015

  Chromosoma · DOI

  A long-standing mystery in the field of Polycomb and Trithorax regulation is how these proteins, which are highly conserved between flies and mammals, can regulate several hundred equally highly conserved target genes, but recognise these targets via cis-regulatory elements that appear to show no conservation in their DNA sequence. These elements, termed Polycomb/Trithorax response elements (PRE/TREs or PREs), are relatively well characterised in flies, but their mammalian counterparts have proved to be extremely difficult to identify. Recent progress in this endeavour has generated a wealth of data and raised several intriguing questions. Here, we ask why and to what extent mammalian PREs are so different to those of the fly. We review recent advances, evaluate current models and identify open questions in the quest for mammalian PREs.

• Theoretical analysis of Polycomb-Trithorax systems predicts that poised chromatin is bistable and not bivalent

  2019

  Nature Communications · DOI

  Polycomb (PcG) and Trithorax (TrxG) group proteins give stable epigenetic memory of silent and active gene expression states, but also allow poised states in pluripotent cells. Here we systematically address the relationship between poised, active and silent chromatin, by integrating 73 publications on PcG/TrxG biochemistry into a mathematical model comprising 144 nucleosome modification states and 8 enzymatic reactions. Our model predicts that poised chromatin is bistable and not bivalent. Bivalent chromatin, containing opposing active and silent modifications, is present as an unstable background population in all system states, and different subtypes co-occur with active and silent chromatin. In contrast, bistability, in which the system switches frequently between stable active and silent states, occurs under a wide range of conditions at the transition between monostable active and silent system states. By proposing that bistability and not bivalency is associated with poised chromatin, this work has implications for understanding the molecular nature of pluripotency.