Epigenetic mechanisms and target discovery in bone and mesenchymal oncology

Background

Epigenetics was initially broadly defined as the ‘causal mechanisms’ that link the genetic information of an organism and how it interacts with the environment in order to produce observable traits. Underlying this early concept is the discovery that posttranslational modifications of histone proteins and DNA bases modify the accessibility of chromatin and alter gene transcription by allowing transcription and accessory factors to bind at promoter sites thus initiating transcription. The dynamic nature of these modifications means that these changes are not always stable, and they can be altered in response to stimuli. Moreover, the sequence and modification-specific context of chromatin modifications, and the particular composition and recognition potential of regulatory factors led to the hypothesis of a “histone code” that controls specific DNA-templated systems such as gene transcription, genome stability, imprinting and X-chromosome inactivation. Since epigenetic modifications are less stable than genome sequences, these processes are subject to variable responses and hence can lead to altered development and disease. Epigenetics and the study of chromatin modifications has gained increased interest because it has been realised that epigenetic modifications may give a mechanistic insight into disease biology and allow development of novel treatment concepts.

Objectives

Our aims are to identify and validate possible new targets in oncology by using chemical biology (e.g. focused tool compound libraries targeting proteins involved in epigenetics) and moleculargenetic approaches (shRNA, locked nucleic acid, CRISPR-CAS9). We employ single cell technologies (mass cytometry, drop-seq) and NGS techniques (CHIPseq, ATACseq, RNAseq) to understand epigenetic mechanisms of drug targets, clonal structures in tumours and development of drug resistance.

In collaboration with clinical and pre-clinical scientists we study several malignant diseases such as hematological disorders (such as multiple myeloma), sarcomas (liposarcoma, Ewings sarcoma, chordoma) and other solid tumours (glioblastoma, olfactory neuroblastoma).