The epigenetic landscape in osteoarthritis: Exploring key histone modifications using EpiTOF technology and delving into their molecular mechanisms

• Applicant: Dr. Ann-Christine Severmann
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 552274895

Osteoarthritis (OA) is the most common joint disease worldwide. It results in cartilage damage, subchondral bone remodelling, and joint inflammation, leading to pain and reduced mobility. Current therapeutic options only offer symptom relief but there is no curative treatment available, making OA a major medical and societal burden. A major hallmark of OA progression is the degradation of the articular cartilage (AC). It’s only resident cells, the chondrocytes, lose their healthy molecular characteristics, produce a biologically inferior extracellular matrix (ECM) and trigger joint damage. Pathological changes in OA chondrocytes have been reported on mRNA and protein levels, with multiple regulatory networks affected. A plausible common cause for the observed alterations are epigenetic modifications dysregulating the gene expression profile of OA chondrocytes. My project will explore the role of epigenetic mechanisms for OA development and progression, focusing specifically on post-translational histone modifications. In brief, histones are proteins that condense and package DNA. The DNA is wrapped around histone complexes that can be biochemically modified by different enzymes, regulating chromatin accessibility and thus gene expression. Histone modifications control cell identity and competence during embryonic cartilage development but are largely unexplored in AC homeostasis and OA development. Based on data from single-cell RNA sequencing, it has been shown that not all chondrocytes from the AC show the same phenotype, and that the composition of these chondrocyte subtypes is altered in OA. In the proposed project, I will investigate differences in a comprehensive panel of histone modifications between healthy and OA-chondrocytes from human patient samples using Epigenetic landscape profiling using cytometry by Time-Of-Flight (or EpiTOF), an advanced technology for single-cell analysis of protein epitopes. I will examine how histone modifications affect the expression of health and disease markers, chondrocyte identity and their cell function. I propose that a shift in the epigenetic landscape of chondrocytes leads to an altered cell identity and thus to the expression of an ECM unfit for joint cartilage. Targeting epigenetic modifications harbours the potential to restore entire regulatory networks and opens a novel gateway for therapeutic interventions.

• DFG Programme: WBP Fellowship
• International Connection: Belgium, Switzerland
• Hosts: Professor Rik Lories, Ph.D.; Professorin Silvia Monteagudo, Ph.D.; Professorin Dr. Caroline Ospelt