Independent Junior Research Group Andergassen
 

Website: www.andergassen.com(link is external)

Decoding the non-coding genome, one allele at a time

A large fraction of disease-associated genetic variants lie in non-coding regions of the genome, previously considered "junk" DNA but now recognized as important regulators of gene expression (Andergassen & Rinn et al., Nat Rev Genet, 2022). Our lab investigates how non-coding RNAs (ncRNAs) influence neighboring protein-coding genes and contribute to complex traits and diseases (Hasenbein*, Hölzl* et al., Nature Communications, 2024). We developed Allelome.LINK, a framework that uses allele-specific expression to uncover potential ncRNA-gene regulatory relationships (Hasenbein et al., bioRxiv, 2025). Using mouse models and thousands of human samples, we mapped thousands of cis-acting interactions, many overlapping known disease variants. We are currently testing top candidate regulatory interactions in pulmonary and cardiovascular disease models to validate their functional relevance. Our work offers a scalable strategy to link non-coding elements to gene targets and accelerate precision medicine.

X-Chromosome Escape and Sex Bias in Disease

Sex differences in diseases such as cardiovascular and pulmonary disorders are not fully explained by hormones. Genes escaping X chromosome inactivation (XCI) may play a critical role, as they are expressed from both X chromosomes in females. We combine allele-specific multi-omics approaches with genetic and disease models to systematically map XCI escape across tissues and investigate its contribution to sex-biased traits. To functionally test candidate genes, we use viral overexpression strategies to determine if increasing gene dosage can modify disease outcomes, aiming to develop RNA-based therapies tailored to sex-specific biology.

Barr body destabilization with age: a new mechanism for disease

The long-term stability of XCI during aging has been unclear since early observations of gene reactivation in aged mice. Using allele-specific multi-omics, we generated a comprehensive atlas of XCI escape across mouse development and aging (Hoelzl et al., Nat Aging, 2025). We found a substantial increase in XCI escape with age, particularly in the lung, heart, and kidney, linked to chromatin remodeling. To address how this contributes to disease, we are investigating age-specific escape genes in models of cardiovascular and pulmonary disease, with the goal of uncovering mechanisms of female-biased protection or vulnerability in aging and informing new therapeutic strategies.

Reactivate X: Unlocking healthy allele

In X-linked disorders, females carrying pathogenic mutations can be symptomatic if the healthy allele is inactivated. Current treatments are limited by the risks of genome editing. We are developing a non-genome-editing approach using AAV-delivered CRISPR activation (CRISPRa) to reactivate endogenous genes from the inactive X chromosome. Supporting this strategy, our previous work demonstrated that targeting key epigenetic pathways can reactivate the inactive X chromosome in vivo (Andergassen et al., Dev Cell, 2021), providing the first direct evidence that the Barr body can be reversed in living tissues. Building on these findings, we aim to restore expression of healthy alleles and create a broadly applicable platform for treating X-linked diseases.