Biology subjects

Andergassen, D.

Publications and source records attributed to Andergassen, D..

4 recordsLinked to original sources

bioRxiv2025

Allele-specific genomics decodes gene targets and mechanisms of the non-coding genome

A large proportion of disease variants is found in non-coding RNAs (ncRNAs), gene loci that have been identified as key regulatory elements. However, for most ncRNAs, their targets are unknown, hindering our ability to understand complex diseases. Here, we found that allele-specific ncRNAs were enriched nearby allelic protein-coding genes (pcGenes), suggesting that the allele-specific information could be used to predict cis-acting ncRNA-targets. We translated this concept into the Allelome.LINK framework and applied it to the major mouse organs, revealing 397 events where the allele-specific expression (ASE) of a ncRNA correlated with the ASE of a nearby pcGene, suggesting either enhancing or repressive regulatory interactions. Next, we applied our strategy to the largest human dataset including tissues from nearly 1,000 individuals. Given the outbred nature of humans, each individual allows for the discovery of novel ASE correlation events. We uncovered 2,291 shared ASE events along with their mechanisms, which we benchmarked against sample-matched eQTLs, yielding a high validation rate of 77.47%. Further GWAS integration assigned 30.59% of variants overlapping informative ncRNAs to their pcGene targets. As more sequencing data and risk variants become available, this strategy has the potential to decode the entire cis-acting landscape of the non-coding genome.

genomics↗

bioRxiv2021

Diverse mechanisms for epigenetic imprinting in mammals

Genomic imprinting and X chromosome inactivation (XCI) require epigenetic mechanisms to direct allele-specific expression. Despite their critical roles in embryonic development, how universal epigenetic regulators coordinate these specific tasks from single locus to chromosome-scale remains understudied. Here, we systematically disrupted multiple essential epigenetic pathways within polymorphic F1 zygotes to examine postimplantation effects on canonical and non-canonical genomic imprinting as well as X chromosome inactivation. We find that DNA methylation and Polycomb group repressors are both indispensable for autosomal imprinting, albeit at distinct gene sets. Moreover, the extraembryonic ectoderm relies on a broader spectrum of unique imprinting mechanisms, including non-canonical targeting of maternal endogenous retrovirus (ERV) driven promoters by G9a. We further utilize our data to identify Polycomb dependent and independent gene clusters on the imprinted X chromosome, which appears to reflect distinct domains of Xist-mediated suppression. Our data has allowed us to assemble a comprehensive inventory of the epigenetic mechanisms utilized in eutherian mammals to maintain parent-specific imprinting, including an expanded view of the placental lineage that comprises multiple unique pathways.

genetics↗

bioRxiv2019

Analysis of regulatory element evolution between human and mouse reveals a lack of cis-trans compensation

Gene expression differences between species are driven by both cis and trans effects. Whereas cis effects are caused by genetic variants in close proximity to the target gene, trans effects are due to distal genetic variants that affect diffusible elements such as transcription factors. Previous studies have mostly assessed the impact of cis and trans effects at the gene level. However, how cis and trans effects differentially impact regulatory elements such as enhancers and promoters remains poorly understood. Here, we used massively parallel reporter assays to directly measure cis and trans effects between human and mouse embryonic stem cells at thousands of individual regulatory elements. Our approach revealed that cis effects are widespread across regulatory elements, and the strongest cis effects are associated with the disruption of motifs recognized by strong transcriptional activators. Conversely, we found that trans effects are rare but stronger in enhancers than promoters, and can be attributed to a subset of transcription factors that are differentially expressed between human and mouse. While previous studies have found extensive co-occurrence of cis and trans effects in opposite directions that stabilize gene expression throughout evolution, we find that cis-trans compensation is uncommon within individual regulatory elements. Thus, our results are consistent with a model wherein compensatory cis-trans effects at the gene level are explained by cis and trans effects that separately impact several regulatory elements rather than cis-trans effects that occur simultaneously within a single regulatory element. Together, these results indicate that studying the evolution of individual regulatory elements is pivotal to understand the tempo and mode of gene expression evolution.

genomics↗

bioRxiv2019

In vivo Firre and Dxz4 deletion elucidates roles for autosomal gene regulation

Recent evidence has determined that the conserved X chromosome \"mega-structures\" controlled by the Firre and Dxz4 alleles are not required for X chromosome inactivation (XCI) in cell lines. Here we determined the in vivo contribution of these alleles by generating mice carrying a single or double deletion of Firre and Dxz4. We found that these mutants are viable, fertile and show no defect in random or imprinted XCI. However, the lack of these elements results in many dysregulated genes on autosomes in an organ-specific manner. By comparing the dysregulated genes between the single and double deletion, we identified superloop, megadomain, and Firre locus dependent gene sets. The largest transcriptional effect was observed in all strains lacking the Firre locus, indicating that this locus is the main driver for these autosomal expression signatures. Collectively, these findings suggest that these X-linked loci are involved in autosomal gene regulation rather than XCI biology.

genetics↗