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Research Group Julien Gagneur

Link to Julien Gagneur

Julien Gagneur

Prof. Dr.

Principal Investigator

Computational Molecular Medicine

Julien Gagneur

is Assistant Professor for Computational Biology at TU Munich.

His research focuses on delineating the genetic basis of gene regulation and its implication in diseases. To this end, he is developing statistical and machine learning algorithms and works with experimentalists to design novel experimental approaches. His group is also developing strategies to pinpoint the cause of genetic disorders by integrating data from genetics and 'multiomics' disciplines such as transcriptomics and proteomics.

Team members @MCML

Link to Pedro Tomaz da Silva

Pedro Tomaz da Silva

Computational Molecular Medicine

Link to Johannes Hingerl

Johannes Hingerl

Computational Molecular Medicine

Link to Alexander Karollus

Alexander Karollus

Computational Molecular Medicine

Publications @MCML

[3]
F. Brechtmann, T. Bechtler, S. Londhe, C. Mertes and J. Gagneur.
Evaluation of input data modality choices on functional gene embeddings.
NAR Genomics and Bioinformatics 5.4 (Dec. 2023). DOI.
Abstract

Functional gene embeddings, numerical vectors capturing gene function, provide a promising way to integrate functional gene information into machine learning models. These embeddings are learnt by applying self-supervised machine-learning algorithms on various data types including quantitative omics measurements, protein–protein interaction networks and literature. However, downstream evaluations comparing alternative data modalities used to construct functional gene embeddings have been lacking. Here we benchmarked functional gene embeddings obtained from various data modalities for predicting disease-gene lists, cancer drivers, phenotype–gene associations and scores from genome-wide association studies. Off-the-shelf predictors trained on precomputed embeddings matched or outperformed dedicated state-of-the-art predictors, demonstrating their high utility. Embeddings based on literature and protein–protein interactions inferred from low-throughput experiments outperformed embeddings derived from genome-wide experimental data (transcriptomics, deletion screens and protein sequence) when predicting curated gene lists. In contrast, they did not perform better when predicting genome-wide association signals and were biased towards highly-studied genes. These results indicate that embeddings derived from literature and low-throughput experiments appear favourable in many existing benchmarks because they are biased towards well-studied genes and should therefore be considered with caution. Altogether, our study and precomputed embeddings will facilitate the development of machine-learning models in genetics and related fields.

MCML Authors
Link to Julien Gagneur

Julien Gagneur

Prof. Dr.

Computational Molecular Medicine


[2]
A. Karollus, J. Hingerl, D. Gankin, M. Grosshauser, K. Klemon and J. Gagneur.
Species-aware DNA language models capture regulatory elements and their evolution.
Genome Biology 35.83 (Apr. 2023). DOI.
Abstract

Background: The rise of large-scale multi-species genome sequencing projects promises to shed new light on how genomes encode gene regulatory instructions. To this end, new algorithms are needed that can leverage conservation to capture regulatory elements while accounting for their evolution.
Results: Here, we introduce species-aware DNA language models, which we trained on more than 800 species spanning over 500 million years of evolution. Investigating their ability to predict masked nucleotides from context, we show that DNA language models distinguish transcription factor and RNA-binding protein motifs from background non-coding sequence. Owing to their flexibility, DNA language models capture conserved regulatory elements over much further evolutionary distances than sequence alignment would allow. Remarkably, DNA language models reconstruct motif instances bound in vivo better than unbound ones and account for the evolution of motif sequences and their positional constraints, showing that these models capture functional high-order sequence and evolutionary context. We further show that species-aware training yields improved sequence representations for endogenous and MPRA-based gene expression prediction, as well as motif discovery.
Conclusions: Collectively, these results demonstrate that species-aware DNA language models are a powerful, flexible, and scalable tool to integrate information from large compendia of highly diverged genomes.

MCML Authors
Link to Alexander Karollus

Alexander Karollus

Computational Molecular Medicine

Link to Johannes Hingerl

Johannes Hingerl

Computational Molecular Medicine

Link to Julien Gagneur

Julien Gagneur

Prof. Dr.

Computational Molecular Medicine


[1]
P. T. da Silva, Y. Zhang, E. Theodorakis, L. D. Martens, V. A. Yépez, V. Pelechano and J. Gagneur.
Cellular energy regulates mRNA translation and degradation in a codon-specific manner.
Preprint (2023). DOI.
Abstract

Background: Codon optimality is a major determinant of mRNA translation and degradation rates. However, whether and through which mechanisms its effects are regulated remains poorly understood.
Results: Here we show that codon optimality associates with up to 2-fold change in mRNA stability variations between human tissues, and that its effect is attenuated in tissues with high energy metabolism and amplifies with age. Biochemical modeling and perturbation data through oxygen deprivation and ATP synthesis inhibition reveal that cellular energy variations non-uniformly affect the decoding kinetics of different codons.
Conclusions: This new mechanism of codon effect regulation, independent of tRNA regulation, provides a fundamental mechanistic link between cellular energy metabolism and eukaryotic gene expression.

MCML Authors
Link to Pedro Tomaz da Silva

Pedro Tomaz da Silva

Computational Molecular Medicine

Link to Julien Gagneur

Julien Gagneur

Prof. Dr.

Computational Molecular Medicine