Transcriptional Adaptation and Genetic Compensation

Projektinformationen

TAaGC

ID Finanzhilfevereinbarung: 101021349

DOI

10.3030/101021349

EK-Unterschriftsdatum 10 Juli 2021

Startdatum 1 Januar 2022

Enddatum 31 Dezember 2026

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 2 500 000,00

EU-Beitrag

€ 2 500 000,00

Koordiniert durch

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany

Periodic Reporting for period 2 - TAaGC (Transcriptional Adaptation and Genetic Compensation)

Berichtszeitraum: 2023-07-01 bis 2024-12-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Genetic robustness refers to the ability of organisms to withstand mutations, showing little or no phenotype, or compromised viability. Our studies on genetic robustness are specifically trying to understand mechanisms of genetic compensation, which is defined as ‘changes in RNA or protein levels that can functionally compensate for the loss of function of another gene’. This work is important for society because it will allow one to better understand phenotypic variability within the human population, i.e. why people with the same mutation often exhibit very different phenotypes. In addition, our work aims to identify genes that can functionally compensate for the loss of function of another gene in the context of certain diseases. In fact, our findings have recently led to a novel therapeutic avenue for several diseases, and we have filed a patent application so far, and are working on another one.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

This project initially started with our efforts to understand the phenotypic differences between knockout (mutant) and knockdown (antisense treated) phenotypes in zebrafish embryos, leading to the publication of a paper entitled ‘Genetic compensation induced by deleterious mutations but not gene knockdowns’ (Rossi, Kontarakis et al., Nature 2015). Since these initial observations, we have been working to understand underlying mechanisms and published a follow up paper entitled ‘Genetic compensation triggered by mutant mRNA degradation’ (El-Brolosy et al., Nature 2019). We also introduced the term ‘transcriptional adaptation (TA)’ to refer to this form of RNA-triggered genetic compensation, where the genes whose expression is directly modulated by TA are referred to as ‘adapting genes’.

We are currently working on TA in several different models including mouse and human cells in culture, zebrafish, C. elegans, and Neurospora. The key questions we are trying to address are 1) what are the adapting genes and 2) how does their expression become modulated?

Thus far, two papers have been published (Jiang et al, Science Advances 2022 and Welker et al., PLoS Genetics 2023), and two more will be published soon (Falcucci et al., under revision for Nature, and Xie et al., under revision for EMBO Reports).

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

We have shown that 1) there is transgenerational inheritance of TA (Jiang et al, Science Advances 2022), and 2) that a 25 bp element with limited sequence similarity present in both the mutant mRNA and the adapting gene locus is sufficient for TA (Welker et al., PLoS Genetics 2023). More recently, we have identified TA in human cells, showed that utrophin upregulation in Duchenne muscular dystrophy patients is due to TA, and that antisense oligonucleotides that induce the skipping of out-of-frame exons in DMD lead to mutant mRNA degradation and UTRN upregulation (Falcucci et al., under revision for Nature). We have also explored other means to cleave mRNAs/RNAs and found that they also induce TA (Xie et al., under revision for EMBO Reports).

Many mechanistic questions remain to be answered of course, and so we are continuing these studies using a variety of state-of-the-art approaches in different model organisms as well as in mammalian cells in culture. In terms of the expected results by the end of the project, we will be investigating additional human disease models including Marfan syndrome and laminopathies, determining whether TA is also at play. We will look for mRNA degradation fragments and investigate their function in the upregulation of the adapting genes. We will also investigate bioinformatic approaches to try and predict the adapting gene(s).

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