Gene expression dosage as a driver of cellular and physiological traits

Projektinformationen

DOSAGE2FUNC

ID Finanzhilfevereinbarung: 101043238

DOI

10.3030/101043238

EK-Unterschriftsdatum 20 Juni 2022

Startdatum 1 Juli 2022

Enddatum 30 Juni 2027

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 1 993 059,00

EU-Beitrag

€ 1 993 059,00

Koordiniert durch

KUNGLIGA TEKNISKA HOEGSKOLAN
Sweden

Periodic Reporting for period 1 - DOSAGE2FUNC (Gene expression dosage as a driver of cellular and physiological traits)

Berichtszeitraum: 2022-07-01 bis 2024-12-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

The expression dosage of a gene is a fundamental determinant of its downstream function at the cellular and organismal level, and its genetic or environmental perturbations are a driving force of most common and rare disease in humans. However, we have limited understanding of the specific shape of dosage-to function-curves for human genes, what factors and mechanisms drive their variation across genes, phenotypes and cellular contexts, and how this contributes to functional architecture of human traits.

This project will characterize the relationship between gene dosage and cellular and physiological function in in unprecedented scale and depth. Using blood cell traits as our study system, will apply both innovative analyses of large human genetic data sets and cutting-edge experimental approaches. We will address fundamental questions in systems biology and produce insights that can benefit genomic medicine and drug development.

The Work Packages of this study will: 1) Establish the dosage-to-function relationship for hundreds of human genes, by associating genetically driven gene dosage to blood cell traits in large human genetic data, and by an innovative CRISPR-based experimental approach that maps gene dosage titration to cellular phenotypes; 2) Elucidate how cellular the dosage-to-cellular-function relationships differ between cellular states, and use single-cell RNA sequencing to analyze how regulatory networks mediate context-specific dosage-to-function effects; 3) Characterize upstream genomic and environmental regulators of gene dosage.

This project will build the first comprehensive, generalizable picture of gene dosage-to-function relationships in humans. Our analysis will link these insights to functional architecture of human traits, providing unique generalizable insights into how disruption of gene dosage and regulatory networks underlies human traits at the cellular and physiological level.

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

During this period, we have made significant technological advancements and produced scientific insights that have been well-received by the research community. Our main achievements focus on two key areas: linking gene dosage changes to regulatory networks and understanding how genetic and environmental factors influence gene expression.

In our work on gene dosage and regulatory networks, we successfully developed, tested and published a new CRISPR-based method for modulating gene expression. This approach allows for precise control of gene activity, helping us understand how changes in gene dosage affect other genes, particularly those involved in diseases. Our findings reveal that these effects are nonlinear, complex and vary by gene, providing valuable insights for future research.

Additionally, we created and published a new tool and data resource that helps researchers map the direct targets of transcription factors in specific cell types. This resource is user-friendly and effective, making it a valuable contribution to the field.
In another project, we explored how both genetics and environmental factors influence gene expression. We introduced a new method that improves the identification of biologically significant changes in gene expression, especially in response to environmental triggers and physiological changes such as disease. This method enhances our ability to identify key pathways involved in cellular responses, offering a clearer understanding of how our genes react to the environment.

Overall, our work lays a strong foundation for future research and provides new tools and insights that will benefit the broader scientific community.

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)

Not applicable for the current reporting period.