Doctoral thesis
Open access

Regulatory mechanisms of gene expression through the lens of genetic variation and epigenetics

Number of pages115
Imprimatur date2023
Defense date2023

Although all our cells share the same genomic material, their functions and purpose are determined by the specific proteins they express and their abundance. Understanding the mechanisms regulating gene expression is essential for comprehending the functional diversity of our cells and shed light on the molecular processes that contribute to complex diseases. By genotyping and phenotyping millions of individuals, and with the advent of genome-wide association studies (GWAS), we have linked thousands of genetic variants to hundreds of complex traits. Most of these variants map to noncoding regions of the genome, where they alter regulatory functions whose mechanisms remain unknown. Molecular quantitative trait locus (QTL) studies testing for associations between genetic variants and intermediate phenotypes, such as gene expression levels, DNA methylation patterns, and chromatin modifications provide powerful approaches to annotate the putative consequence of disease associations. Integrating a variety of biological measurements enables a better understanding of complex traits, and the etiology of diseases. This thesis contributes to our comprehension of gene expression regulation and how it affects human cells and diseases.

In this thesis, I examined regulatory networks of gene-expression in immune cells, focusing on cell type-specific gene regulation through the integration of multi-omics data. To address this challenge, I conducted an analysis of genetic, epigenetic, and transcriptomic data in three major human immune cell types from 200 blood donors, and integrated multiple genome wide data types such as three-dimensional genome structure and functional annotation of the genome, examining the interplay between these factors and the cell-specific regulation of transcription (Chapter 1).

In chronic immune diseases, the dysregulation of immune and inflammatory activity is a prominent feature. Expanding upon the findings from Chapter 1, I employed a multi-omics approach and integrated whole blood RNA-seq deconvolution to assess the contributions of various cell types within the blood samples. This allowed for a comprehensive investigation into the disrupted regulatory pathways of gene expression in five specific chronic immune diseases (Chapter 2).

Finally, I explored how regulatory variants affect the extent to which deleterious coding mutations manifest in individuals. Indeed, we do not fully understand why people with the same coding risk variant can show a wide range of disease severity. To unravel this mystery, I studied the associations between genetic variants and gene expression (expression QTLs) using phased genotype data from 167,103 individuals (Chapter 3).

  • QTLs
  • CRDs
  • Immune cells
  • Immune
  • Multi omics
  • Omics
  • Blueprint
  • Complex diseases cell specificity
  • Functional population genomics
  • Complex traits
  • European Commission - A Systems medicine approach to chronic inflammatory disease [733100]
  • European Commission - A high-dimensional approach for unwinding immune-metabolic causes of cardiovascular disease-depression multimorbidities [848146]
Citation (ISO format)
AVALOS MTZ DE ESCOBAR, Diana. Regulatory mechanisms of gene expression through the lens of genetic variation and epigenetics. 2023. doi: 10.13097/archive-ouverte/unige:175560
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Technical informations

Creation10/04/2023 12:49:00 PM
First validation03/12/2024 10:35:54 AM
Update time03/12/2024 10:35:54 AM
Status update03/12/2024 10:35:54 AM
Last indexation05/06/2024 6:08:59 PM
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