Context matters: DNA methylation in human disease

Abstract

In this thesis, we focused on CDCA7, which, when homozygously mutated, can cause Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome in humans, and examined how CDCA7 influences DNA methylation genome-wide. We generated and characterized two novel CDCA7 mouse models: Cdca7G305V, carrying an ICF3-causing missense mutation, and a CDCA7 knockout (KO). Using these models and CDCA7 (ICF3) and HELLS (ICF4) patient-derived T cells, we found that CDCA7 is important for maintaining DNA methylation within the B genomic compartment. CDCA7-associated DNA hypomethylation led to localized, tissue-specific transcriptional dysregulation. Specifically, in the cerebrum of both mouse models, hypomethylation of clustered protocadherins correlated with altered gene expression. We also observed DNA methylation loss at T cell receptor (TCR) loci in patient cells, underscoring the need for more detailed studies on how the ICF syndrome causing genes function in T cell development. This work identifies the B genomic compartment—rich in large, cell type-specifically expressed gene clusters—as a major target of ICF syndrome-associated DNA methylation defects. Although methylation loss overlapped across tissues and developmental stages, transcriptional effects were cell type-specific. These findings emphasize an intricate, context-dependent relationship between DNA methylation and gene expression, offering new insights into the molecular mechanisms underlying ICF syndrome and gene regulation in general.