M.Sc Thesis

M.Sc StudentLarom-Khan Gal
SubjectTelomeric Abnormalities in a Mouse Model
for ICF Syndrome
DepartmentDepartment of Medicine
Supervisors ASSOCIATE PROF. Sara Selig
Full Thesis textFull thesis text - English Version


Telomeric regions in animal cells are packed as constitutive heterochromatin. The heterochromatin packaging is characterized by specific histone modifications, binding of heterochromatin protein 1 and subtelomeric DNA methylation. Subtelomeres are hypomethylated in sperm and ova and undergo de novo methylation during early development by DNA methyl transferase 3B (DNMT3B). Loss of function mutations in human DNMT3B gene result in the autosomal recessive disorder - ICF (Immunodeficiency, Centromeric region instability, Facial anomalies) syndrome type I. Among many phenotypic components, subtelomeres in ICF patients are abnormally hypomethylated and this hypomethylation is associated with enhanced levels of telomeric repeat-containing RNA (TERRA) and abnormally short telomeres.

The molecular pathology of ICF syndrome initiates during the first days of embryonic development. Therefore an appropriate model that mimics this development stage is essential in order to study the mechanism by which the hypomethylation leads to telomeric abnormalities. ICF model mice were generated by two groups by introducing human described ICF mutations into the mouse Dnmt3b gene. These mice are viable and display many components of the human syndrome, including hypomethylation of minor satellite repeats, however the status of the telomeres in these mice was not reported.

Bisulfite analysis of four subtelomeres demonstrated that ICF-mouse embryonic fibroblasts (MEFs) are not significantly hypomethylated in comparison to WT-MEF subtelomeres. Also dissimilar to human ICF cells, the ICF model MEFs were found to possess normal telomere length and TERRA levels were reduced in comparison to the WT mice cells.

Based on our findings, we conclude that the mouse model for ICF syndrome does not exhibit the telomeric phenotypes observed in human ICF cells and therefore is not a good surrogate model for studying this specific phenotypic aspect of human ICF syndrome.