In this thesis two diseases that share a common feature of hypomethylation of repetitive DNA are studied: facioscapulohumeral muscular dystrophy (FSHD) and immunodeficiency, centromeric... Show moreIn this thesis two diseases that share a common feature of hypomethylation of repetitive DNA are studied: facioscapulohumeral muscular dystrophy (FSHD) and immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. In FSHD there is hypomethylation of the macrosatellite repeat D4Z4 and the associated DUX4 gene, which is caused by a repeat contraction and/or variants in chromatin modifiers essential for a repressive D4Z4 chromatin structure in somatic cells. In ICF there is hypomethylation of centromeric repeats, which is caused by recessive variants in one of four ICF genes, of which two are established chromatin modifiers. In this thesis, the mutation spectrum of FSHD and ICF has been expanded. The SMCHD1 mutation spectrum in FSHD2 has been expanded with the discovery of exonic SMCHD1 variants, intronic SMCHD1 variants, and whole SMCHD1 gene deletions. In addition, we identified heterozygous variants in a new FSHD2 gene, DNMT3B, in two FSHD2 families. For ICF syndrome we expanded the mutation spectrum in the two most common ICF genes, DNMT3B and ZBTB24. Show less
A large part of the human genome consists of repetitive DNA. In this thesis two human diseases have been studied in which deregulation of repetitive DNA is a central feature: facioscapulohumeral... Show moreA large part of the human genome consists of repetitive DNA. In this thesis two human diseases have been studied in which deregulation of repetitive DNA is a central feature: facioscapulohumeral muscular dystrophy (FSHD) and immunodeficiency, centromere instability and facial anomalies (ICF) syndrome. FSHD is caused by the misexression of the transcription factor DUX4 in skeletal muscle. DUX4 is encoded in the D4Z4 repeat array and is silenced in healthy somatic tissues. In this thesis, several aspects of the epigenetic deregulation of DUX4 in FSHD are described. We have analysed possible correlations between disease severity and epigenetic organization of the D4Z4 repeat. Next we showed that cellular ageing results in deregulation of genomic regions like D4Z4. Moreover, we show that SMCHD1 is the main epigenetic repressor of DUX4 in somatic cells. We next showed that DUX4 misexpression results in the activation of an FSHD candidate gene, FRG2. Finally, we report the generation of a transgenic mouse model for FSHD. The disease mechanism of ICF syndrome remains to be elucidated. However, in this thesis we identify two new ICF disease genes. We highlight a role for all four known ICF genes in repressing repetitive DNA, suggesting functional convergence of these genes. Show less
