RIF1, ZBTB24 and repeat silencing

Abstract

In this thesis, we aim to characterize the molecular functions of RIF1 and ZBTB24 two factors proposed to be involved in epigenetic regulation. We use cutting-edge technologies in combination with next-generation sequencing to comprehensively study the two proteins, their functions and targets. By integrating all the data together, we can get a better understanding of the molecular mechanisms of their function in transcription regulation. In chapter 2, our study revealed that Rif1 deficiency leads to de-repression of X-linked ampliconic gene clusters and a set of germline genes, which are probably mediated in an H3K9me- or DNA methylation-dependent manner. In chapters 3, 4, and 5, we focused on dissecting the molecular function of ZBTB24 in relation to ICF syndrome. In chapter 3, we reported that ZBTB24 functions as a transcription factor and positively regulates expression of the ICF3 gene CDCA7 by directly activating its promoter. Chapter 4 describes a robust method to distinguish neutral from pathogenic ZBTB24 variants. In chapter 5, we investigated ZBTB24 binding sites genome-wide, identified a putative DNA binding motif, and assessed how the loss of Zbtb24 and Cdca7 affects DNA methylation patterns in mESCs.