Genomic imprinting is a gene regulatory mechanism that is essential for embryonic development. Imprinted genes are mono-allelically expressed based on parental origin. The CTCF insulator protein binds imprinted gene domains at regulatory elements, including the Imprinting Control Regions. We study how this CTCF binding structures allele-specific TAD organization, how this regulates imprinted gene expression and how this type of chromosome structuration relates to other types of chromatin structures.
TADs are insulated chromosomal structures guide the correct activity of genes. The CTCF insulator protein binds at the boundaries of many TADs. We recently showed that most TADs are relatively weakly insulated and that their boundaries are often organized as extended ‘transition zones’. Using newly developed multi-contact 3C technology, incorporating single-molecule Nanopore sequencing, we are characterizing these transition zones at the single cell level.
The presence of specific histone modifications directly correlates with 3D genome structure. Both at early stages of embryonic development and in ageing cells, the presence of histone modifications changes. We are using mouse and Drosophila cells to determine how reorganized domains of histone modifications change 3D genome structure and, combined with changes in insulator protein binding, what is the impact on gene activity.
Binding sites for the CTCF insulator protein are hotspots for mutations in certain human cancers. In this project, we are determining how changes in CTCF binding cause reorganization of TAD structure in breast cancer cells and how this subsequently results in the activation of oncogenes. By using multi-contact 3C and advanced modeling approaches we aim to address this question in an allele-specific manner.