Chromatin reorganisation in cell differentiation and cancer: focus on nucleosomes and CTCF
Vladimir B. Teif
In eukaryotes protein-DNA binding happens in the context of chromatin, where nucleosome positioning defines accessibility of DNA for binding of transcription factors (TFs) and many other chromatin proteins. On the other hand, nucleosome positioning is governed by binding of architectural proteins (CTCF, cohesin and their multiple “friends”), as well as other strong DNA binders such as pioneering factors.
The interplay between nucleosome positioning and protein-DNA binding is further shaped by changes in DNA cytosine modifications and post-translational modifications of histones. In addition, at a larger scale, differences in nucleosome positioning lead to differences in local 3D packing of the genome. CTCF and cohesin form DNA loops and set boundaries isolating different chromatin states in 1D, but how exactly this is achieved is not well understood.
In our several ongoing projects we aim to dissect such interplay. Recently we showed that CTCF can set boundaries for DNA methylation spreading (Wiehle et al., Genome Res., 2019) and that CTCF-dependent chromatin boundaries are defined by asymmetric arrays of nucleosomes with decreased nucleosome repeat length (Clarkson et al., Nucleic Acids Res., 2019). In order to understand such interactions we developed a theory of formation of heterochromatin microdomains. These small domains of size ~2kb defined by H3K9me3 marks appear to be mostly bounded by DNA motifs bearing similarity to consensus CTCF sites (Thorn et al., in preparation).
I will also present our new experimental results concerning formation of CTCF-dependent chromatin boundaries in cancer patients and will discuss these from the point of view of potential implications for novel diagnostic assays based on so-called "liquid biopsy".
Wiehle L., Thorn G.J., Raddatz G., Clarkson C.T., Rippe K., Lyko F., Breiling A., Teif V.B. (2019) DNA (de)methylation in embryonic stem cells controls CTCF-dependent chromatin boundaries. Genome Research 29, 750-761
Clarkson C.T., Deeks E.A., Samarista R., Mamayusupova H., Zhurkin V.B., Teif V.B. (2019) CTCF-dependent chromatin boundaries formed by asymmetric nucleosome arrays with decreased linker length. Nucleic Acids Res 47, 11181-11196.