What is it about?
In eukaryotes, DNA is embedded into a higher-order structure called chromatin that varies between a closed state that is inaccessible to DNA-binding proteins, and an open state that allows the assembly of the transcriptional machinery on DNA. The state of chromatin is dynamic and is controlled locally by sequence-specific transcription factors (TFs). How local chromatin opening and closing initiated by TFs alter the long-range dynamics of chromatin structures is unknown. We chose one pioneer TF (CDX2) and one repressor TF (SIX6), which both bind many sites genome-wide upon expression, to study the large-scale alterations of chromatin dynamics triggered by local chromatin opening or closing. CDX2 plays a key role in regulating the identity of cell types, such as the trophectoderm and epithelial cells of the intestine, also involved in colon cancer as well as in intestinal-type metaplasia. While SIX6 is involved in eye development.
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Why is it important?
We show that the expression of either an individual transcriptional activator (CDX2) or repressor (SIX6) with large numbers of binding sites increases chromatin mobility nucleus-wide, yet they induce opposite coherent chromatin motions at the micron scale. Hi-C analysis of higher-order chromatin structures shows that induction of the pioneer factor CDX2 leads both to changes in local chromatin interactions and the distribution of A and B compartments, thus relating the micromovement of chromatin with changes in compartmental structures. Given that inhibition of transcription initiation and elongation by RNA Pol II has a partial impact on the global chromatin dynamics induced by CDX2, we suggest that CDX2 overexpression alters chromatin structure dynamics both dependently and independently of transcription. Our biophysical analysis shows that sequence-specific TFs can influence chromatin structure on multiple architectural levels, arguing that local chromatin changes brought by TFs alter long-range chromatin mobility and its organization.
Perspectives
The quantitative dynamics analysis of chromatin and TFs in their physiological environment provides a biophysical understanding of how chromatin structure responds dynamically to TF functions. This analysis can be a basis for studying the impact of other TFs and chromatin-binding proteins on chromatin dynamics for genome organization and gene expression regulation in living cells.
Haitham Shaban
University of Geneva
Read the Original
This page is a summary of: Individual transcription factors modulate both the micromovement of chromatin and its long-range structure, Proceedings of the National Academy of Sciences, April 2024, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2311374121.
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