Transcription Factor OCT4 influences cell fate by interacting with packaged DNA
05 Aug 2021
A new study in Nature Cell Biology has brought clarity to how cells become or stay pluripotent - the ability to go on to produce multiple cell types.
Through painstaking study of the structure and binding of pioneer transcription factor OCT4, CRM scientists were able to “dissect” the importance of interaction of OCT4 with the nucleosome, a key DNA packaging structure.
Our genome consists of billions of DNA molecules arranged as a unique code, which is often described as the blueprint for life. Genes are the sequences of DNA provide the code for proteins which make up and control the functions of our cells.
The different cell types in our body contain the same DNA sequence and are only different by which genes are switched on and off (gene expression). Gene expression is affected by how the 2 meter long DNA is packaged to fit inside the nucleus, which is only about few micrometres in diameter, in a structure called chromatin. Key to this clever packaging are nucleosomes, important protein structures around which DNA wraps.
Transcription factors interact with DNA and control which genes are expressed. Generally, genes in nucleosome-dense regions (closed chromatin) are switched off (silent genes) and genes in regions with fewer nucleosomes (open chromatin) are switched on (active genes).
Until now it has not been clear whether nucleosomes obstruct or help the interaction of transcription factors with DNA to change and maintain a cell type such as pluripotent stem cells. A team of scientists led by CRM group leader Dr Abdenour Soufi have systematically mapped the important binding regions of OCT4. They did this by editing out sections of the protein 5 amino acids at a time, and looking at the structure using electron microscopy.
Using mutations in the DNA binding domain of OCT4 researchers were able to “uncouple” OCT4-nucleosome binding from DNA binding resulting in reduced pluripotency. However enhancing this binding also reduced pluripotency. The team conclude that stable interactions between OCT4 and nucleosomes are required to both establish and maintain pluripotency.
What is surprising about this work is that you need nucleosome binding not only to access closed chromatin but also to maintain open chromatin. So rather than being a barrier, nucleosomes actually make the DNA code more readable by transcription factors like OCT4
This study is published in Nature Cell Biology. It was supported by funding from the Medical Research Council, with additional funding from the BBSRC, EPSRC, CRUK, The Darwin Trust of Edinburgh and Wellcome Trust.