Transcription Factor OCT4 influences cell fate by interacting with packaged DNA
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.
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 Dr Abdenour Soufi, PI in the UK Centre for Mammalian Synthetic Biology and CRM Group leader at the University of Edinburgh, 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.
This study 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.
Additional support came from Edinburgh Genome Foundry and the UK Centre for Mammalian Synthetic Biology with generating the synthetic DNA constructs.