Scientists Unlock Mystery of Reprogramming Factor Loosening Heterochromatin

Rejuvenation had long been the pursuit of mankind in their thousand years’ history, till the iPS reprogramming enables it in cellular level in the year of 2006. A new study defined the pioneer role of Oct4, a transcription factor which plays a key part in mammal embryonic development and stem cell fate regulation, at the early stage of reprogramming. 

Chromatin can be divided into euchromatin and heterochromatin. The former is in the relaxed state and has transcription activity, while the latter is in the condensed state and has no transcription activity. The transition between them is the key in cell fate determination. 

Compared with somatic cells, pluripotent stem cells have an open chromatin state and less heterochromatin. Therefore, the success of Yamanaka factor reprogramming of somatic cells into iPSCs requires chromatin remodeling. 

The new study by researchers from Guangzhou Institutes of Biomedicine and Health (GIBH) of the Chinese Academy of Sciences showed that Oct4 loosens heterochromatin and facilitates the binding of transcription factor Klf4 and the expression of epithelial genes in early reprogramming, leading to enhanced mesenchymal-to-epithelial transition. 

“Most of the target genes of Klf4 located in heterochromatin. Whether KLF4 can bind and activate the target genes determines whether the somatic cells can change from the mesenchymal state to the epithelial state to initiate reprogramming,” said Dr. LIU Xingguo, one of the leading researchers of the study from GIBH. 

Oct4, dependent on its L80 residue, can loosen heterochromatin to facilitate Klf4 binding and epithelial gene expression, and activate mesenchymal-to-epithelial transition (MET). These studies reveal a cooperation between Oct4 and Klf4 at the chromatin level that facilitates MET at the cellular level and shed light into the research of multiple factors in cell fate determination. 

This finding entitled “Heterochromatin loosening by the Oct4 linker region facilitates Klf4 binding and iPSC reprogramming” was published on Jan 2, 2020, in The EMBO Journal (https://www.embopress.org/journal/14602075). 

This study was carried out by LIU’s group and Dr. PEI Duanqing’s group in GIBH, in collaboration with Professor Hans R Sch？ler from the Max Planck Institute of molecular biomedicine, Germany. This research was supported by the state key R & D projects, Chinese Academy of Sciences, National Natural Science Foundation of China, Guangdong Province and Guangzhou city.