The molecular players for epigenetic regulation of gene expression has remained largely uncovered. Korean researchers at Korea Advanced Institute of Science and Technology (KAIST) report the discovery of a molecular mechanism underlying recruitment of the major epigenetic complex SWI/SNF in mouse embryonic stem cells. This study has been published in the journal eLife in May. 

Gene expression is highly coordinated through diverse epigenetic enzymes including SWI/SNF complex. SWI/SNF is a protein complex which is able to remodel chromatin organization by consuming ATP energy. Discovery of SWI/SNF control mechanisms has drawn attention due to the key contribution of SWI/SNF to the control of cell proliferation, differentiation as well as disease like cancer. A collaborative research led by Prof. Seyun Kim and Daeyoup Lee at KAIST elucidated an enzyme called IPMK (Inositol polyphosphate multikinase), which dieretly interacts with SWI/SNF complex and regulates its chromatin association. IPMK is known as a key metabolic enzyme needed to produce inositol phosphate metabolites, thereby pursuing multiple signaling actions in mammals.

Throughout extensive collaboration with Seoul National University and Ulsan National Institute of Science and Technology, the researchers employed various screening methods such as yeast-two hybrid, APEX-coupled mass spectrometry, as well as co-immunoprecipitation to validate IPMK-SWI/SNF interactions. When IPMK is depleted in mouse embryonic stem cells, the SWI/SNF complex cannot properly associate with its cognate promoter regions, revealed throughout Ch-IP and ATAC sequencing experiments. These defects further leads to gene expression changes, and importantly, alters stem cell differentiation (e.g. reduced formation of endodermal cells). 

Prof. Kim and Lee said that "We showed for the first time the principle how two different systems like epigenetics and inositol metabolism can be functionally connected in the process of gene expression and cell fate control. This new regulatory link will help us to better understand our gene expression system and provide insight to develop therapeutic tools to treat major diseases (e.g. cancer) in the future”.

[Reference] Beon, J.*, Han, S.*, Park, S.E., Hyun, K., Lee, S., Rhee, H., Seo, J.K., Kim, J., Kim, S.+, Lee, D.+ (2022) IPMK physically binds to the SWI/SNF complex and modulates BRG1 occupancy. eLife 11:e73523.(*equally contributed to this work, +co-corresponding authors)

[Main Author] Seyun Kim (KAIST, seyunkim@kaist.ac.kr), Daeyoup Lee (KAIST, dylee@kaist.ac.kr)