Distinct role of INO80 complex in the Naïve vs Primed pluripotent state

Authors

• K Gwilliam
• B Milon
• M Eshel
• M McMurray
• Y Song
• I Belyantseva
• S Jones
• MR Bowl
• R Elkon
• R Hertzano

Abstract

Pluripotent stem cells (PSCs) can self-renew and differentiate into various cell types. Different pluripotent states corresponding to different developmental stages can be recapitulated in-vitro. Among those, the Naïve and Primed pluripotent states represent two consecutive stages in early embryonic development and are most widely studied.
The developmental plasticity of PSCs is attributed to the unique epigenetic features. Of particular interest, the pluripotent chromatin contains regions that are occupied by both the active (H3K4me3) and repressive (H3K27me3) histone marks. These bivalent chromatin domains are enriched at the promoters of key developmental genes, and are crucial for cell fate transitions. Our previous work showed that the INO80 chromatin remodeler is selectively required for the maintenance of the Primed but not the Naïve state. It promotes the occupancy of H2AZ histone variant to facilitate the establishment and maintenance of the bivalent promoters during the Naïve to Primed transition. These results identified a state-specific role of INO80. However, the underlying mechanism remained elusive.
We hypothesize that additional factors may contribute to the different functions of INO80 in the Naïve and Primed state. To test that, we tagged INO80 with the TurboID biotin ligase and employed proximity labeling strategy to identify novel INO80-interacting factors in the Naïve vs. Primed state. We observed distinct bands in biotin-labeled proteins purified from the two states and are in the process of identifying them via Mass spectrometry. Further characterization of the identified hits will provide new insights to the function of INO80-mediated chromatin regulation in stem cell fate transitions.

Scientific Focus Area: Stem Cell Biology

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