Pluripotent cells can develop into many different cell types, which allows them to support both organismal development and tissue repair. To maintain this flexibility, they keep a careful balance: genes linked to differentiation are kept inactive through epigenetic mechanisms, but remain ready to be switched on when needed. Although the core gene regulatory networks involved in this process have been studied extensively, it is still not fully clear how they are coordinated with signals that control cell growth and differentiation and - specifically in this project - how growth and gene regulatory signals are integrated together.
We discovered that the key growth regulator mTOR - which is a decisive regulator of dormancy - directly associates with the promoters of developmental genes in pluripotent mouse embryonic stem cells. This binding is closely linked to a specific histone modification added by the Polycomb Repressor Complex 1 (PRC1). When the PRC1 component RING1b is rapidly removed, mTOR is quickly lost from these gene regions. Similarly, disrupting the enzymatic activity of RING1b—while leaving the rest of PRC1 intact—also prevents mTOR from binding, indicating that RING1b’s activity is necessary for this interaction. At these target genes, mTOR is found together with parts of the transcription machinery. Notably, genes bound by mTOR show high levels of paused RNA Polymerase II, a state that keeps them ready for rapid activation. Together, these results suggest that mTOR plays a direct role in regulating pluripotency and point to a close connection between gene regulation and cell growth control in stem cells.
In addition to these advances, we continue to survey the chromatin of dormant stem cells for factors that play distinct regulatory roles during dormancy. Candidates are identified via omics analysis and are being validated.
