Rcor2, the corepressor 2 of REST (a transcriptional repressor), is predominantly expressed in embryonic stem cells (ESCs). It is essential for maintaining ESC pluripotency and plays a key role in neurogenesis. Rcor2 is also involved in epigenetic regulatory complexes, interacting with proteins like LSD1, and is associated with pathways related to cell differentiation and inflammation [1,3].

Using a Rcor2 -/- mouse embryonic stem cell (mESC) line, researchers found that Rcor2 -/- mESC shows reduced proliferation and severely compromised capacity to differentiate into all three germ layers. Conversely, Rcor2 knockout promotes primordial germ cells (PGCs) specific gene expression and possibly PGC formation. Mechanistically, Rcor2 inhibits PGC-related gene expression by associating with their promoters and enhancing local suppressive H3K9me3 modifications [1]. In senescent mice, Rcor2 gene expression is dramatically decreased compared to controls, accompanied by increased basal expression of inflammatory genes like Il-6, suggesting its role in inflammaging [2]. In mesenchymal stromal cells (MSC), lentiviral silencing of Rcor2 in vitro led to decreased osteoblast differentiation, while conditional deletion in limb-bud mesenchymal cells in vivo led to a moderate decrease in cortical bone volume and decreased adiposity in fracture callus [4].

In conclusion, Rcor2 is crucial for somatic cell fate determination by suppressing PGC differentiation through epigenetic modifications. Its dysregulation is associated with age-related inflammation and affects mesenchymal stromal cell differentiation. Gene knockout models in mice have been instrumental in revealing these functions, providing insights into its role in development and disease-related processes such as inflammaging and bone-related disorders.

References:

1. Pei, Lijuan, Zhang, Hongjie, Zhang, Meihui, Wang, Yixuan, Wei, Ke. 2022. Rcor2 Is Required for Somatic Differentiation and Represses Germline Cell Fate. In Stem cells international, 2022, 5283615. doi:10.1155/2022/5283615. https://pubmed.ncbi.nlm.nih.gov/35345626/

2. Alvarez-López, María J, Molina-Martínez, Patricia, Castro-Freire, Marco, Sanfeliu, Coral, Kaliman, Perla. 2014. Rcor2 underexpression in senescent mice: a target for inflammaging? In Journal of neuroinflammation, 11, 126. doi:10.1186/1742-2094-11-126. https://pubmed.ncbi.nlm.nih.gov/25051986/

3. Yang, Peng, Wang, Yixuan, Chen, Jiayu, Zhu, Bing, Gao, Shaorong. . RCOR2 is a subunit of the LSD1 complex that regulates ESC property and substitutes for SOX2 in reprogramming somatic cells to pluripotency. In Stem cells (Dayton, Ohio), 29, 791-801. doi:10.1002/stem.634. https://pubmed.ncbi.nlm.nih.gov/21433225/

4. Rummukainen, Petri, Tarkkonen, Kati, Al Majidi, Rana, Ivaska, Kaisa K, Kiviranta, Riku. 2024. The complex role of Rcor2: Regulates mesenchymal stromal cell differentiation in vitro but is dispensable in vivo. In Bone, 187, 117180. doi:10.1016/j.bone.2024.117180. https://pubmed.ncbi.nlm.nih.gov/38944098/