| First Author | Daniel B | Year | 2018 |
| Journal | Immunity | Volume | 49 |
| Issue | 4 | Pages | 615-626.e6 |
| PubMed ID | 30332629 | Mgi Jnum | J:305322 |
| Mgi Id | MGI:6706532 | Doi | 10.1016/j.immuni.2018.09.005 |
| Citation | Daniel B, et al. (2018) The Nuclear Receptor PPARgamma Controls Progressive Macrophage Polarization as a Ligand-Insensitive Epigenomic Ratchet of Transcriptional Memory. Immunity 49(4):615-626.e6 |
| abstractText | Macrophages polarize into distinct phenotypes in response to complex environmental cues. We found that the nuclear receptor PPARgamma drove robust phenotypic changes in macrophages upon repeated stimulation with interleukin (IL)-4. The functions of PPARgamma on macrophage polarization in this setting were independent of ligand binding. Ligand-insensitive PPARgamma bound DNA and recruited the coactivator P300 and the architectural protein RAD21. This established a permissive chromatin environment that conferred transcriptional memory by facilitating the binding of the transcriptional regulator STAT6 and RNA polymerase II, leading to robust production of enhancer and mRNAs upon IL-4 re-stimulation. Ligand-insensitive PPARgamma binding controlled the expression of an extracellular matrix remodeling-related gene network in macrophages. Expression of these genes increased during muscle regeneration in a mouse model of injury, and this increase coincided with the detection of IL-4 and PPARgamma in the affected tissue. Thus, a predominantly ligand-insensitive PPARgamma:RXR cistrome regulates progressive and/or reinforcing macrophage polarization. |
