| First Author | Amatullah H | Year | 2022 |
| Journal | Cell | Volume | 185 |
| Issue | 17 | Pages | 3232-3247.e18 |
| PubMed ID | 35952671 | Mgi Jnum | J:333206 |
| Mgi Id | MGI:7332641 | Doi | 10.1016/j.cell.2022.06.048 |
| Citation | Amatullah H, et al. (2022) Epigenetic reader SP140 loss of function drives Crohn's disease due to uncontrolled macrophage topoisomerases. Cell 185(17):3232-3247.e18 |
| abstractText | How mis-regulated chromatin directly impacts human immune disorders is poorly understood. Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containing epigenetic "reader," and SP140 loss-of-function mutations associate with Crohn's disease (CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). However, the relevance of these mutations and mechanisms underlying SP140-driven pathogenicity remains unexplored. Using a global proteomic strategy, we identified SP140 as a repressor of topoisomerases (TOPs) that maintains heterochromatin and macrophage fate. In humans and mice, SP140 loss resulted in unleashed TOP activity, de-repression of developmentally silenced genes, and ultimately defective microbe-inducible macrophage transcriptional programs and bacterial killing that drive intestinal pathology. Pharmacological inhibition of TOP1/2 rescued these defects. Furthermore, exacerbated colitis was restored with TOP1/2 inhibitors in Sp140(-/-) mice, but not wild-type mice, in vivo. Collectively, we identify SP140 as a TOP repressor and reveal repurposing of TOP inhibition to reverse immune diseases driven by SP140 loss. |
