Center for the Study of Inflammatory Bowel Disease, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital Research Institute, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
Center for the Study of Inflammatory Bowel Disease, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital Research Institute, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2022 Aug 18;185(17):3232-3247.e18. doi: 10.1016/j.cell.2022.06.048. Epub 2022 Aug 10.
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.
染色质调控失调如何直接影响人类免疫紊乱尚不清楚。斑点蛋白 140（SP140）是一种免疫受限的 PHD 和溴结构域包含的表观遗传“读取器”，SP140 功能丧失突变与克罗恩病（CD）、多发性硬化症（MS）和慢性淋巴细胞白血病（CLL）相关。然而，这些突变的相关性及其背后的 SP140 驱动的致病性机制仍未被探索。使用全局蛋白质组学策略，我们确定 SP140 是拓扑异构酶（TOPs）的抑制剂，可维持异染色质和巨噬细胞命运。在人类和小鼠中，SP140 的缺失导致 TOP 活性失控、发育沉默基因的去抑制以及最终导致微生物诱导的巨噬细胞转录程序和细菌杀伤缺陷，从而导致肠道病理学。TOP1/2 的药物抑制可挽救这些缺陷。此外，在体内，用 TOP1/2 抑制剂可恢复 Sp140 小鼠而非野生型小鼠的加重结肠炎。总的来说，我们确定 SP140 是 TOP 的抑制剂，并揭示了重新利用 TOP 抑制来逆转由 SP140 缺失驱动的免疫疾病。
