小柯机器人

美国莫德纳公司Kate L. Jeffrey研究团发现，表观遗传学阅读器SP140功能丧失通过巨噬细胞中拓扑异构酶的失调驱动克罗恩病。相关论文于2022年8月10日在线发表在《细胞》杂志上。

研究人员表示，人们对调控不当的染色质如何直接影响人类免疫性疾病知之甚少。Speckled Protein140（SP140）是一种免疫限制性的PHD和bromodomain的表观遗传"阅读器"，SP140功能丧失的突变与克罗恩病（CD）、多发性硬化（MS）和慢性淋巴细胞白血病（CLL）有关。然而，这些突变的相关性和SP140驱动的致病性机制仍未得到探索。

利用全局蛋白质组学策略，研究人员发现SP140是拓扑异构酶（TOP）的抑制因子，并维持异染色质和巨噬细胞的命运。在人类和小鼠中，SP140的缺失导致了TOP活性的释放，发育沉默基因的去抑制，并最终导致了微生物诱导的巨噬细胞转录程序和细菌杀伤的缺陷，从而驱动了肠道病理。对TOP1/2的药物抑制挽救了这些缺陷。此外，用TOP1/2抑制剂可以恢复体内Sp140^-/-小鼠而非野生型小鼠的恶化结肠炎。总之，研究人员确定SP140是一个TOP抑制因子，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。

附：英文原文

Title: Epigenetic reader SP140 loss of function drives Crohn’s disease due to uncontrolled macrophage topoisomerases

Author: Hajera Amatullah, Isabella Fraschilla, Sreehaas Digumarthi, Julie Huang, Fatemeh Adiliaghdam, Gracia Bonilla, Lai Ping Wong, Marie-Eve Rivard, Claudine Beauchamp, Virginie Mercier, Philippe Goyette, Ruslan I. Sadreyev, Robert M. Anthony, John D. Rioux, Kate L. Jeffrey

Issue&Volume: 2022-08-010

Abstract: How mis-regulated chromatin directly impacts human immune disorders is poorly understood.Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containingepigenetic “reader,” and SP140 loss-of-function mutations associate with Crohn’s disease(CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). However, therelevance of these mutations and mechanisms underlying SP140-driven pathogenicityremains unexplored. Using a global proteomic strategy, we identified SP140 as a repressorof topoisomerases (TOPs) that maintains heterochromatin and macrophage fate. In humansand mice, SP140 loss resulted in unleashed TOP activity, de-repression of developmentallysilenced genes, and ultimately defective microbe-inducible macrophage transcriptionalprograms and bacterial killing that drive intestinal pathology. Pharmacological inhibitionof TOP1/2 rescued these defects. Furthermore, exacerbated colitis was restored withTOP1/2 inhibitors in Sp140/ mice, but not wild-type mice, in vivo. Collectively, we identify SP140 as a TOP repressor and reveal repurposing of TOPinhibition to reverse immune diseases driven by SP140 loss.

DOI: 10.1016/j.cell.2022.06.048

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00841-8