UM171介導CoREST功能喪失的機制
作者：
小柯機器人發布時間：2021/1/9 21:07:08
加拿大蒙特婁大學免疫學與癌症研究所（IRIC）Guy Sauvageau研究組取得最新進展。他們提出UM171保留了通過增強CLR3-KBTBD4複合物的強度在人類造血幹細胞（HSC）的原代培養中減少的表觀遺傳標記。相關論文於2021年1月7日發表在《細胞-幹細胞》雜誌上。
他們報告UM171增強了CULLIN3-E3泛素連接酶（CRL3）複合物的活性，該複合物的靶標特異性由表徵不良的Kelch / BTB結構域蛋白KBTBD4決定。CRL3 KBTBD4靶向賴氨酸特異性脫甲基酶LSD1）/ RCOR1核心共抑制複合物的組分以進行蛋白酶體降解，因此重新建立了H3K4me2和H3K27ac表觀遺傳標記，這些標記在離體培養人HSC時迅速降低。
據介紹，離體培養時，HSC會顯示其自我更新能力的下降，這一過程在使用表觀遺傳修飾劑，尤其是組蛋白脫乙醯基酶（HDACs）或LSD1的治療後會部分逆轉。最近的一項研究表明，人類HSC自我更新激動劑UM171調節CoREST複合物，導致LSD1降解，其抑制作用模擬UM171的活性。UM171介導的CoREST功能喪失的潛在機制尚未確定。
附：英文原文
Title: UM171 Preserves Epigenetic Marks that Are Reduced in Ex Vivo Culture of Human HSCs via Potentiation of the CLR3-KBTBD4 Complex
Author: Jalila Chagraoui, Simon Girard, Jean-Francois Spinella, Laura Simon, Eric Bonneil, Nadine Mayotte, Tara MacRae, Jasmin Coulombe-Huntington, Thierry Bertomeu, Celine Moison, Elisa Tomellini, Pierre Thibault, Mike Tyers, Anne Marinier, Guy Sauvageau
Issue&Volume: 2021/01/07
Abstract: Human hematopoietic stem cells (HSCs) exhibit attrition of their self-renewal capacitywhen cultured ex vivo, a process that is partially reversed upon treatment with epigenetic modifiers, mostnotably inhibitors of histone deacetylases (HDACs) or lysine-specific demethylaseLSD1. A recent study showed that the human HSC self-renewal agonist UM171 modulatesthe CoREST complex, leading to LSD1 degradation, whose inhibition mimics the activityof UM171. The mechanism underlying the UM171-mediated loss of CoREST function remainsundetermined. We now report that UM171 potentiates the activity of a CULLIN3-E3 ubiquitinligase (CRL3) complex whose target specificity is dictated by the poorly characterizedKelch/BTB domain protein KBTBD4. CRL3KBTBD4 targets components of the LSD1/RCOR1 corepressor complex for proteasomal degradation,hence re-establishing H3K4me2 and H3K27ac epigenetic marks, which are rapidly decreasedupon ex vivo culture of human HSCs.
DOI: 10.1016/j.stem.2020.12.002
Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30586-5