動態3D基因組控制HSC狀態轉換
作者：
小柯機器人發布時間：2020/11/27 13:20:20
加拿大大學健康網瑪格麗特公主癌症中心Mathieu Lupien和John E. Dick課題組合作取得最新進展。他們揭示人類造血幹細胞從靜止狀態到活躍狀態的轉換由動態3D基因組重組控制。該項研究成果發表在2020年11月25日出版的《細胞-幹細胞》雜誌上。
由於造血幹細胞轉換所基於的轉錄變化很少，因此他們使用單細胞和批量測定法對人類HSC和造血幹細胞和祖細胞（HSPC）亞群進行轉座酶可及的染色質測序（ATAC-seq），以揭示染色質可及性特徵，其中包括長期造血幹細胞（LT-HSC）（LT / HSPC特徵）和另一個不包括LT-HSC（激活的HSPC [Act / HSPC]特徵）。這些特徵在早期造血的產生和分化過程中相反。Act / HSPC特徵包含CCCTC結合因子（CTCF）結合位點，該位點介導參與短期HSC（ST-HSC）而不是LT-HSC的351個染色質相互作用，並封閉了在LT-HSC中活躍並在ST-HSC中受阻的多個乾性途徑基因。
CTCF沉默可抑制乾性基因，抑制靜態LT-HSC轉換成活躍的ST-HSC。因此，由CTCF集中介導的3D染色質相互作用賦予了關守功能，該功能通過協調與靜止和自我更新有關的不同乾性途徑來控制HSC最早進行的命運轉變。
研究人員表示，終身造血需要LT-HSC（以涉及靜止和自我更新的乾性為標誌）轉變為具有降低乾性活躍ST-HSC。
附：英文原文
Title: The Transition from Quiescent to Activated States in Human Hematopoietic Stem Cells Is Governed by Dynamic 3D Genome Reorganization
Author: Naoya Takayama, Alex Murison, Shin-ichiro Takayanagi, Christopher Arlidge, Stanley Zhou, Laura Garcia-Prat, Michelle Chan-Seng-Yue, Sasan Zandi, Olga I. Gan, Héléna Boutzen, Kerstin B. Kaufmann, Aaron Trotman-Grant, Erwin Schoof, Ken Kron, Noelia Díaz, John J.Y. Lee, Tiago Medina, Daniel D. De Carvalho, Michael D. Taylor, Juan M. Vaquerizas, Stephanie Z. Xie, John E. Dick, Mathieu Lupien
Issue&Volume: 2020-11-25
Abstract: Lifelong blood production requires long-term hematopoietic stem cells (LT-HSCs), markedby stemness states involving quiescence and self-renewal, to transition into activatedshort-term HSCs (ST-HSCs) with reduced stemness. As few transcriptional changes underliethis transition, we used single-cell and bulk assay for transposase-accessible chromatinsequencing (ATAC-seq) on human HSCs and hematopoietic stem and progenitor cell (HSPC)subsets to uncover chromatin accessibility signatures, one including LT-HSCs (LT/HSPCsignature) and another excluding LT-HSCs (activated HSPC [Act/HSPC] signature). Thesesignatures inversely correlated during early hematopoietic commitment and differentiation.The Act/HSPC signature contains CCCTC-binding factor (CTCF) binding sites mediating351 chromatin interactions engaged in ST-HSCs, but not LT-HSCs, enclosing multiplestemness pathway genes active in LT-HSCs and repressed in ST-HSCs. CTCF silencingderepressed stemness genes, restraining quiescent LT-HSCs from transitioning to activatedST-HSCs. Hence, 3D chromatin interactions centrally mediated by CTCF endow a gatekeeperfunction that governs the earliest fate transitions HSCs make by coordinating disparatestemness pathways linked to quiescence and self-renewal.
DOI: 10.1016/j.stem.2020.11.001
Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30539-7