加拿大大学健康网玛格丽特公主癌症中心Mathieu Lupien和John E. Dick课题组合作取得最新进展。他们揭示人类造血干细胞从静止状态到活跃状态的转换由动态3D基因组重组控制。该项研究成果发表在2020年11月25日出版的《细胞-干细胞》杂志上。
由于造血干细胞转换所基于的转录变化很少，因此他们使用单细胞和批量测定法对人类HSC和造血干细胞和祖细胞（HSPC）亚群进行转座酶可及的染色质测序（ATAC-seq），以揭示染色质可及性特征，其中包括长期造血干细胞（LT-HSC）（LT / HSPC特征）和另一个不包括LT-HSC（激活的HSPC [Act / HSPC]特征）。这些特征在早期造血的产生和分化过程中相反。Act / HSPC特征包含CCCTC结合因子（CTCF）结合位点，该位点介导参与短期HSC（ST-HSC）而不是LT-HSC的351个染色质相互作用，并封闭了在LT-HSC中活跃并在ST-HSC中受阻的多个干性途径基因。
CTCF沉默可抑制干性基因，抑制静态LT-HSC转换成活跃的ST-HSC。因此，由CTCF集中介导的3D染色质相互作用赋予了关守功能，该功能通过协调与静止和自我更新有关的不同干性途径来控制HSC最早进行的命运转变。
研究人员表示，终身造血需要LT-HSC（以涉及静止和自我更新的干性为标志）转变为具有降低干性活跃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
Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
官方网址：https://www.cell.com/cell-stem-cell/home
投稿链接：https://www.editorialmanager.com/cell-stem-cell/default.aspx
本期文章：《细胞—干细胞》：Online/在线发表
