Chen Zhe, Wu Feng, Li Yan, Li Lei, Lei Yufei, Gao Siwei, Chen Tao, Xie Yuxin, Xiao Jianwen, Zeng Hanqing, Deng Jianchuan, Zhao Xueya, Hou Yu
Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China.
School of Basic Medical Sciences, Chongqing Medical University , Chongqing, China.
J Exp Med. 2025 Mar 3;222(3). doi: 10.1084/jem.20241248. Epub 2025 Jan 21.
Hematopoietic stem cells (HSCs) are susceptible to replication stress, which is a major contributor to HSC defects in Fanconi anemia (FA). Here, we report that HSCs relax the global chromatin by downregulating the expression of a chromatin architectural protein, DEK, in response to replication stress. DEK is abnormally accumulated in bone marrow (BM) CD34+ cells from patients with FA and in Fancd2-deficient HSCs. DEK haploinsufficiency promotes chromatin relaxation, replication stress relief, and function recovery of Fancd2-deficient HSCs. Furthermore, inhibition of DEK restores the proliferation of FA CD34+ cells in vitro and enhances their engraftment in vivo. Mechanistically, the activating transcription factor 2 (ATF2), specifically phosphorylated ATF2 at Thr69/71, was identified as a promoter of DEK transcription. Fancd2 deficiency results in p38 hyperphosphorylation, which in turn phosphorylates ATF2 at Thr69/71, leading to DEK accumulation in HSCs. In conclusion, our findings establish a functional link between chromatin relaxation and replication stress tolerance in HSCs and highlight DEK as a target for FA.
造血干细胞（HSCs）易受复制应激影响，而复制应激是范可尼贫血（FA）中造血干细胞缺陷的主要促成因素。在此，我们报告造血干细胞通过下调一种染色质结构蛋白DEK的表达来缓解整体染色质状态，以应对复制应激。DEK在FA患者的骨髓（BM）CD34 +细胞和Fancd2缺陷的造血干细胞中异常积累。DEK单倍体不足促进了Fancd2缺陷造血干细胞的染色质松弛、复制应激缓解和功能恢复。此外，抑制DEK可恢复FA CD34 +细胞在体外的增殖，并增强它们在体内的植入。从机制上讲，激活转录因子2（ATF2），特别是在苏氨酸69/71位点特异性磷酸化的ATF2，被确定为DEK转录的启动子。Fancd2缺陷导致p38过度磷酸化，进而在苏氨酸69/71位点磷酸化ATF2，导致DEK在造血干细胞中积累。总之，我们的研究结果建立了造血干细胞中染色质松弛与复制应激耐受性之间的功能联系，并突出了DEK作为FA治疗靶点的地位。
