Atf7ip and Setdb1 interaction orchestrates the hematopoietic stem and progenitor cell state with diverse lineage differentiation.
Atf7ip and Setdb1 interaction orchestrates the hematopoietic stem and progenitor cell state with diverse lineage differentiation.
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DOI：
10.1073/pnas.2209062120
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发表时间：
2023-01-03
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
造血干细胞分化的多样性和平衡性对维持外周血稳态至关重要。在这项研究中，我们采用全基因组分析结合延时成像和功能分析来表征发展中的HSPCs。首先，我们分析了斑马鱼突变体，并阐明了Atf7ip和Setdb1在控制决定性造血中的相互作用。然后，我们分析了表观遗传调控，确定了由Atf7ip和Setdb1介导的H3K9me3沉积是协调HSPC干细胞状态与造血分化的关键表观遗传检查点。Atf7ip和Setdb1的相互作用也需要沉默逆转录因子以防止rlr介导的炎症和偏倚的骨髓形成。最后，我们发现ATF7IP/SETDB1缺失抑制白血病细胞生长，诱导分化和炎症，这可能与开发人类恶性肿瘤的表观遗传疗法有关。造血干细胞和祖细胞（HSPCs）是一种异质细胞群，具有扩增、分化和再生能力。在稳定条件下或急性应激下，HSPCs如何协调不同谱系分化的干性状态仍然是未知的。在这里，我们发现缺乏表观遗传调节剂Atf7ip或Setdb1甲基转移酶的斑马鱼突变体会经历过度的髓系分化，同时HSPC扩增受损，表现为T细胞和红系的下降。我们发现Atf7ip通过setdb1介导的H3K9me3修饰和染色质重塑调节造血功能。在造血过程中，Atf7ip和Setdb1的相互作用触发H3K9me3沉积在造血调节基因中，包括cebpβ和cdkn1a，阻止HSPCs失去扩张和过早分化为髓系。同时，Atf7ip或Setdb1的缺失会抑制激活病毒传感器Mda5/ rig - 1样受体（RLR）信号的反转录转座子，从而导致应激驱动的骨髓生成和炎症。我们发现ATF7IP或SETDB1缺失抑制人类白血病细胞生长并诱导髓细胞分化与反转录转座子引发的炎症。这些发现表明，Atf7ip/ setdb1介导的H3K9me3沉积构成了一个全基因组检查点，它阻碍髓细胞潜能并维持HSPC干细胞的多样性血细胞生成，为血液恶性肿瘤的潜在干预提供了独特的见解。
The diverse and balanced differentiation of HSPCs is essential for sustaining the peripheral blood homeostasis. In this study, we employ genome-wide profiling analyses combined with time-lapse imaging and functional assays to characterize developing HSPCs. First, we analyze zebrafish mutants and elucidate the interaction of Atf7ip and Setdb1 in controlling definitive hematopoiesis. We then dissect epigenetic regulations, identifying H3K9me3 deposition mediated by Atf7ip and Setdb1 as a key epigenetic checkpoint that coordinates the HSPC stemness state with hematopoietic differentiation. Atf7ip and Setdb1 interaction is also required for silencing retroelements to prevent RLR-mediated inflammation and biased myelopoiesis. Finally, we uncover that ATF7IP/SETDB1 depletion suppresses leukemic cell growth, inducing differentiation and inflammation, which might be relevant in developing epigenetic therapies for human malignancy. Hematopoietic stem and progenitor cells (HSPCs) are a heterogeneous group of cells with expansion, differentiation, and repopulation capacities. How HSPCs orchestrate the stemness state with diverse lineage differentiation at steady condition or acute stress remains largely unknown. Here, we show that zebrafish mutants that are deficient in an epigenetic regulator Atf7ip or Setdb1 methyltransferase undergo excessive myeloid differentiation with impaired HSPC expansion, manifesting a decline in T cells and erythroid lineage. We find that Atf7ip regulates hematopoiesis through Setdb1-mediated H3K9me3 modification and chromatin remodeling. During hematopoiesis, the interaction of Atf7ip and Setdb1 triggers H3K9me3 depositions in hematopoietic regulatory genes including cebpβ and cdkn1a, preventing HSPCs from loss of expansion and premature differentiation into myeloid lineage. Concomitantly, loss of Atf7ip or Setdb1 derepresses retrotransposons that instigate the viral sensor Mda5/Rig-I like receptor (RLR) signaling, leading to stress-driven myelopoiesis and inflammation. We find that ATF7IP or SETDB1 depletion represses human leukemic cell growth and induces myeloid differentiation with retrotransposon-triggered inflammation. These findings establish that Atf7ip/Setdb1-mediated H3K9me3 deposition constitutes a genome-wide checkpoint that impedes the myeloid potential and maintains HSPC stemness for diverse blood cell production, providing unique insights into potential intervention in hematological malignancy.
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影响因子：
10.5
作者：
Liu S;Brind'Amour J;Karimi MM;Shirane K;Bogutz A;Lefebvre L;Sasaki H;Shinkai Y;Lorincz MC
通讯作者：
Lorincz MC
DOI：
10.1242/dev.131193
发表时间：
2016-04-15
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Rybtsov S;Ivanovs A;Zhao S;Medvinsky A
通讯作者：
Medvinsky A
影响因子：
4.8
作者：
Liu, Lifeng;Ishihara, Ko;Nakao, Mitsuyoshi
通讯作者：
Nakao, Mitsuyoshi
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
56.9
作者：
Cheng, T;Rodrigues, N;Scadden, DT
通讯作者：
Scadden, DT