ETV6 represses inflammatory response genes and regulates HSPC function during stress hematopoiesis in mice.
ETV6 represses inflammatory response genes and regulates HSPC function during stress hematopoiesis in mice.
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ETV6 在小鼠应激造血过程中抑制炎症反应基因并调节 HSPC 功能。
DOI：
10.1182/bloodadvances.2022009313
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发表时间：
2023-09-26
期刊：
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
--
作者：
血小板减少症5相关ETV 6变体的种系杂合性损害小鼠HSPC的再增殖能力在HSPCs中，ETV 6与Tnf和其他炎性基因位点结合，并在应激造血过程中抑制其表达。ETS变体6（ETV 6）编码在造血干细胞和祖细胞（HSPC）中表达的转录阻遏物，其中它是成人造血所需的。杂合致病种系ETV 6变体与血小板减少症5（T5）相关，这是一种人们知之甚少的遗传性疾病，可导致血小板减少症和血液恶性肿瘤的易感性。为了阐明种系ETV 6变体如何影响HSPC并促成疾病，我们产生了携带Etv 6 R355 X功能丧失变体的小鼠模型，其相当于T5相关变体ETV 6 R359 X。在稳态条件下，Etv 6 R355 X/+小鼠的骨髓（BM）中存在所有HSPC亚群;然而，这些动物显示祖细胞亚型的比例和/或数量发生变化。为了检查Etv 6 R355 X/+突变是否影响HSPC功能，我们进行了系列竞争性移植，并观察到Etv 6 R355 X/+谱系− sca 1 +cKit+（LSK）细胞表现出受损的重建，几乎完全无法通过第三次移植重新填充受照射者。结合靶下切割和核酸酶测定下释放、转座酶可及染色质测序测定和高通量染色体构象捕获的机制研究鉴定了ETV 6在炎性基因位点的结合，包括ETV 6充足的小鼠和人HSPC中肿瘤坏死因子（TNF）信号通路内的多个基因。此外，移植后分离的BM细胞的单细胞RNA测序揭示了与Etv 6 +/+对应物相比，Etv 6 R355 X/+祖细胞中炎性基因的上调。证实了这些发现，Etv 6 R355 X/+ HSPC在移植后比Etv 6 +/+细胞产生显著更多的TNF。我们的结论是，ETV 6需要抑制造血应激条件下HSPC中的炎症基因表达，这种机制可能是维持HSPC功能的关键。
Germline heterozygosity for a thrombocytopenia 5–associated ETV6 variant impairs the repopulating capacity of mouse HSPCs. In HSPCs, ETV6 binds to Tnf and other inflammatory gene loci and represses their expression during stress hematopoiesis. ETS variant 6 (ETV6) encodes a transcriptional repressor expressed in hematopoietic stem and progenitor cells (HSPCs), where it is required for adult hematopoiesis. Heterozygous pathogenic germline ETV6 variants are associated with thrombocytopenia 5 (T5), a poorly understood genetic condition resulting in thrombocytopenia and predisposition to hematologic malignancies. To elucidate how germline ETV6 variants affect HSPCs and contribute to disease, we generated a mouse model harboring an Etv6R355X loss-of-function variant, equivalent to the T5-associated variant ETV6R359X. Under homeostatic conditions, all HSPC subpopulations are present in the bone marrow (BM) of Etv6R355X/+ mice; however, these animals display shifts in the proportions and/or numbers of progenitor subtypes. To examine whether the Etv6R355X/+ mutation affects HSPC function, we performed serial competitive transplantation and observed that Etv6R355X/+ lineage−sca1+cKit+ (LSK) cells exhibit impaired reconstitution, with near complete failure to repopulate irradiated recipients by the tertiary transplant. Mechanistic studies incorporating cleavage under target and release under nuclease assay, assay for transposase accessible chromatin sequencing, and high-throughput chromosome conformation capture identify ETV6 binding at inflammatory gene loci, including multiple genes within the tumor necrosis factor (TNF) signaling pathway in ETV6-sufficient mouse and human HSPCs. Furthermore, single-cell RNA sequencing of BM cells isolated after transplantation reveals upregulation of inflammatory genes in Etv6R355X/+ progenitors when compared to Etv6+/+ counterparts. Corroborating these findings, Etv6R355X/+ HSPCs produce significantly more TNF than Etv6+/+ cells post-transplantation. We conclude that ETV6 is required to repress inflammatory gene expression in HSPCs under conditions of hematopoietic stress, and this mechanism may be critical to sustain HSPC function.
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影响因子：
30.8
作者：
Doerfler PA;Feng R;Li Y;Palmer LE;Porter SN;Bell HW;Crossley M;Pruett-Miller SM;Cheng Y;Weiss MJ
通讯作者：
Weiss MJ
DOI：
10.1056/nejmoa1512234
发表时间：
2016-03-17
期刊：
The New England journal of medicine
影响因子：
--
作者：
Kuehn HS;Boisson B;Cunningham-Rundles C;Reichenbach J;Stray-Pedersen A;Gelfand EW;Maffucci P;Pierce KR;Abbott JK;Voelkerding KV;South ST;Augustine NH;Bush JS;Dolen WK;Wray BB;Itan Y;Cobat A;Sorte HS;Ganesan S;Prader S;Martins TB;Lawrence MG;Orange JS;Calvo KR;Niemela JE;Casanova JL;Fleisher TA;Hill HR;Kumánovics A;Conley ME;Rosenzweig SD
通讯作者：
Rosenzweig SD
影响因子：
7.5
作者：
Bellissimo, Dana C.;Chen, Chia-hui;Speck, Nancy A.
通讯作者：
Speck, Nancy A.
DOI：
10.1038/s41568-020-00315-z
发表时间：
2021-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Klco JM;Mullighan CG
通讯作者：
Mullighan CG
影响因子：
20.3
作者：
do O, PP;Carlsson, L
通讯作者：
Carlsson, L