Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor.
Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor.
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DOI：
10.1016/j.celrep.2017.10.112
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发表时间：
2017-11-21
期刊：
影响因子：
8.8
通讯作者：
Bryder D
中科院分区：
文献类型：
--
作者：
Wahlestedt M;Ladopoulos V;Hidalgo I;Sanchez Castillo M;Hannah R;Säwén P;Wan H;Dudenhöffer-Pfeifer M;Magnusson M;Norddahl GL;Göttgens B;Bryder D
多能干/祖细胞谱系潜能的逐渐限制是成人造血的标志，但支配这些过程的潜在分子事件仍不完全清楚。在这里，我们确定了强大的表达白血病相关的转录因子肝白血病因子（HLF）在正常的多能造血祖细胞，分化后迅速下调。干扰其正常下调揭示Hlf作为淋巴发育的强负调节剂，同时保持与髓系命运相容。反过来，我们观察到快速淋巴承诺后减少HLF活动。Hlf与髓样感受态细胞的活性增强子结合、髓样细胞的转录诱导和淋巴样基因程序的消融导致出现表型，其中Hlf诱导核因子IC（Nfic）作为功能相关的靶基因。因此，我们的研究建立了HLF作为一个关键的调节剂的最早的谱系承诺事件的过渡，从多能性谱系限制的后代，正常和恶性造血的影响。在造血过程中，Hlf在退出多能性时急剧下调。延长的Hlf表达指示GMLP采用髓样命运。下调Hlf的失败与适当的B和T淋巴细胞生成不相容。Hlf控制驱动骨髓生成和抑制淋巴细胞生成的分子程序。Wahlestedt等人鉴定造血分化过程中转录因子Hlf的突然下调。下调Hlf的失败导致成熟血细胞的急剧偏斜的输出，将Hlf定位为造血的关键调节剂。
A gradual restriction in lineage potential of multipotent stem/progenitor cells is a hallmark of adult hematopoiesis, but the underlying molecular events governing these processes remain incompletely understood. Here, we identified robust expression of the leukemia-associated transcription factor hepatic leukemia factor (Hlf) in normal multipotent hematopoietic progenitors, which was rapidly downregulated upon differentiation. Interference with its normal downregulation revealed Hlf as a strong negative regulator of lymphoid development, while remaining compatible with myeloid fates. Reciprocally, we observed rapid lymphoid commitment upon reduced Hlf activity. The arising phenotypes resulted from Hlf binding to active enhancers of myeloid-competent cells, transcriptional induction of myeloid, and ablation of lymphoid gene programs, with Hlf induction of nuclear factor I C (Nfic) as a functionally relevant target gene. Thereby, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis. During hematopoiesis, Hlf is sharply downregulated upon exit from multipotency Prolonged Hlf expression instructs GMLPs to adopt myeloid fates Failure to downregulate Hlf is incompatible with appropriate B and T lymphopoiesis Hlf governs molecular programs driving myelopoiesis and inhibiting lymphopoiesis Regulators of early blood cell formation are important in both health and disease. Wahlestedt et al. identify abrupt downregulation of the transcription factor Hlf during hematopoietic differentiation. Failure to downregulate Hlf leads to a drastically skewed output of mature blood cells, positioning Hlf as a critical regulator of hematopoiesis.
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影响因子：
5.9
作者：
Gazit, Roi;Garrison, Brian S.;Rao, Tata Nageswara;Shay, Tal;Costello, James;Ericson, Jeff;Kim, Francis;Collins, James J.;Regev, Aviv;Wagers, Amy J.;Rossi, Derrick J.
通讯作者：
Rossi, Derrick J.
NFIL3/E4BP4是在体内开发和成熟所必需的。
DOI：
10.1084/jem.20092176
发表时间：
2009-12-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kamizono S;Duncan GS;Seidel MG;Morimoto A;Hamada K;Grosveld G;Akashi K;Lind EF;Haight JP;Ohashi PS;Look AT;Mak TW
通讯作者：
Mak TW
影响因子：
30.8
作者：
Fischer U;Forster M;Rinaldi A;Risch T;Sungalee S;Warnatz HJ;Bornhauser B;Gombert M;Kratsch C;Stütz AM;Sultan M;Tchinda J;Worth CL;Amstislavskiy V;Badarinarayan N;Baruchel A;Bartram T;Basso G;Canpolat C;Cario G;Cavé H;Dakaj D;Delorenzi M;Dobay MP;Eckert C;Ellinghaus E;Eugster S;Frismantas V;Ginzel S;Haas OA;Heidenreich O;Hemmrich-Stanisak G;Hezaveh K;Höll JI;Hornhardt S;Husemann P;Kachroo P;Kratz CP;Te Kronnie G;Marovca B;Niggli F;McHardy AC;Moorman AV;Panzer-Grümayer R;Petersen BS;Raeder B;Ralser M;Rosenstiel P;Schäfer D;Schrappe M;Schreiber S;Schütte M;Stade B;Thiele R;von der Weid N;Vora A;Zaliova M;Zhang L;Zichner T;Zimmermann M;Lehrach H;Borkhardt A;Bourquin JP;Franke A;Korbel JO;Stanulla M;Yaspo ML
通讯作者：
Yaspo ML
DOI：
10.1084/jem.20072168
发表时间：
2008-05-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Benz C;Martins VC;Radtke F;Bleul CC
通讯作者：
Bleul CC
影响因子：
56.9
作者：
INABA, T;ROBERTS, WM;LOOK, AT
通讯作者：
LOOK, AT