Tcf7 is an important regulator of the switch of self-renewal and differentiation in a multipotential hematopoietic cell line.
Jia Qian Wu,Montrell Seay,Vincent P. Schulz,Manoj Hariharan,David Tuck,Jin Lian,Jiang Du,Minyi Shi,Zhijia Ye,Mark Gerstein,Michael Snyder,Sherman M. Weissman +11 more
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TLDR
Fundamental cell-intrinsic properties of the switch between self-renewal and differentiation, and valuable insights for manipulating HSCs and other differentiating systems are demonstrated.Abstract:
A critical problem in biology is understanding how cells choose between self-renewal and differentiation. To generate a comprehensive view of the mechanisms controlling early hematopoietic precursor self-renewal and differentiation, we used systems-based approaches and murine EML multipotential hematopoietic precursor cells as a primary model. EML cells give rise to a mixture of self-renewing Lin-SCA+CD34+ cells and partially differentiated non-renewing Lin-SCA-CD34− cells in a cell autonomous fashion. We identified and validated the HMG box protein TCF7 as a regulator in this self-renewal/differentiation switch that operates in the absence of autocrine Wnt signaling. We found that Tcf7 is the most down-regulated transcription factor when CD34+ cells switch into CD34− cells, using RNA–Seq. We subsequently identified the target genes bound by TCF7, using ChIP–Seq. We show that TCF7 and RUNX1 (AML1) bind to each other's promoter regions and that TCF7 is necessary for the production of the short isoforms, but not the long isoforms of RUNX1, suggesting that TCF7 and the short isoforms of RUNX1 function coordinately in regulation. Tcf7 knock-down experiments and Gene Set Enrichment Analyses suggest that TCF7 plays a dual role in promoting the expression of genes characteristic of self-renewing CD34+ cells while repressing genes activated in partially differentiated CD34− state. Finally a network of up-regulated transcription factors of CD34+ cells was constructed. Factors that control hematopoietic stem cell (HSC) establishment and development, cell growth, and multipotency were identified. These studies in EML cells demonstrate fundamental cell-intrinsic properties of the switch between self-renewal and differentiation, and yield valuable insights for manipulating HSCs and other differentiating systems.read more
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Defining CD8 + T cells that provide the proliferative burst after PD-1 therapy
Se Jin Im,Masao Hashimoto,Michael Y. Gerner,Michael Y. Gerner,Junghwa Lee,Haydn T. Kissick,Matheus Carvalho Bürger,Qiang Shan,J. Scott Hale,Judong Lee,Tahseen H. Nasti,Arlene H. Sharpe,Arlene H. Sharpe,Gordon J. Freeman,Ronald N. Germain,Helder I. Nakaya,Hai-Hui Xue,Rafi Ahmed +17 more
TL;DR: A population of virus-specific CD8+ T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus is identified and its findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD- 1-directed immunotherapy in chronic infections and cancer.
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The Robustness and Evolvability of Transcription Factor Binding Sites
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Large-Scale Quality Analysis of Published ChIP-seq Data
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TCF-1 and LEF-1 act upstream of Th-POK to promote the CD4 + T cell fate and interact with Runx3 to silence Cd4 in CD8 + T cells
Farrah C. Steinke,Shuyang Yu,Xinyuan Zhou,Bing He,Wenjing Yang,Bo Zhou,Hiroshi Kawamoto,Jun Zhu,Kai Tan,Hai-Hui Xue +9 more
TL;DR: In this paper, the role of TCF-1 and LEF1 in the CD4-versus-CD8 lineage 'choice' was mediated in part by direct positive regulation of the transcription factor Th-POK.
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Gene Regulatory Programs Conferring Phenotypic Identities to Human NK Cells.
Patrick L. Collins,Marina Cella,Sofia I. Porter,Shasha Li,Greer L. Gurewitz,Henoch S. Hong,R. Paul Johnson,Eugene M. Oltz,Marco Colonna +8 more
TL;DR: In this paper, the authors report integrated analysis of human natural killer (NK) subsets, which revealed super-enhancers associated with gene cohorts that may coordinate NK functions and localization.
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