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Bradley J. Merrill - One of the best experts on this subject based on the ideXlab platform.
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stage specific regulation of reprogramming to induced pluripotent stem cells by wnt signaling and t cell factor proteins
Cell Reports, 2013Co-Authors: Bernadett Papp, Jackson A. Hoffman, Bradley J. Merrill, Kathrin PlathAbstract:Wnt signaling is intrinsic to mouse embryonic stem cell self-renewal. Therefore, it is surprising that reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is not strongly enhanced by Wnt signaling. Here, we demonstrate that active Wnt signaling inhibits the early stage of reprogramming to iPSCs, whereas it is required and even stimulating during the late stage. Mechanistically, this biphasic effect of Wnt signaling is accompanied by a change in the requirement of all four of its transcriptional effectors: T cell factor 1 (Tcf1), Lef1, TCF3, and Tcf4. For example, TCF3 and Tcf4 are stimulatory early but inhibitory late in the reprogramming process. Accordingly, ectopic expression of TCF3 early in reprogramming combined with its loss of function late enables efficient reprogramming in the absence of ectopic Sox2. Together, our data indicate that the stepwise process of reprogramming to iPSCs is critically dependent on the stage-specific control and action of all four Tcfs and Wnt signaling.
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function of wnt β catenin in counteracting TCF3 repression through the TCF3 β catenin interaction
Development, 2012Co-Authors: Jackson A. Hoffman, Hoang Nguyen, Elaine Fuchs, Brian R Shy, Erin M Ford, Bradley J. MerrillAbstract:The canonical Wnt/β-catenin signaling pathway classically functions through the activation of target genes by Tcf/Lef-β-catenin complexes. In contrast to β-catenin-dependent functions described for Tcf1, Tcf4 and Lef1, the known embryonic functions for TCF3 in mice, frogs and fish are consistent with β-catenin-independent repressor activity. In this study, we genetically define TCF3-β-catenin functions in mice by generating a TCF3ΔN knock-in mutation that specifically ablates TCF3-β-catenin. Mouse embryos homozygous for the knock-in mutation (TCF3(ΔN/ΔN)) progress through gastrulation without apparent defects, thus genetically proving that TCF3 function during gastrulation is independent of β-catenin interaction. TCF3(ΔN/ΔN) mice were not viable, and several post-gastrulation defects revealed the first in vivo functions of TCF3-β-catenin interaction affecting limb development, vascular integrity, neural tube closure and eyelid closure. Interestingly, the etiology of defects indicated an indirect role for TCF3-β-catenin in the activation of target genes. TCF3 directly represses transcription of Lef1, which is stimulated by Wnt/β-catenin activity. These genetic data indicate that TCF3-β-catenin is not necessary to activate target genes directly. Instead, our findings support the existence of a regulatory circuit whereby Wnt/β-catenin counteracts TCF3 repression of Lef1, which subsequently activates target gene expression via Lef1-β-catenin complexes. We propose that the Tcf/Lef circuit model provides a mechanism downstream of β-catenin stability for controlling the strength of Wnt signaling activity during embryonic development.
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t cell factor 3 TCF3 deletion increases somatic cell reprogramming by inducing epigenome modifications
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Frederic Lluis, Bradley J. Merrill, Luigi Ombrato, Elisa Pedone, Stefano Pepe, Maria Pia CosmaAbstract:The heterochromatin barrier must be overcome to generate induced pluripotent stem cells and cell fusion-mediated reprogrammed hybrids. Here, we show that the absence of T-cell factor 3 (TCF3), a repressor of β-catenin target genes, strikingly and rapidly enhances the efficiency of neural precursor cell (NPC) reprogramming. Remarkably, TCF3−/− ES cells showed a genome-wide increase in AcH3 and decrease in H3K9me3 and can reprogram NPCs after fusion greatly. In addition, during reprogramming of NPCs into induced pluripotent stem cells, the silencing of TCF3 increased AcH3 and decreased the number of H3K9me3-positive heterochromatin foci early and long before reactivation of the endogenous stem cell genes. In conclusion, our data suggest that TCF3 functions as a repressor of the reprogramming potential of somatic cells.
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opposing effects of TCF3 and tcf1 control wnt stimulation of embryonic stem cell self renewal
Nature Cell Biology, 2011Co-Authors: Fei Yi, Jackson A. Hoffman, Laura Pereira, Courtney M Yuen, Bradley J. MerrillAbstract:Inhibition of the repressor function of the Wnt3a effector β-catenin–TCF3 is shown to be required to maintain pluripotency in cooperation with the activating role of the second Wnt effector β-catenin–TCF1. Both TCF3 and Tcf1 are involved in the recruitment of β-catenin to Oct4 binding sites in embryonic stem cell chromatin.
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opposing effects of TCF3 and tcf1 control wnt stimulation of embryonic stem cell self renewal
Nature Cell Biology, 2011Co-Authors: Laura Pereira, Jackson A. Hoffman, Courtney M Yuen, Brian R Shy, David R Liu, Bradley J. MerrillAbstract:The co-occupancy of TCF3 with Oct4, Sox2 and Nanog on embryonic stem cell (ESC) chromatin indicated that TCF3 has been suggested to play an integral role in a poorly understood mechanism underlying Wnt-dependent stimulation of mouse ESC self-renewal of mouse ESCs. Although the conventional view of Tcf proteins as the β-catenin-binding effectors of Wnt signalling suggested TCF3-β-catenin activation of target genes would stimulate self-renewal, here we show that an antagonistic relationship between Wnt3a and TCF3 on gene expression regulates ESC self-renewal. Genetic ablation of TCF3 replaced the requirement for exogenous Wnt3a or GSK3 inhibition for ESC self-renewal, demonstrating that inhibition of TCF3 repressor is the necessary downstream effect of Wnt signalling. Interestingly, both TCF3-β-catenin and Tcf1-β-catenin interactions contributed to Wnt stimulation of self-renewal and gene expression, and the combination of TCF3 and Tcf1 recruited Wnt-stabilized β-catenin to Oct4 binding sites on ESC chromatin. This work elucidates the molecular link between the effects of Wnt and the regulation of the Oct4/Sox2/Nanog network.
Elaine Fuchs - One of the best experts on this subject based on the ideXlab platform.
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in vivo transcriptional governance of hair follicle stem cells by canonical wnt regulators
Nature Cell Biology, 2014Co-Authors: Wen-hui Lien, Lisa Polak, Deyou Zheng, Elaine FuchsAbstract:Hair follicle stem cells (HFSCs) regenerate hair in response to Wnt signalling. Here, we unfold genome-wide transcriptional and chromatin landscapes of β-catenin-TCF3/4-TLE circuitry, and genetically dissect their biological roles within the native HFSC niche. We show that during HFSC quiescence, TCF3, TCF4 and TLE (Groucho) bind coordinately and transcriptionally repress Wnt target genes. We also show that β-catenin is dispensable for HFSC viability, and if TCF3/4 levels are sufficiently reduced, it is dispensable for proliferation. However, β-catenin is essential to activate genes that launch hair follicle fate and suppress sebocyte fate determination. TCF3/4 deficiency mimics Wnt-β-catenin-dependent activation of these hair follicle fate targets; TCF3 overexpression parallels their TLE4-dependent suppression. Our studies unveil TCF3/4-TLE histone deacetylases as a repressive rheostat, whose action can be relieved by Wnt-β-catenin signalling. When TCF3/4 and TLE levels are high, HFSCs can maintain stemness, but remain quiescent. When these levels drop or when Wnt-β-catenin levels rise, this balance is shifted and hair regeneration initiates. © 2014 Macmillan Publishers Limited. All rights reserved.
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function of wnt β catenin in counteracting TCF3 repression through the TCF3 β catenin interaction
Development, 2012Co-Authors: Jackson A. Hoffman, Hoang Nguyen, Elaine Fuchs, Brian R Shy, Erin M Ford, Bradley J. MerrillAbstract:The canonical Wnt/β-catenin signaling pathway classically functions through the activation of target genes by Tcf/Lef-β-catenin complexes. In contrast to β-catenin-dependent functions described for Tcf1, Tcf4 and Lef1, the known embryonic functions for TCF3 in mice, frogs and fish are consistent with β-catenin-independent repressor activity. In this study, we genetically define TCF3-β-catenin functions in mice by generating a TCF3ΔN knock-in mutation that specifically ablates TCF3-β-catenin. Mouse embryos homozygous for the knock-in mutation (TCF3(ΔN/ΔN)) progress through gastrulation without apparent defects, thus genetically proving that TCF3 function during gastrulation is independent of β-catenin interaction. TCF3(ΔN/ΔN) mice were not viable, and several post-gastrulation defects revealed the first in vivo functions of TCF3-β-catenin interaction affecting limb development, vascular integrity, neural tube closure and eyelid closure. Interestingly, the etiology of defects indicated an indirect role for TCF3-β-catenin in the activation of target genes. TCF3 directly represses transcription of Lef1, which is stimulated by Wnt/β-catenin activity. These genetic data indicate that TCF3-β-catenin is not necessary to activate target genes directly. Instead, our findings support the existence of a regulatory circuit whereby Wnt/β-catenin counteracts TCF3 repression of Lef1, which subsequently activates target gene expression via Lef1-β-catenin complexes. We propose that the Tcf/Lef circuit model provides a mechanism downstream of β-catenin stability for controlling the strength of Wnt signaling activity during embryonic development.
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TCF3 and Tcf4 are essential for long-term homeostasis of skin epithelia
Nature Genetics, 2009Co-Authors: Hoang Nguyen, Bradley J. Merrill, Lisa Polak, Maria Nikolova, Michael Rendl, Timothy M Shaver, H Amalia Pasolli, Elaine FuchsAbstract:Single-layered embryonic skin either stratifies to form epidermis or responds to Wnt signaling (stabilized beta-catenin) to form hair follicles. Postnatally, stem cells continue to differentially use Wnt signaling in long-term tissue homeostasis. We have discovered that embryonic progenitor cells and postnatal hair follicle stem cells coexpress TCF3 and Tcf4, which can act as transcriptional activators or repressors. Using loss-of-function studies and transcriptional analyses, we uncovered consequences to the absence of TCF3 and Tcf4 in skin that only partially overlap with those caused by beta-catenin deficiency. We established roles for TCF3 and Tcf4 in long-term maintenance and wound repair of both epidermis and hair follicles, suggesting that Tcf proteins have both Wnt-dependent and Wnt-independent roles in lineage determination.
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TCF3 governs stem cell features and represses cell fate determination in skin
Cell, 2006Co-Authors: Hoang Nguyen, Michael Rendl, Elaine FuchsAbstract:Many stem cells (SCs) respond to Wnt signaling, but whether β-catenin's DNA binding partners, the Tcfs, play a role in SCs in the absence of Wnts, is unknown. In adult skin, quiescent multipotent progenitors express TCF3 and commit to a hair cell fate in response to Wnt signaling. We find that embryonic skin progenitors also express TCF3. Using an inducible system in mice, we show that upon TCF3 reactivation, committed epidermal cells induce genes associated with an undifferentiated, Wnt-inhibited state and TCF3 promotes a transcriptional program shared by embryonic and postnatal SCs. Further, TCF3-repressed genes include transcriptional regulators of the epidermal, sebaceous gland and hair follicle differentiation programs, and correspondingly, all three terminal differentiation pathways are suppressed when TCF3 is induced postnatally. These data suggest that in the absence of Wnt signals, TCF3 may function in skin SCs to maintain an undifferentiated state and, through Wnt signaling, directs these cells along the hair lineage.
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TCF3 a transcriptional regulator of axis induction in the early embryo
Development, 2003Co-Authors: Bradley J. Merrill, Lisa Polak, Michael Rendl, Amalia H Pasolli, Maria J Garciagarcia, Kathryn V Anderson, Elaine FuchsAbstract:The roles of Lef/Tcf proteins in determining cell fate characteristics have been described in many contexts during vertebrate embryogenesis, organ and tissue homeostasis, and cancer formation. Although much of the accumulated work on these proteins involves their ability to transactivate target genes when stimulated by beta-catenin, Lef/Tcf proteins can repress target genes in the absence of stabilized beta-catenin. By ablating TCF3 function, we have uncovered an important requirement for a repressor function of Lef/Tcf proteins during early mouse development. TCF3-/- embryos proceed through gastrulation to form mesoderm, but they develop expanded and often duplicated axial mesoderm structures, including nodes and notochords. These duplications are preceded by ectopic expression of Foxa2, an axial mesoderm gene involved in node specification, with a concomitant reduction in Lefty2, a marker for lateral mesoderm. By contrast, expression of a beta-catenin-dependent, Lef/Tcf reporter (TOPGal), is not ectopically activated but is faithfully maintained in the primitive streak. Taken together, these data reveal a unique requirement for TCF3 repressor function in restricting induction of the anterior-posterior axis.
Ai Yoshimi - One of the best experts on this subject based on the ideXlab platform.
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znf384 related fusion genes define a subgroup of childhood b cell precursor acute lymphoblastic leukemia with a characteristic immunotype
Haematologica, 2017Co-Authors: Shinsuke Hirabayashi, Kentaro Ohki, Kazuhiko Nakabayashi, Hitoshi Ichikawa, Yukihide Momozawa, Kohji Okamura, Akinori Yaguchi, Kazuki Terada, Yuya Saito, Ai YoshimiAbstract:Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 7 fusion partners have been reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or polymerase chain reaction. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384 . Including the EP300-ZNF384 that we reported recently, the total frequency of ZNF384 -related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotype of weak CD10 and aberrant CD13 and/or CD33 expression was revealed to be a common feature of the leukemic cells harboring ZNF384 -related fusion genes. The signature gene expression profile in TCF3-ZNF384 -positive patients was enriched in hematopoietic stem cell features and related to that of EP300-ZNF384 -positive patients, but was significantly distinct from that of TCF3-PBX1 -positive and ZNF384 -fusion-negative patients. However, clinical features of TCF3-ZNF384 -positive patients are markedly different from those of EP300-ZNF384 -positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3-ZNF384 -positive patients revealed a significantly poorer steroid response and a higher frequency of relapse, and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384 -related fusion genes consist of a distinct subgroup of B-cell precursor acute lymphoblastic leukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.
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znf384 related fusion genes consist of a subgroup with a characteristic immunophenotype in childhood b cell precursor acute lymphoblastic leukemia
Haematologica, 2016Co-Authors: Shinsuke Hirabayashi, Kentaro Ohki, Kazuhiko Nakabayashi, Hitoshi Ichikawa, Yukihide Momozawa, Kohji Okamura, Akinori Yaguchi, Kazuki Terada, Yuya Saito, Ai YoshimiAbstract:Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 6 fusion partners have reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or PCR. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384. Including EP300-ZNF384 that we reported recently, the total frequency of ZNF384-related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotype of weak CD10 and aberrant CD13 and/or CD33 expression was revealed to be a common feature of the leukemic cells harboring ZNF384-related fusion genes. The signature gene expression profile in TCF3-ZNF384-positive patients was enriched in hematopoietic stem cell features and related to that of EP300-ZNF384-positive patients, but significantly distinct from that of TCF3-PBX1-positive and ZNF384-fusions-negative patients. However, clinical features of TCF3-ZNF384-positive patients are markedly different from those of EP300-ZNF384-positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3-ZNF384-positive patients revealed a significantly poorer steroid response and higher frequency of relapse and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384-related fusion genes consist of a distinct subgroup of B-cell precursor acute lymphoblastic leukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.
Shinsuke Hirabayashi - One of the best experts on this subject based on the ideXlab platform.
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znf384 related fusion genes define a subgroup of childhood b cell precursor acute lymphoblastic leukemia with a characteristic immunotype
Haematologica, 2017Co-Authors: Shinsuke Hirabayashi, Kentaro Ohki, Kazuhiko Nakabayashi, Hitoshi Ichikawa, Yukihide Momozawa, Kohji Okamura, Akinori Yaguchi, Kazuki Terada, Yuya Saito, Ai YoshimiAbstract:Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 7 fusion partners have been reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or polymerase chain reaction. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384 . Including the EP300-ZNF384 that we reported recently, the total frequency of ZNF384 -related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotype of weak CD10 and aberrant CD13 and/or CD33 expression was revealed to be a common feature of the leukemic cells harboring ZNF384 -related fusion genes. The signature gene expression profile in TCF3-ZNF384 -positive patients was enriched in hematopoietic stem cell features and related to that of EP300-ZNF384 -positive patients, but was significantly distinct from that of TCF3-PBX1 -positive and ZNF384 -fusion-negative patients. However, clinical features of TCF3-ZNF384 -positive patients are markedly different from those of EP300-ZNF384 -positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3-ZNF384 -positive patients revealed a significantly poorer steroid response and a higher frequency of relapse, and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384 -related fusion genes consist of a distinct subgroup of B-cell precursor acute lymphoblastic leukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.
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znf384 related fusion genes consist of a subgroup with a characteristic immunophenotype in childhood b cell precursor acute lymphoblastic leukemia
Haematologica, 2016Co-Authors: Shinsuke Hirabayashi, Kentaro Ohki, Kazuhiko Nakabayashi, Hitoshi Ichikawa, Yukihide Momozawa, Kohji Okamura, Akinori Yaguchi, Kazuki Terada, Yuya Saito, Ai YoshimiAbstract:Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 6 fusion partners have reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or PCR. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384. Including EP300-ZNF384 that we reported recently, the total frequency of ZNF384-related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotype of weak CD10 and aberrant CD13 and/or CD33 expression was revealed to be a common feature of the leukemic cells harboring ZNF384-related fusion genes. The signature gene expression profile in TCF3-ZNF384-positive patients was enriched in hematopoietic stem cell features and related to that of EP300-ZNF384-positive patients, but significantly distinct from that of TCF3-PBX1-positive and ZNF384-fusions-negative patients. However, clinical features of TCF3-ZNF384-positive patients are markedly different from those of EP300-ZNF384-positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3-ZNF384-positive patients revealed a significantly poorer steroid response and higher frequency of relapse and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384-related fusion genes consist of a distinct subgroup of B-cell precursor acute lymphoblastic leukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.
Anthony V Moorman - One of the best experts on this subject based on the ideXlab platform.
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molecular cytogenetic characterization of TCF3 e2a 19p13 3 rearrangements in b cell precursor acute lymphoblastic leukemia
Genes Chromosomes and Cancer, 2007Co-Authors: Kerry E Barber, Christine J Harrison, Zoe J Broadfield, Adam Stewart, Sarah L Wright, M Martineau, Jonathan C Strefford, Anthony V MoormanAbstract:The t(1; 19)(q23;p 13.3) is one of the most common chromosomal abnormalities in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and usually gives rise to the TCF3-PBXI fusion gene. Additional rare, and sometimes cytogenetically cryptic, translocations involving the TCF3 gene have also been described. Using a dual color split-signal fluorescence in situ hybridization (FISH) probe, we have investigated the involvement of this gene in a series of BCP-ALLs harboring 19p 13 translocations, as well as an unselected patient cohort. The TCF3 gene was shown to be involved in the majority of cases with a cytogenetically visible t(1; 19) translocation, while the remaining TCF3-negative ALLs demonstrated breakpoint heterogeneity. Although most "other" 19p 13 translocations did not produce a split-signal FISH pattern, a novel t(13; 1 9)(q 14;p 13) involving TCF3 was discovered. A prospective screen of 161 children with BCP-ALL revealed a cryptic t(12; 19)(p13;p 13), another novel TCF3 rearrangement, and a series of patients with submicroscopic deletions of TCF3. These results demonstrate the utility of a split-signal FISH strategy in confirming the involvement of the TCF3 gene in 19p 13 rearrangements and in identifying novel and cryptic TCF3 translocations. In addition to its role as a fusion partner gene, we propose that TCF3 can also act as a tumor suppressor gene in BCP-ALL. (c) 2007 Wiley-Liss, Inc
