c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation

Wilson, Anne; Murphy, Mark; Oskarsson, Thordur; Kaloulis, Konstantinos; Bettess, Michael D.; Oser, Gabriela M.; Pasche, Anne Catherine; Knabenhans, Christian; MacDonald, H. Robson; Trumpp, Andreas

doi:10.1101/gad.313104

Cited by 727 publications

(716 citation statements)

References 87 publications

Supporting

Mentioning

662

Contrasting

Unclassified

Order By: Relevance

“…Removal of HSCs from this niche may induce a genetic program promoting cell lineage commitment to the detriment of replication. Interestingly, low levels of c-myc were recently shown to be indispensable for sustaining undifferentiated HSCs within the bone marrow niche while high levels induced a transient-amplifying cell population which proliferated while differentiating [52]. Likewise, we found that c-myc mRNA levels were higher in cell clusters as compared to control or treated rat samples (data not show), thus providing a potential explanation for the loss of self-renewal competence of the cells.…”

Section: Discussionmentioning

confidence: 56%

Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins

Corcelle¹,

Stieger

Gjinovci³

et al. 2006

Experimental Cell Research

View full text Add to dashboard Cite

Despite extensive studies, the hematopoietic versus hepatic origin of liver progenitor oval cells remains controversial. The aim of this study was to determine the origin of such cells after liver injury and to establish an oval cell line. Rat liver injury was induced by subcutaneous insertion of 2-AAF pellets for 7 days with subsequent injection of CCl 4 . Livers were removed 9 to 13 days post-CCl 4 treatment. Immunohistochemistry was performed using anti-c-kit, OV6, Thy1, CK19, AFP, vWF and Rab3b. Isolated non-parenchymal cells were grown on mouse embryonic fibroblast, and their gene expression profile was characterized by RT-PCR. We identified a subpopulation of OV6/CK19/Rab3b-expressing cells that was activated in the periportal region of traumatized livers. We also characterized a second subpopulation that expressed the HSCs marker c-kit but not Thy1. Although we successfully isolated both cell types, OV6/CK19/Rab3b + cells fail to propagate while c-kit + -HSCs appeared to proliferate for up to 7 weeks. Cells formed clusters which expressed c-kit, Thy1 and albumin. Our results indicate that a bona fide oval progenitor cell population resides within the liver and is distinct from c-kit + -HSCs. Oval cells require the hepatic niche to proliferate, while cells mobilized from the circulation proliferate and transdifferentiate into hepatocytes without evidence of cell fusion.

show abstract

Section: Discussionmentioning

confidence: 56%

Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins

Corcelle¹,

Stieger

Gjinovci³

et al. 2006

Experimental Cell Research

View full text Add to dashboard Cite

show abstract

“…The most likely cause of HSC expansion was altered proliferative behavior. Thus, ki67 and Hoechst staining were used to assign cells to G 0 , G 1 or S/G 2 /M cell cycle phases 24,25 (Figure 2f (Primers P1, P2 (P3 not shown, binding Rosa26 wild-type allele)) and specific shLSD1 (P4, P5) genotyping PCR protocols. (c) Schematic drawing of the TET-ON system used to induce the LSD1-specific shRNA in vivo.…”

Section: Resultsmentioning

confidence: 99%

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Sprüssel¹,

Schulte²,

et al. 2012

View full text Add to dashboard Cite

“…Together with the other hematopoietic and HSC deficits, the image suggests that HSCs lacking FBP aberrantly partition between renewal and commitment. Although disturbances in the expression of Myc and Mycn alter the balance between HSC self-renewal and differentiation, 43,44 the scarcity of HSCs and their relatively low level of Myc expression (in comparison with high Myc expression states or tumors) thwarted several attempts to assess the levels and variation in Myc between individual WT and Fubp1 À/À HSCs. Therefore, the influence of FBP on Myc expression was assessed in other embryonic cells.…”

Section: Fbp Is Essential For Hsc Functionmentioning

confidence: 99%

Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

Zhou

Chung

Castellar

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

The transcription factor far upstream element binding protein (FBP) binds and activates the MYC promoter when far upstream element is via TFIIH helicase activity early in the transcription cycle. The fundamental biology and pathology of FBP are complex. In some tumors FBP seems pro-oncogenic, whereas in others it is a tumor suppressor. We generated an FBP knockout (Fubp1 À/À ) mouse to study FBP deficiency. FBP is embryo lethal from embryonic day 10.5 to birth. A spectrum of pathology is associated with FBP loss; besides cerebral hyperplasia and pulmonary hypoplasia, pale livers, hypoplastic spleen, thymus, and bone marrow, cardiac hypertrophy, placental distress, and small size were all indicative of anemia. Immunophenotyping of hematopoietic cells in wild-type versus knockout livers revealed irregular trilineage anemia, with deficits in colony formation. Despite normal numbers of hematopoietic stem cells, transplantation of Fubp1 À/À hematopoietic stem cells into irradiated mice entirely failed to reconstitute hematopoiesis. In competitive transplantation assays against wild-type donor bone marrow, Fubp1 À/À hematopoietic stem cells functioned only sporadically at a low level. Although cultures of wild-type mouse embryo fibroblasts set Myc levels precisely, Myc levels of mouse varied wildly between fibroblasts harvested from different Fubp1 À/À embryos, suggesting that FBP contributes to Myc set point fixation. FBP helps to hold multiple physiologic processes to close tolerances, at least in part by constraining Myc expression. The transcription factor Myc plays a decisive role in cell growth, differentiation, and senescence and so must be highly regulated. The far upstream element (FUSE) binding protein (FBP) binds single-stranded DNA of FUSE 1.7 kb upstream of the major P2 promoter of the human MYC gene. 1e3 FUSE melting in response to dynamic supercoils propagated from the MYC promoters enables FBP binding. FBP activates TFIIH helicase activity to accelerate the transcription cycle from preinitiation complex assembly through promoter escape and onto pause release. 4e6 Positive regulation of MYC is at least in part counteracted by FBP interacting repressor (FIR) that binds FBP and FUSE and opposes TFIIH helicase activity, retarding the transcription cycle. 5,7 Besides MYC, FBP regulates the expression of the cyclin-dependent kinase inhibitor p21, stathmin, and USP29, a powerful stabilizer of p53 induced by oxidative stress. 8e10 Because the FBP/FIR system reads single-stranded DNA sequences exposed by transcriptionally generated dynamic supercoiling, it is proposed that the FBP/ FIR/FUSE system serves as a molecular cruise control that monitors the mechanical output of promoters in real time while providing both positive and negative feedback. 11e13Supported by the NIH

show abstract

c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation

Cited by 727 publications

References 87 publications

Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins

Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

Contact Info

Product

Resources

About