scholarly journals Bone morphogenetic protein 4 reduces global H3K4me3 to inhibit proliferation and promote differentiation of human neural stem cells

2020 ◽  
Author(s):  
Sonali Nayak ◽  
Benjamin Best ◽  
Emily Hayes ◽  
Ashorne Mahenthiran ◽  
Nitin R Wadhwani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Bone Morphogenetic Protein ◽  
Neural Stem Cell ◽  
Posttranslational Modifications ◽  
Transforming Growth Factor ◽  
Ectopic Expression ◽  
Nervous System Development ◽  
Epigenetic Mechanism ◽  
Bone Morphogenetic Protein 4 ◽  
Morphogenetic Protein

ABSTRACTPosttranslational modifications (PTMs) on histone tails spatiotemporally dictate mammalian neural stem cell (NSC) fate. Bone morphogenetic protein 4 (BMP4), a member of the transforming growth factor β (TGF-β) superfamily, suppresses NSC proliferation and fosters differentiation into astroglial cells. Whether PTMs mediate these effects of BMP4 is unknown. Here we demonstrate that BMP4 signaling causes a net reduction in cellular histone H3 lysine 4 trimethylation (H3K4me3), an active histone mark at promoters of genes associated with human NSC proliferation. We also show that H3K4me3 reduction by BMP4 is mediated by decreased expression of SETD1A and WDR82, two methyltransferase components of SETD1A-COMPASS. Down-regulation of these components decreases expression of key genes expressed in hNSCs, while ectopic expression via transfection dedifferentiates human astrocytes (HAs). These observations suggest that BMP4 influences NSC fate by regulating PTMs and altering chromatin structure.SIGNIFICANCE STATEMENTBMP4 is critical in determining hNSC fate. Whether histone posttranslational modifications (PTM) mediate the effects of BMP4 is unknown. Here we report that H3K4me3, brought about by its methyltransferases SETD1A and WDR82, at promoters of stem cell genes OCT4 and NESTIN is involved in human neural stem cell (hNSC) maintenance. BMP4 promotes hNSC astroglial differentiation in part through reduction of SETD1A and WDR82 and thus decreased frequency of H3K4me3 at the promoters of these genes. These results provide evidence that BMP4 promotes hNSC differentiation through a potential epigenetic mechanism and extend our understanding of the role of histone PTM in central nervous system development.

Bone Morphogenetic Protein 4 Regulates Hematopoietic Stem Cell Maintenance in Vivo.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1399-1399
Author(s):  
Devorah C. Goldman ◽  
Alexis S. Bailey ◽  
Dana L. Pfaffle ◽  
Jan L. Christian ◽  
William H. Fleming
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Bone Morphogenetic Protein ◽  
Peripheral Blood ◽  
Bone Morphogenetic Protein 4 ◽  
Hematopoietic Stem ◽  
Morphogenetic Protein ◽  
Fold Reduction ◽  
Donor Cells

Abstract The secreted signaling molecule Bone Morphogenetic Protein 4 (BMP4) is expressed by osteoblasts and other cell types that comprise the hematopoietic microenvironment. Therefore, we hypothesized that BMP4 may play an important regulatory role in the maintenance and function of hematopoietic stem cells (HSCs). As the deletion of BMP4 is lethal during early embryogenesis, we exploited a viable BMP4 hypomorph in which a point mutation in BMP4 reduces, but does not abolish the amount of active BMP4 ligand. In these mutants, peripheral blood cell lineages and bone marrow cellularity are normal during steady state conditions. However, consistent with our hypothesis, 40% fewer c-kit+, Sca-1+, lineage- (KSL) cells were present in the femurs of mutants (7.4 x103 ± 0.4 x103 SEM) than in age-and sex-matched wild-type (WT) controls (12.4 x103 ± 1.3 x103, p<0.005). Transplantation of mutant KSL cells produced levels of hematopoietic engraftment indistinguishable from transplanted WT KSL cells, consistent with a stem cell extrinsic effect of BMP4. To functionally assess the mutant hematopoietic microenvironment, unfractionated WT bone marrow cells (BM) were transplanted into lethally irradiated mutants or WT controls. Although WT cells could engraft mutant primary recipients to the same degree as WT recipients, serial transplantation of these WT cells into secondary WT hosts revealed a marked depletion of hematopoietic reconstitution activity. Specifically, nearly a 4-fold reduction of donor cells was found in the peripheral blood of secondary recipients that received BM from reconstituted mutant hosts (p<0.0005). To determine whether such defects in the mutant microenvironment exist in the absence of myeloablative conditioning and transplantation, a parabiotic mouse model was employed. CD45.1 WT mice were joined to CD45.2 BMP4 hypomorphs for 8 weeks and then separated. As early as one month following separation, a greater than 2- fold reduction in circulating WT donor cells was detected in mutant hosts relative to the number of mutant donor cells detected in the WT hosts (p<0.005). Analysis of BM at 24 weeks following separation revealed a striking 23- fold reduction in WT donor hematopoietic cells in the mutant host BM compared to the number of mutant hematopoietic cells detected in WT host BM. Together, our findings reveal a novel, critical role for BMP4 in maintaining HSCs in vivo.

Bone morphogenetic protein 4: a ventralizing factor in early Xenopus development

Development ◽  
1992 ◽  
Vol 115 (2) ◽  
pp. 573-585 ◽  
Author(s):  
L. Dale ◽  
G. Howes ◽  
B.M. Price ◽  
J.C. Smith
Keyword(s):  
Growth Factor ◽  
Bone Morphogenetic Protein ◽  
Transforming Growth Factor ◽  
Bone Morphogenetic Protein 4 ◽  
Tgf Beta ◽  
Simultaneous Treatment ◽  
Animal Pole ◽  
Morphogenetic Protein ◽  
Pole Cells

The mesoderm of amphibian embryos such as Xenopus laevis arises through an inductive interaction in which cells of the vegetal hemisphere of the embryo act on overlying equatorial and animal pole cells. Three classes of ‘mesoderm-inducing factor’ (MIF) that might be responsible for this interaction in vivo have been discovered. These are members of the transforming growth factor type beta (TGF-beta), fibroblast growth factor (FGF) and Wnt families. Among the most potent MIFs are the activins, members of the TGF-beta family, but RNA for activin A and B is not detectable in the Xenopus embryo until neurula and late blastula stages, respectively, and this is probably too late for the molecules to act as natural inducers. In this paper, we use the polymerase chain reaction to clone additional members of the TGF-beta family that might possess mesoderm-inducing activity. We show that transcripts encoding Xenopus bone morphogenetic protein 4 (XBMP-4) are detectable in the unfertilized egg, and that injection of XBMP-4 RNA into the animal hemisphere of Xenopus eggs causes animal caps isolated from the resulting blastulae to express mesoderm-specific markers. Surprisingly, however, XBMP-4 preferentially induces ventral mesoderm, whereas the closely related activin induces axial tissues. Furthermore, the action of XBMP-4 is ‘dominant’ over that of activin. In this respect, XBMP-4 differs from basic FGF, another ventral inducer, where simultaneous treatment with FGF and activin results in activin-like responses. The dominance of XBMP-4 over activin may account for the ability of injected XBMP-4 RNA to ‘ventralize’ whole Xenopus embryos. It is interesting, however, that blastopore formation in such embryos can occur perfectly normally. This contrasts with embryos ventralized by UV-irradiation and suggests that XBMP-4-induced ventralization occurs after the onset of gastrulation.

scholarly journals Evaluation of specific germ cell genes expression in mouse embryonic stem cell-derived germ cell like cells treated with bone morphogenetic protein 4 in vitro

2018 ◽  
Vol 16 (8) ◽  
pp. 507-518
Author(s):  
Maryam Gholamitabar Tabari ◽  
Seyed Gholam Ali Jorsaraei ◽  
Mohammad Ghasemzadeh-Hasankolaei ◽  
Ali Asghar Ahmadi ◽  
Neda Mahdinezhad Gorji ◽  
...  
Keyword(s):  
Stem Cell ◽  
Germ Cell ◽  
Embryonic Stem Cell ◽  
Bone Morphogenetic Protein ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cell ◽  
Bone Morphogenetic Protein 4 ◽  
Morphogenetic Protein ◽  
Genes Expression
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