scholarly journals EED-mediated histone methylation is critical for CNS myelination and remyelination by inhibiting WNT, BMP, and senescence pathways

2020 ◽  
Vol 6 (33) ◽  
pp. eaaz6477 ◽  
Author(s):  
Jiajia Wang ◽  
Lijun Yang ◽  
Chen Dong ◽  
Jincheng Wang ◽  
Lingli Xu ◽  
...  
Keyword(s):  
White Matter ◽  
Histone Methylation ◽  
Bmp Signaling ◽  
Polycomb Repressive Complex 2 ◽  
Morphogenetic Protein ◽  
Specific Manner ◽  
Embryonic Ectoderm Development ◽  
Cns Myelination ◽  
Embryonic Ectoderm

Mutations in the polycomb repressive complex 2 (PRC2) can cause Weaver-like syndrome, wherein a patient cohort exhibits abnormal white matter; however, PRC2 functions in CNS myelination and regeneration remain elusive. We show here that H3K27me3, the PRC2 catalytic product, increases during oligodendrocyte maturation. Depletion of embryonic ectoderm development (EED), a core PRC2 subunit, reduces differentiation of oligodendrocyte progenitors (OPCs), and causes an OPC-to-astrocyte fate switch in a region-specific manner. Although dispensable for myelin maintenance, EED is critical for oligodendrocyte remyelination. Genomic occupancy and transcriptomic analyses indicate that EED establishes a chromatin landscape that selectively represses inhibitory WNT and bone morphogenetic protein (BMP) signaling, and senescence-associated programs. Blocking WNT or BMP pathways partially restores differentiation defects in EED-deficient OPCs. Thus, our findings reveal that EED/PRC2 is a crucial epigenetic programmer of CNS myelination and repair, while demonstrating a spatiotemporal-specific role of PRC2-mediated chromatin silencing in shaping oligodendrocyte identity and lineage plasticity.

scholarly journals EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Shanshan Ai ◽  
Yong Peng ◽  
Chen Li ◽  
Fei Gu ◽  
Xianhong Yu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Histone Deacetylases ◽  
Heart Function ◽  
Histone Mark ◽  
Gene Repression ◽  
Normal Heart ◽  
Proliferating Cells ◽  
Polycomb Repressive Complex 2 ◽  
Embryonic Ectoderm Development ◽  
Embryonic Ectoderm

In proliferating cells, where most Polycomb repressive complex 2 (PRC2) studies have been performed, gene repression is associated with PRC2 trimethylation of H3K27 (H3K27me3). However, it is uncertain whether PRC2 writing of H3K27me3 is mechanistically required for gene silencing. Here, we studied PRC2 function in postnatal mouse cardiomyocytes, where the paucity of cell division obviates bulk H3K27me3 rewriting after each cell cycle. EED (embryonic ectoderm development) inactivation in the postnatal heart (EedCKO) caused lethal dilated cardiomyopathy. Surprisingly, gene upregulation in EedCKO was not coupled with loss of H3K27me3. Rather, the activating histone mark H3K27ac increased. EED interacted with histone deacetylases (HDACs) and enhanced their catalytic activity. HDAC overexpression normalized EedCKO heart function and expression of derepressed genes. Our results uncovered a non-canonical, H3K27me3-independent EED repressive mechanism that is essential for normal heart function. Our results further illustrate that organ dysfunction due to epigenetic dysregulation can be corrected by epigenetic rewiring.

Abstract 15833: LRP1 is a Novel Receptor of Bmper and Required for Pathological Angiogenesis

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Xi Li ◽  
Xinchun Pi
Keyword(s):  
Endothelial Cells ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Bmp Signaling ◽  
Functional Roles ◽  
Oxygen Induced Retinopathy ◽  
Morphogenetic Protein ◽  
Density Lipoprotein Receptor

Low density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional member of the LDL receptor family, impacting a variety of biological processes such as lipid metabolism, endocytosis and signal transduction. However, the role of LRP1 in endothelium was almost unknown. Until recently we discovered that LRP1 is a novel regulator of bone morphogenetic protein (Bmp) signaling through its association with the extracellular modulator-Bmper (Bmp-binding endothelial cell precursor-derived regulator) and regulates zebrafish vascular development. Here we studied the functional roles of LRP1 in mammalian system by performing cell culture studies with endothelial cells (ECs) and analyzing angiogenic defects in oxygen-induced retinopathy model with LRP1flox/flox;Tie2-Cre+/- mice (EC-LRP1 KO). In MECs, we observed that the activation of Src, ERK and tyrosine phosphorylation of multiple proteins were induced by Bmper and this activation was LRP1-dependent since LRP1 knockdown inhibited their activation. However, this Bmper-induced activation was not blocked by Bmp4 neutralized antibody, which suggests that LRP1 is required for Bmp4-independent signaling for Bmper. These data also indicate that Bmper and LRP1 is a novel ligand receptor pair. Moreover, we observed that LRP1 protein was induced in response to 1% hypoxia in both mouse ECs (MECs) and human retinal microvascular endothelial cells, suggesting that LRP1 is required for hypoxia induced endothelial function. In hypoxia condition, EC-LRP1 KO mice resulted in accelerated angiogenesis in retinal endothelial cells, similar to the pattern of Bmper deleted mice. Therefore, we identify that the Bmper/LRP1 signaling is a novel signaling pathway in endothelial cells and their activity regulates angiogenic responses during oxygen-induced retinopathy. This study provides mechanistic insights for angiogenesis-related pathophysiologic conditions.

scholarly journals ALMS1 Regulates TGF-β Signaling and Morphology of Primary Cilia

2021 ◽  
Vol 9 ◽  
Author(s):  
María Álvarez-Satta ◽  
Mauro Lago-Docampo ◽  
Brais Bea-Mascato ◽  
Carlos Solarat ◽  
Sheila Castro-Sánchez ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Line ◽  
Transforming Growth Factor Beta ◽  
Primary Cilia ◽  
Transforming Growth Factor ◽  
Cellular Signaling ◽  
Bmp Signaling ◽  
Morphogenetic Protein ◽  
Growth Factor Beta

In this study, we aimed to evaluate the role of ALMS1 in the morphology of primary cilia and regulation of cellular signaling using a knockdown model of the hTERT-RPE1 cell line. ALMS1 depletion resulted in the formation of longer cilia, which often displayed altered morphology as evidenced by extensive twisting and bending of the axoneme. Transforming growth factor beta/bone morphogenetic protein (TGF-β/BMP) signaling, which is regulated by primary cilia, was similarly affected by ALMS1 depletion as judged by reduced levels of TGFβ-1-mediated activation of SMAD2/3. These results provide novel information on the role of ALMS1 in the function of primary cilia and processing of cellular signaling, which when aberrantly regulated may underlie Alström syndrome.

scholarly journals Noggin Is Novel Inducer of Mesenchymal Stem Cell Adipogenesis

2012 ◽  
Vol 287 (15) ◽  
pp. 12241-12249 ◽  
Author(s):  
Anandi Sawant ◽  
Diptiman Chanda ◽  
Tatyana Isayeva ◽  
George Tsuladze ◽  
W. T. Garvey ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bmp Signaling ◽  
Peroxisome Proliferator ◽  
Inhibitory Effects ◽  
Immunocompetent Mouse ◽  
Peroxisome Proliferator Activated Receptor ◽  
Morphogenetic Protein ◽  
First Time

Noggin is a glycosylated-secreted protein known so far for its inhibitory effects on bone morphogenetic protein (BMP) signaling by sequestering the BMP ligand. We report here for the first time a novel mechanism by which noggin directly induces adipogenesis of mesenchymal stem cells independently of major human adipogenic signals through C/EBPδ, C/EBPα and peroxisome proliferator-activated receptor-γ. Evaluation of a possible mechanism for noggin-induced adipogenesis of mesenchymal stem cells identified the role of Pax-1 in mediating such differentiation. The relevance of elevated noggin levels in obesity was confirmed in a preclinical, immunocompetent mouse model of spontaneous obesity and in human patients with higher body mass index. These data clearly provide a novel role for noggin in inducing adipogenesis and possibly obesity and further indicates the potential of noggin as a therapeutic target to control obesity.

scholarly journals EZH1/2 function mostly within canonical PRC2 and exhibit proliferation-dependent redundancy that shapes mutational signatures in cancer

2019 ◽  
Vol 116 (13) ◽  
pp. 6075-6080 ◽  
Author(s):  
Michel Wassef ◽  
Armelle Luscan ◽  
Setareh Aflaki ◽  
Dina Zielinski ◽  
Pascal W. T. C. Jansen ◽  
...  
Keyword(s):  
Tumor Type ◽  
Loss Of Function ◽  
Polycomb Repressive Complex 2 ◽  
Lymphoid Malignancies ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Chromatin Regulators ◽  
Recurrent Mutations ◽  
Embryonic Ectoderm Development ◽  
Embryonic Ectoderm

Genetic mutations affecting chromatin modifiers are widespread in cancers. In malignant peripheral nerve sheath tumors (MPNSTs), Polycomb repressive complex 2 (PRC2), which plays a crucial role in gene silencing, is inactivated through recurrent mutations in core subunits embryonic ectoderm development (EED) and suppressor of zeste 12 homolog (SUZ12), but mutations in PRC2’s main catalytic subunit enhancer of zeste homolog 2 (EZH2) have never been found. This is in contrast to myeloid and lymphoid malignancies, which harbor frequent loss-of-function mutations in EZH2. Here, we investigated whether the absence of EZH2 mutations in MPNST is due to a PRC2-independent (i.e., noncanonical) function of the enzyme or to redundancy with EZH1. We show that, in the absence of SUZ12, EZH2 remains bound to EED but loses its interaction with all other core and accessory PRC2 subunits. Through genetic and pharmacological analyses, we unambiguously establish that EZH2 is functionally inert in this context, thereby excluding a PRC2-independent function. Instead, we show that EZH1 and EZH2 are functionally redundant in the slowly proliferating MPNST precursors. We provide evidence that the compensatory function of EZH1 is alleviated upon higher proliferation. This work reveals how context-dependent redundancies can shape tumor-type specific mutation patterns in chromatin regulators.

scholarly journals Bone morphogenetic protein signaling in inflammation

2019 ◽  
Vol 244 (2) ◽  
pp. 147-156 ◽  
Author(s):  
David H Wu ◽  
Antonis K Hatzopoulos
Keyword(s):  
Bone Morphogenetic Protein ◽  
Bmp Signaling ◽  
Therapeutic Interventions ◽  
Protein Signaling ◽  
Bone Morphogenetic Protein Signaling ◽  
Morphogenetic Protein ◽  
Therapeutic Value ◽  
Organ Systems ◽  
Different Tissues

Bone morphogenetic protein signaling has long been established as a crucial pathway during embryonic development. In recent years, our knowledge of the function of bone morphogenetic protein signaling has expanded dramatically beyond solely its important role in development. Today, the pathway is known to have important homeostatic functions across multiple different tissues in the adult. Even more importantly, bone morphogenetic protein signaling is now known to function as a driver of diseases in the adult spanning different organ systems. In this review, we will explore the functions of bone morphogenetic protein signaling in diseases of inflammation. Through this exploration, we will highlight the value and challenges in targeting bone morphogenetic protein signaling for therapeutic interventions. Impact statement By compiling findings from recent studies, this review will garner novel insight on the dynamic and complex role of BMP signaling in diseases of inflammation, highlighting the specific roles played by both individual ligands and endogenous antagonists. Ultimately, this summary will help inform the high therapeutic value of targeting this pathway for modulating diseases of inflammation.

scholarly journals TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family

2018 ◽  
Vol 19 (9) ◽  
pp. 2585 ◽  
Author(s):  
Nina Rol ◽  
Konda Kurakula ◽  
Chris Happé ◽  
Harm Bogaard ◽  
Marie-José Goumans
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Cardiovascular Research ◽  
Black Sheep ◽  
Research Fields ◽  
Morphogenetic Protein ◽  
Pulmonary Arterial ◽  
Extended View

Knowledge pertaining to the involvement of transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling in pulmonary arterial hypertension (PAH) is continuously increasing. There is a growing understanding of the function of individual components involved in the pathway, but a clear synthesis of how these interact in PAH is currently lacking. Most of the focus has been on signaling downstream of BMPR2, but it is imperative to include the role of TGF-β signaling in PAH. This review gives a state of the art overview of disturbed signaling through the receptors of the TGF-β family with respect to vascular remodeling and cardiac effects as observed in PAH. Recent (pre)-clinical studies in which these two pathways were targeted will be discussed with an extended view on cardiovascular research fields outside of PAH, indicating novel future perspectives.

scholarly journals The BMP signaling pathway is required together with the FGF pathway for notochord induction in the ascidian embryo

Development ◽  
2001 ◽  
Vol 128 (14) ◽  
pp. 2629-2638 ◽  
Author(s):  
Sébastien Darras ◽  
Hiroki Nishida
Keyword(s):  
Time Window ◽  
Bmp Signaling ◽  
Cell Stage ◽  
Morphogenetic Protein ◽  
Positive Target ◽  
Bmp Pathway ◽  
Notochord Cells ◽  
Bmp Antagonist ◽  
Ascidian Embryo

The 40 notochord cells of the ascidian tadpole invariably arise from two different lineages: the primary (A-line) and the secondary (B-line) lineages. It has been shown that the primary notochord cells are induced by presumptive endoderm blastomeres between the 24-cell and the 64-cell stage. Signaling through the fibroblast growth factor (FGF) pathway is required for this induction. We have investigated the role of the bone morphogenetic protein (BMP) pathway in ascidian notochord formation. HrBMPb (the ascidian BMP2/4 homologue) is expressed in the anterior endoderm at the 44-cell stage before the completion of notochord induction. The BMP antagonist Hrchordin is expressed in a complementary manner in all surrounding blastomeres and appears to be a positive target of the BMP pathway. Unexpectedly, chordin overexpression reduced formation of both primary and secondary notochord. Conversely, primary notochord precursors isolated prior to induction formed notochord in presence of BMP-4 protein. While bFGF protein had a similar activity, notochord precursors showed a different time window of competence to respond to BMP-4 and bFGF. Our data are consistent with bFGF acting from the 24-cell stage, while BMP-4 acts during the 44-cell stage. However, active FGF signaling was also required for induction by BMP-4. In the secondary lineage, notochord specification also required two inducing signals: an FGF signal from anterior and posterior endoderm from the 24-cell stage and a BMP signal from anterior endoderm during the 44-cell stage.

scholarly journals Smad1 expands the hemangioblast population within a limited developmental window

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 516-523 ◽  
Author(s):  
Brian T. Zafonte ◽  
Susanna Liu ◽  
Macarena Lynch-Kattman ◽  
Ingrid Torregroza ◽  
Luke Benvenuto ◽  
...  
Keyword(s):  
Embryoid Body ◽  
Es Cells ◽  
Embryonic Stem ◽  
Bmp Signaling ◽  
Relative Role ◽  
Es Cell ◽  
Morphogenetic Protein ◽  
Important Regulator ◽  
Functional Relevance

Abstract Bone morphogenetic protein (BMP) signaling is an important regulator of hematovascular development. However, the progenitor population that responds to BMP signaling is undefined, and the relative role of downstream mediators including Smad1 is unclear. We find that Smad1 shows a distinctive expression profile as embryonic stem (ES) cells undergo differentiation in the embryoid body (EB) system, with peak levels in cell populations enriched for the hemangioblast. To test the functional relevance of this observation, we generated an ES cell line that allows temporal control of ectopic Smad1 expression. Continuous expression of Smad1 from day 2 of EB culture does not disturb hematopoiesis, according to colony assays. In contrast, a pulse of Smad1 expression exclusively between day 2 and day 2.25 expands the population of progenitors for primitive erythroblasts and other hematopoietic lineages. This effect correlates with increased levels of transcripts encoding markers for the hemangioblast, including Runx1, Scl, and Gata2. Indeed, the pulse of Smad1 induction also expands the blast colony-forming cell (BL-CFC) population at a level that is fully sufficient to explain subsequent increases in hematopoiesis. Our data demonstrate that Smad1 expression is sufficient to expand the number of cells that commit to hemangioblast fate.

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