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J Dent Res ; 93 : — Feng XH, Derynck R. Annu Rev Cell Dev Biol ; 21 : — Balemans W, Hul WV. Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators.

Moustakas A, Heldin CH. Development ; : — Schmierer B, Hill CS. Nat Rev Mol Cell Biol ; 8 : — The role of microRNAs in self-renewal and differentiation of mesenchymal stem cells. Exp Hematol ; 39 : — Bone morphogenetic proteins in tissue engineering: the road from the laboratory to the clinic, part I basic concepts. J Tissue Eng Regen Med ; 2 : 1— A review of hedgehog signaling in cranial bone development. Front Physiol ; 4 : Sonic hedgehog regulates osteoblast function by focal adhesion kinase signaling in the process of fracture healing.

Synergistic effect of Indian hedgehog and bone morphogenetic protein-2 gene transfer to increase the osteogenic potential of human mesenchymal stem cells.

Stem Cell Res Ther ; 4 : Wnt signaling in bone formation and its therapeutic potential for bone diseases. Ther Adv Musculoskelet Dis ; 5 : 13— Role of Wnt signaling in bone remodeling and repair. HSS J ; 4 : 66— PubMed Google Scholar. Int J Cell Biol ; : Integration of BMP, Wnt, and notch signaling pathways in osteoblast differentiation. J Cell Biochem ; : — Cancer Res ; 73 : — Osteogenic activity of the fourteen types of human bone morphogenetic proteins BMPs.

Google Scholar. Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery.

Gene Therapy ; 11 : — BMP-9 induced osteogenic differentiation of mesenchymal stem cells: molecular mechanism and therapeutic potential. Curr Gene Ther ; 11 : — BMP9 signaling in stem cell differentiation and osteogenesis.

Am J Stem Cells ; 2 : 1— Beyond osteogenesis: an in vitro comparison of the potentials of six bone morphogenetic proteins. Front Pharmacol ; 4 : Bone morphogenetic protein signaling modulates myocardin transactivation of cardiac genes. Circ Res ; 97 : — Update on bone morphogenetic proteins and their application in spine surgery.

J Am Coll Surg ; : — Overexpression of BMP3 in the developing skeleton alters endochondral bone formation resulting in spontaneous rib fractures. Dev Dyn ; : — Mech Dev ; : 79— Dev Biol ; : 39— A novel role of bone morphogenetic protein-6 BMP-6 as an endocrine regulator of bone and glucose homeostasis. Bone ; 47 : S Tsumaki N, Yoshikawa H. The role of bone morphogenetic proteins in endochondral bone formation. Cytokine Growth Factor Rev ; 16 : — Brain Res ; : 49— Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior—posterior axis.

EMBO Rep ; 7 : — BMP emerges as a potential inhibitor of bone formation. Int J Biol Sci ; 5 : — Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein BMP15 gene.

Am J Hum Genet ; 75 : — Japanese case of hereditary hemorrhagic telangiectasia type 2 with a novel mutation, c. Neurol Clin Neurosci ; 2 : — J Biol Chem ; : — Germ line mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet ; 28 : — Int J Biol Sci ; 8 : — The genetics of pulmonary arterial hypertension in the post-BMPR2 era.

Pulm Circ ; 1 : — A soluble activin type IIA receptor induces bone formation and improves skeletal integrity. Goncalves MD. Bone morphogenetic protein receptors and signal transduction. J Biochem ; : 35— Wang T, Xu Z. Biochem Biophys Res Commun ; : — Smad transcription factors. Genes Dev ; 19 : — Smad6 is essential to limit BMP signaling during cartilage development. J Bone Miner Res ; 26 : — A common SMAD7 variant is associated with risk of colorectal cancer: evidence from a case-control study and a meta-analysis.

AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell ; 84 : — Smad signal pathway in BMPinduced osteogenesis a mini review. J Dent Sci ; 3 : 13— Runx3 controls the axonal projection of proprioceptive dorsal root ganglion neurons. Nat Neurosci ; 5 : — Regulation of bone morphogenetic protein activity by prodomains and proprotein convertases.

J Cell Biol ; : — Szpalski M, Gunzburg R. Recombinant human bone morphogenetic protein a novel osteoinductive alternative to autogenous bone graft? Acta Orthop Belg ; 71 : — Osteogenic molecules for clinical applications: improving the BMP-collagen system. Biol Res ; 46 : — Bone morphogenetic proteins: from structure to clinical use. Braz J Med Biol Res ; 38 : — Bone morphogenetic proteins: periodontal regeneration.

N Am J Med Sci ; 5 : — Antagonism of activin by activin chimeras. Vitam Horm ; 85 : — Initiation of BMP2 signaling in domains on the plasma membrane. J Cell Physiol ; : — Structure of the ternary signaling complex of a TGF-beta superfamily member. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Nat Genet ; 38 : — Cell J ; 16 : 91— Observations on the induction of bone in soft tissues. J Bone Joint Surg Br ; 57 : 36— Fibrodysplasia ossificans progressiva.

Best Pract Res Clin Rheumatol ; 22 : — When one skeleton is enough: approaches and strategies for the treatment of fibrodysplasia ossificans progressiva FOP. Drug Discov Today Ther Strateg ; 5 : — BMP type I receptor inhibition reduces heterotopic ossification. Nat Med ; 14 : — Bone ; 48 : — Hum Mutat ; 30 : — Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients.

Rarely occurring mutation of ACVR1 gene in Moroccan patient with fibrodysplasia ossificans progressiva. Clin Rheumatol ; 29 : — Clin Genet ; 77 : — Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements.

Eur J Hum Genet ; 17 : — Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva.

Mol Cell Biol ; 33 : — Lowery JW, Rosen V. Gene Therapy ; 19 : — Crystal structure of a phosphorylated Smad2. Mol Cell ; 8 : — J Mol Graph Model ; 27 : — Signaling inputs converge on nuclear effectors in TGF-beta signaling.

Trends Biochem Sci ; 25 : 64— BMP induces cochlin expression to facilitate self-renewal and suppress neural differentiation of mouse embryonic stem cells. Embo J ; 17 : — A human Mad protein acting as a BMP-regulated transcriptional activator.

Nature ; : — Characterization of a bone morphogenetic protein-responsive Smad-binding element. Mol Biol Cell ; 11 : — BMP signaling dynamics in embryonic orofacial tissue. Nucleic Acids Res ; 39 : — Smads orchestrate specific histone modifications and chromatin remodeling to activate transcription. EMBO J ; 25 : — James AW. Scientifica Cairo ; : The zinc finger transcription factor Gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling.

Mol Cell Biol ; 26 : — Sonic hedgehog gene-enhanced tissue engineering for bone regeneration. Gene Therapy ; 12 : 75— J Cell Sci ; : — Sonic hedgehog is involved in osteoblast differentiation by cooperating with BMP Mechanisms of bone repair and regeneration.

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This is reflected in the use of different control strategies at genes with different sets of functional constraints. Variation in gene expression is observed between closely related species, even when the specific gene coding sequence is largely conserved, e. Within a species, expression can fluctuate following a perturbation environmental or genetic and even in the absence of perturbations variation among individuals is found — this being often interpreted as disturbing noise[ 2 ].

What molecular factors determine these fluctuations? Are these factors subjected to selection pressures? And which general trends on expression variability can one identify at the genomic level?

Partial answers to these questions were recently reached by using high-throughput experiments on the budding yeast Saccharomyces cerevisiae.

Both protein function e. Moreover, expression plasticity responsiveness of S. Genes presenting a TATA box in their promoter showed higher interspecies variability, controlling for function, which suggested the influence of transcription re-initiation mechanisms and bursting expression[ 5 ].

Similarly, response to mutations using mutation-accumulation experiments[ 6 ] identified TATA boxes and trans -mutational target sizes number of proteins influencing the expression of a focal gene as determinants of neutral variability.

These initial findings are leading to new questions. This is clearly suggested in recent studies, with an emphasis on the role of chromatin regulation[ 8 — 10 ]. This strategy could be positive in terms of the economics of regulation[ 11 ], but negative in terms of functional conflicts, e. An additional question is to what extent a demand for variation acts as a central force for the organization of genomes and vice versai. Here, we first revisited the influence of chromatin regulation in the linkage of noise and plasticity.

We observe that both regulatory strength and character modulates this linkage. Plastic genes exhibiting relatively strong chromatin regulation can appear independent of noise, but an extra increase in plasticity associates plasticity with noise. This association —or the lack of it—is revealed in the type of chromatin control, with a contrast between global and specific regulation. While these patterns indicate transcriptional initiation as fundamental mechanism of modulation as previously suggested, e.

These distinct modes are confirmed by the differential influence of genomic neighborhood on coupling depending on plasticity. Interestingly, short intergenic distance and bidirectional promoter architecture can both be related to high and low noise. TATA boxes and high nucleosomal occupancy at the proximal regions of transcriptional starting sites TSSs have been recognized as fundamental promoter features leading to gene expression variability[ 4612 ].

Both features were shown to couple two specific forms of variability, i. Linkage between noise and plasticity was additionally associated to a highly dynamic chromatin, as quantified by histone exchange rates[ 14 ].

However, histone exchange rates do not fully describe the many trans factors influencing nucleosome dynamics. To better understand how such factors determine the noise-plasticity coupling, we used a score that assesses chromatin regulation effects CREi.

We then grouped genes in terms of proximal nucleosome occupancy and computed mean plasticity for those genes exhibiting high or low CRE within each group. Notably, chromatin regulation can induce a relatively high level of plasticity independent of nucleosomal occupancy and presence of TATA promoters Figure 1.

Is it possible to identify genes with particularly strong plasticity? This distinguishes genes whose promoters present both high proximal nucleosomal occupancy —increasing sensitivity to regulation Additional file 1 : Figure S1 [ 10 ]— and presence of TATA box —that results in bursting transcription and increased transcriptional efficiency[ 5 ]— which in turn involves coupling to noise confirming earlier reports[ 38 ], Additional file 1 : Figure S2. Proximal nucleosomal occupancy, chromatin regulation, and the noise-plasticity coupling.

In each bin, we computed the median chromatin regulation effect CRE. Plasticity is always enhanced by strong chromatin regulation; however, regulation enhances noise only in promoters with high proximal nucleosome occupancy and TATA box shaded area in AB. Moreover, if the noise-plasticity coupling had its origin in the stability of the transcriptional apparatus at the promoter, this would predict the presence of coupling in TATAless genes with a SAGA-dominated initiation that also produces transcriptional bursting[ 19 ].

To further appreciate what determines the coupling or uncoupling of noise with plasticity, we inspected potential differences in the type of chromatin regulation. We computed the mean effect in expression of a compendium of mutations in regulators[ 18 ] CRE score before represents a subset, see Methods on plastic genes. This confirms mechanistically a complementary program of regulation between these two groups of genes enriched by growth —ribosomal— and stress genes, respectively[ 1220 ]to be added to the previously observed distinctions in promoter nucleosome occupancy Additional file 1 : Figure S6and histone modification enrichment[ 13 ].

More specifically, perturbations affecting LNHP genes commonly cause a decrease in expression Figure 2Ared dotsi. Even if most of these perturbations involved mutations in TAF1 —which is a general transcription factor also associated to chromatin modulation activities, e.

In contrast, a wider range of different regulators affected HNHP genes, and the majority of these were independent trans -acting chromatin regulators 92 out of whose deletion activated gene expression Figure 2Ablue dotsi. We also found that some regulators whose deletion results in decreasing expression level in the majority of LNHP genes tends in comparison to increase it in the majority of HNHP Figure 3. As expected, this is not related to general transcription factors, whose deletion reduce expression level, but to many specific chromatin regulators and, notably, to histones.

A recent result can help us understand this[ 13 ]. Namely, LNHP genes are greatly enriched in activating marks mostly acetylationsa strong change in acetylation level being observed when repressed.

Therefore, acetylated histones are probably essential for the expression of these genes. On the contrary, HNHP genes do not show such changes in histone acetylation status, but they reduce their occupancy level when activated.

Histone deletion is in this case more likely to impede the formation of repressive nucleosomes, resulting in a more frequently open promoter and increasing expression level see Additional file 1 : Supplement for more discussion, and Additional file 1 : Figure S8 for a detailed profile of histone modifications. Distinct chromatin regulation strategies to achieve noisy or quiet plasticity. A Each dot represents the mean effect in the expression of a set of genes in a subclass HNHP, x coordinate; LNHP, y coordinate; normalized by effect in HP class when a particular regulator is mutated[ 18 ].

This confirms that these groups are enriched by complementary functional classes stress and growth related genes, respectively which are generally regulated in opposite sense[ 121320 ]. Dot colors denote the dominant effect of the regulator on the HP class blue; regulator is mostly repressing expression, red; regulator is commonly activating while sizes describe the strength of the dominant effect; e.

Except rsc30 a regulator of ribosomal proteins[ 21 ] all these mutations involved TAF1, which is part of the general transcription factor TFIID[ 2223 ]. Dual action of histones. We noted that LP genes also present differential coupling to noise. In contrast to HP genes, this disparity does not seem to respond to transcriptional-based determinants. A notable feature of these genes is their enrichment in histone H2A.

Z at promoters, which has been already noted[ 13 ] and is thought to help stabilizing the NDR with our dataset, mean LP: 0. Indeed, there are not observable differences in all these factors when considering low and high noise subgroups within the LP set data not shown. We thus inspected if uncoupling could be associated in these genes to translation as this is known to control noise[ 2425 ]. If translation FOP (Forms Of Plasticity) - Fip Fop (CD) noise in LP genes, then noise should also covariate with factors influencing translation efficiency such as ORF length or codon bias see, for instance,[ 2728 ].

These genes may exhibit short length due to minimization of biosynthetic costs given their high expression[ 29 ]. What other mechanisms could modulate the noise-plasticity coupling?

The specific architecture of the genomic neighborhood of a gene appears as a possible candidate. Indeed, it was recently found evidence for how bidirectional promoters bipromoters could reduce noise by favoring nucleosome depletion[ 1617 ]. However, as we have shown, noise in low-plasticity genes is modulated mostly at the translational level, and consequently should not be affected by the presence of bipromoters. Although nucleosome depletion is observed independently of plasticity, it does not seem to affect noise in the LP class.

In contrast, the noise-reduction effect of bipromoters is observed in HP genes, as expected[ 16 ] Additional file 3 : Table S2.

If not to bipromoters, this difference could be attributed, as we discussed, to differences in ORF length mean length noise-sensitive: Reducing noise by bipromoters could additionally decrease expression plasticity due to their association to short intergenic distance and nucleosome depletion, and this we actually distinguished Additional file 3 : Table S2. This suggests then a limitation on the adequacy of bipromoters for reducing noise. Interestingly, we detect a strong bipromoter-independent effect in noise-sensitive HP genes Additional file 4 : Table S3.

We thus hypothesized that there could be a tendency to evolve noise-abating mechanisms that affect plasticity more weakly, thereby uncoupling it from noise. Can we identify further features illustrating that noise-sensitive bipromoter genes tend to maintain plasticity levels? The above can be complementary analyzed if we consider all possible local genomic architectures around a focal gene Figure 5Ai. We computed the coupling between noise and plasticity for each architecture.

Coupling is strong for genes with divergent transcripts independent of the type of upstream partner and weak for those with a bipromoter with a coding partner Figure 5A. Overall, this emphasizes bipromoters as noise-abating architecture only when noise and plasticity are transcriptionally modulated. We analyzed the molecular determinants that adjust the linkage between gene expression plasticity and noise in S.

Noise was confirmed to be connected to plasticity when genes exhibit particular modes of transcription initiation and re-initiation related to the presence of TATA boxes at the promoter and strong chromatin regulation[ 57 — 1012 ]. This could suggest a model in which intrinsic noise is a byproduct of the need for plasticity[ 14 ].

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9 Responses to FOP (Forms Of Plasticity) - Fip Fop (CD)

  1. Arazahn says:

    FOP (Forms Of Plasticity), Category: Artist, Top Tracks: Avalon - Remix, Monthly Listeners: 26, Where People Listen: Twickenham, London, Guadalajara, Augsburg, Frankfurt am Main. We and our partners use cookies to personalize your experience, to show you ads based on your interests, and for measurement and analytics purposes.

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  3. Kazigrel says:

    Dec 02,  · In June , the International Clinical Council (ICC) on Fibrodysplasia Ossificans Progressiva FOP was established to help consolidate a global voice for the best practices for clinical care and clinical research for people who suffer from FOP. The ICC is an autonomous and independent group of 21 internationally-recognized clinician experts in.

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