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1.  EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion 
Scientific Reports  2015;5:10643.
The roles of EZH2 in various subsets of CD4+ T cells are controversial and its mechanisms of action are incompletely understood. FOXP3-positive Treg cells are a critical helper T cell subset, and dysregulation of Treg generation or function results in systemic autoimmunity. FOXP3 associates with EZH2 to mediate gene repression and suppressive function. Herein, we demonstrate that deletion of Ezh2 in CD4 T cells resulted in reduced numbers of Treg cells in vivo and differentiation in vitro and an increased proportion of memory CD4 T cells in part due to exaggerated production of effector cytokines. Furthermore, we found that both Ezh2-deficient Treg cells and T effector cells were functionally impaired in vivo: Tregs failed to constrain autoimmune colitis and T effector cells neither provided a protective response to T. gondii infection nor mediated autoimmune colitis. The dichotomous function of EZH2 in regulating differentiation and senescence in effector and regulatory T cells helps to explain the apparent existing contradictions in literature.
doi:10.1038/srep10643
PMCID: PMC4473539  PMID: 26090605
2.  Gcn5 and PCAF Regulate PPARγ and Prdm16 Expression To Facilitate Brown Adipogenesis 
Molecular and Cellular Biology  2014;34(19):3746-3753.
The acetyltransferase Gcn5 is critical for embryogenesis and shows partial functional redundancy with its homolog PCAF. However, the tissue- and cell lineage-specific functions of Gcn5 and PCAF are still not well defined. Here we probe the functions of Gcn5 and PCAF in adipogenesis. We found that the double knockout (DKO) of Gcn5/PCAF inhibits expression of the master adipogenic transcription factor gene PPARγ, thereby preventing adipocyte differentiation. The adipogenesis defects in Gcn5/PCAF DKO cells are rescued by ectopic expression of peroxisome proliferator-activated receptor γ (PPARγ), suggesting Gcn5/PCAF act upstream of PPARγ to facilitate adipogenesis. The requirement of Gcn5/PCAF for PPARγ expression was unexpectedly bypassed by prolonged treatment with an adipogenic inducer, 3-isobutyl-1-methylxanthine (IBMX). However, neither PPARγ ectopic expression nor prolonged IBMX treatment rescued defects in Prdm16 expression in DKO cells, indicating that Gcn5/PCAF are essential for normal Prdm16 expression. Gcn5/PCAF regulate PPARγ and Prdm16 expression at different steps in the transcription process, facilitating RNA polymerase II recruitment to Prdm16 and elongation of PPARγ transcripts. Overall, our study reveals that Gcn5/PCAF facilitate adipogenesis through regulation of PPARγ expression and regulate brown adipogenesis by influencing Prdm16 expression.
doi:10.1128/MCB.00622-14
PMCID: PMC4187735  PMID: 25071153
3.  IL-6 Blockade as a Therapeutic Approach for Duchenne Muscular Dystrophy 
EBioMedicine  2015;2(4):274-275.
doi:10.1016/j.ebiom.2015.03.018
PMCID: PMC4486189  PMID: 26137566
4.  Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation 
Cell  2013;155(7):1507-1520.
A key finding of the ENCODE project is that the enhancer landscape of mammalian cells undergoes marked alterations during ontogeny. However, the nature and extent of these changes are unclear. As part of the NIH Mouse Regulome Project, we here combined DNaseI hypersensitivity, ChIP-Seq, and ChIA-PET technologies to map the promoter-enhancer interactomes of pluripotent ES cells and differentiated B lymphocytes. We confirm that enhancer usage varies widely across tissues. Unexpectedly, we find that this feature extends to broadly-transcribed genes, including Myc and Pim1 cell cycle regulators, which associate with an entirely different set of enhancers in ES and B cells. By means of high-resolution CpG methylomes, genome editing, and digital footprinting we show that these enhancers recruit lineage-determining factors. Furthermore, we demonstrate that the turning on and off of enhancers during development correlates with promoter activity. We propose that organisms rely on a dynamic enhancer landscape to control basic cellular functions in a tissue-specific manner.
doi:10.1016/j.cell.2013.11.039
PMCID: PMC3905448  PMID: 24360274
5.  eRNAs Promote Transcription by Establishing Chromatin Accessibility at Defined Genomic Loci 
Molecular cell  2013;51(5):606-617.
SUMMARY
Transcription factors and DNA regulatory binding motifs are fundamental components of the gene regulatory network. Here, by using genome-wide binding profiling, we show extensive occupancy of transcription factors of myogenesis (MyoD and Myogenin) at extragenic enhancer regions coinciding with RNA synthesis (i.e. eRNA). In particular, multiple regions were transcribed to eRNA within regulatory region of MYOD1, including previously characterized Distal Regulatory Regions (DRR) and Core Enhancer (CE). While CERNA enhanced RNA polymerase II (PolII) occupancy and transcription at MYOD1, DRRRNA acted to activate the downstream myogenic genes. The deployment of transcriptional machinery to appropriate loci is contingent on chromatin accessibility, a rate-limiting step preceding PolII assembly. By nuclease sensitivity assay, it appear that eRNAs regulate genomic access of the transcriptional complex to defined regulatory regions. In conclusion, our data suggest that eRNAs contribute to establishing a cell-type-specific transcriptional circuitry by directing chromatin-remodeling events.
doi:10.1016/j.molcel.2013.07.022
PMCID: PMC3786356  PMID: 23993744
7.  Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocaine and Morphine Action 
The Journal of Neuroscience  2013;33(41):16088-16098.
Sirtuins (SIRTs), class III histone deacetylases, are well characterized for their control of cellular physiology in peripheral tissues, but their influence in brain under normal and pathological conditions remains poorly understood. Here, we establish an essential role for SIRT1 and SIRT2 in regulating behavioral responses to cocaine and morphine through actions in the nucleus accumbens (NAc), a key brain reward region. We show that chronic cocaine administration increases SIRT1 and SIRT2 expression in the mouse NAc, while chronic morphine administration induces SIRT1 expression alone, with no regulation of all other sirtuin family members observed. Drug induction of SIRT1 and SIRT2 is mediated in part at the transcriptional level via the drug-induced transcription factor ΔFosB and is associated with robust histone modifications at the Sirt1 and Sirt2 genes. Viral-mediated overexpression of SIRT1 or SIRT2 in the NAc enhances the rewarding effects of both cocaine and morphine. In contrast, the local knockdown of SIRT1 from the NAc of floxed Sirt1 mice decreases drug reward. Such behavioral effects of SIRT1 occur in concert with its regulation of numerous synaptic proteins in NAc as well as with SIRT1-mediated induction of dendritic spines on NAc medium spiny neurons. These studies establish sirtuins as key mediators of the molecular and cellular plasticity induced by drugs of abuse in NAc, and of the associated behavioral adaptations, and point toward novel signaling pathways involved in drug action.
doi:10.1523/JNEUROSCI.1284-13.2013
PMCID: PMC3792451  PMID: 24107942
8.  An evolutionarily biased distribution of miRNA sites toward regulatory genes with high promoter-driven intrinsic transcriptional noise 
Background
miRNAs are a major class of regulators of gene expression in metazoans. By targeting cognate mRNAs, miRNAs are involved in regulating most, if not all, biological processes in different cell and tissue types. To better understand how this regulatory potential is allocated among different target gene sets, we carried out a detailed and systematic analysis of miRNA target sites distribution in the mouse genome.
Results
We used predicted conserved and non-conserved sites for 779 miRNAs in 3′ UTR of 18440 genes downloaded from TargetScan website. Our analysis reveals that 3′ UTRs of genes encoding regulatory proteins harbor significantly greater number of miRNA sites than those of non-regulatory, housekeeping and structural, genes. Analysis of miRNA sites for orthologous 3′UTR’s in 10 other species indicates that the regulatory genes were maintaining or accruing miRNA sites while non-regulatory genes gradually shed them in the course of evolution. Furthermore, we observed that 3′ UTR of genes with higher gene expression variability driven by their promoter sequence content are targeted by many more distinct miRNAs compared to genes with low transcriptional noise.
Conclusions
Based on our results we envision a model, which we dubbed “selective inclusion”, whereby non-regulatory genes with low transcription noise and stable expression profile lost their sites, while regulatory genes which endure higher transcription noise retained and gained new sites. This adaptation is consistent with the requirements that regulatory genes need to be tightly controlled in order to have precise and optimum protein level to properly function.
doi:10.1186/1471-2148-14-74
PMCID: PMC4031498  PMID: 24707827
microRNAs; Transcriptional noise; Nucleosome occupancy; Evolution
9.  Bach2 represses effector programmes to stabilize Treg-mediated immune homeostasis 
Nature  2013;498(7455):10.1038/nature12199.
Through their functional diversification, distinct lineages of CD4+ T cells play key roles in either driving or constraining immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment1. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma2, Crohn’s disease3–4, coeliac disease5, vitiligo6, multiple sclerosis7 and type 1 diabetes8. While these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for Bach2 in the maintenance of immune homeostasis has not been established. Here, we define Bach2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programmes of multiple effector lineages in CD4+ T cells. Bach2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg cell dependent. Assessment of the genome-wide function of Bach2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, Bach2 constrained full effector differentiation within Th1, Th2 and Th17 cell lineages. These findings identify Bach2 as a key regulator of CD4+ T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity.
doi:10.1038/nature12199
PMCID: PMC3710737  PMID: 23728300
10.  H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation 
eLife  2013;2:e01503.
Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for H3K4me1/2 on enhancers remain elusive. Furthermore, how these enzymes function on enhancers to regulate cell-type-specific gene expression is unclear. In this study, we identify MLL4 (KMT2D) as a major mammalian H3K4 mono- and di-methyltransferase with partial functional redundancy with MLL3 (KMT2C). Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of Mll4 markedly decreases H3K4me1/2, H3K27ac, Mediator and Polymerase II levels on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Together, these findings identify MLL4 as a major mammalian H3K4 mono- and di-methyltransferase essential for enhancer activation during cell differentiation.
DOI: http://dx.doi.org/10.7554/eLife.01503.001
eLife digest
Almost every cell in a human body carries the same genes, but not every cell will express all of these genes as proteins. As different types of cells, such as brain, liver, fat or muscle cells, develop, they will express different genes; or they will express the same genes, but at different times and in different amounts. Enhancers are short stretches of DNA that boost the amount of protein that is produced when a gene is expressed, and they are particularly important for those genes that are expressed differently between cell types.
Enhancers bolster expression of a gene by interacting with the DNA nearby. Even genes separated from enhancers by a long stretches of DNA can benefit because the way that DNA is tightly packed inside the nucleus means that two distant sequences can actually end up close together. Proteins called transcription factors will bind to enhancers and recruit the cell’s protein ‘machinery’ required to express nearby genes. Enhancers can be identified by specific chemical marks associated with their DNA, but little is known about the enzymes that leave these marks in mammals. Moreover, it is not clear which genes are influenced by these marks.
Now, by examining fat cells and muscle cells as they mature, Lee et al. have found that an enzyme called MLL4 is responsible for adding chemical marks to enhancers in both humans and mice. Further, MLL4 is required both to allow cells to specialize into different cell types, and to boost the expression of genes that are specific to each type of mature cells. Since faulty MLL4 has been implicated in several cancers and developmental defects, the findings of Lee et al. may lead to a better understanding of these diseases.
DOI: http://dx.doi.org/10.7554/eLife.01503.002
doi:10.7554/eLife.01503
PMCID: PMC3869375  PMID: 24368734
enhancer chromatin modification; MLL4; H3K4me1; KMT2D; enhancer activation; H3K27ac; adipogenesis; myogenesis; cell differentiation; Human; Mouse
11.  STATs Shape the Active Enhancer Landscape of T Cell Populations 
Cell  2012;151(5):981-993.
SUMMARY
Signaling pathways are intimately involved in cellular differentiation, allowing cells to respond to their environment by regulating gene expression. While enhancers are recognized as key elements that regulate selective gene expression, the interplay between signaling pathways and actively used enhancer elements is not clear. Here, we use CD4+ T cells as a model of differentiation, mapping the acquisition of cell-type-specific enhancer elements in T-helper 1 (Th1) and Th2 cells. Our data establish that STAT proteins have a major impact on the acquisition of lineage-specific enhancers and the suppression of enhancers associated with alternative cell fates. Transcriptome analysis further supports a functional role for enhancers regulated by STATs. Importantly, expression of lineage-defining master regulators in STAT-deficient cells fails to fully recover the chromatin signature of STAT-dependent enhancers. Thus, these findings point to a critical role of STATs as environmental sensors in dynamically molding the specialized enhancer architecture of differentiating cells.
doi:10.1016/j.cell.2012.09.044
PMCID: PMC3509201  PMID: 23178119
14.  Decreased microRNA-214 levels in breast cancer cells coincides with increased cell proliferation, invasion and accumulation of the Polycomb Ezh2 methyltransferase 
Carcinogenesis  2011;32(11):1607-1614.
MicroRNAs (miRNAs) are small non-coding RNAs, which regulate gene expression by inhibiting translation or promoting degradation of specific target messenger RNAs (mRNAs). Alteration of the levels of a number of miRNAs is common in solid and hematological tumors. We have shown previously that miR-214 regulates Ezh2 in skeletal muscle and embryonic stem cells. The current study was aimed at examining the role of miR-214 in breast cancer where miR-214 levels are reduced but whether this phenomenon bears a functional relevance is unknown. MiR-214 expression was inversely correlated with Ezh2 mRNA and protein levels in breast cancer cell lines and at least one copy of the miR-214 alleles was found to be deleted in 24% (6/25) of primary breast tumors. Experimental increase of miR-214 in breast cancer cell lines correlated with reduction of Ezh2 protein levels, a known marker of invasion and aggressive breast cancer behavior. Supporting a direct targeting mechanism, miR-214 decreased luciferase activity from a construct containing the Ezh2 3′ untranslated region. Expression of miR-214 specifically reduced cell proliferation of breast cancer cells and inhibited the invasive potential of a highly metastatic breast cancer cell line. These findings indicate that reduced miR-214 levels may contribute to breast tumorigenesis by allowing abnormally elevated Ezh2 accumulation and subsequent unchecked cell proliferation and invasion.
doi:10.1093/carcin/bgr184
PMCID: PMC3204346  PMID: 21828058
15.  Sculpting Chromatin Beyond the Double Helix: Epigenetic Control of Skeletal Myogenesis 
Satellite cells (SCs) are the main source of adult skeletal muscle stem cells responsible for muscle growth and regeneration. By interpreting extracellular cues, developmental regulators control quiescence, proliferation, and differentiation of SCs by influencing coordinate gene expression. The scope of this review is limited to the description and discussion of protein complexes that introduce and decode heritable histone and chromatin modifications and how these modifications are relevant for SC biology.
doi:10.1016/B978-0-12-385940-2.00003-6
PMCID: PMC3172892  PMID: 21621067
16.  Who Needs Microtubules? Myogenic Reorganization of MTOC, Golgi Complex and ER Exit Sites Persists Despite Lack of Normal Microtubule Tracks 
PLoS ONE  2011;6(12):e29057.
A wave of structural reorganization involving centrosomes, microtubules, Golgi complex and ER exit sites takes place early during skeletal muscle differentiation and completely remodels the secretory pathway. The mechanism of these changes and their functional implications are still poorly understood, in large part because all changes occur seemingly simultaneously. In an effort to uncouple the reorganizations, we have used taxol, nocodazole, and the specific GSK3-β inhibitor DW12, to disrupt the dynamic microtubule network of differentiating cultures of the mouse skeletal muscle cell line C2. Despite strong effects on microtubules, cell shape and cell fusion, none of the treatments prevented early differentiation. Redistribution of centrosomal proteins, conditional on differentiation, was in fact increased by taxol and nocodazole and normal in DW12. Redistributions of Golgi complex and ER exit sites were incomplete but remained tightly linked under all circumstances, and conditional on centrosomal reorganization. We were therefore able to uncouple microtubule reorganization from the other events and to determine that centrosomal proteins lead the reorganization hierarchy. In addition, we have gained new insight into structural and functional aspects of the reorganization of microtubule nucleation during myogenesis.
doi:10.1371/journal.pone.0029057
PMCID: PMC3246457  PMID: 22216166
17.  Myc-Nick: The Force Behind c-Myc 
Science signaling  2010;3(152):pe49.
In the field of molecular oncology, the Myc basic helix-loop-helix family of transcription factors has been extensively studied. The Myc proto-oncogene c-Myc binds DNA, activates or represses gene transcription, and consequently affects cellular proliferation. However, emerging evidence presents the existence of c-Myc variants that lack transcriptional activity. A cytoplasmic variant of c-Myc called “Myc-nick,” which arises from calpain-mediated cleavage of c-Myc, assists in stable microtubule assembly. Furthermore, Myc-nick promotes MyoD-mediated myogenic differentiation, thus antagonizing its precursor. These results provide exciting new opportunities in formulating molecular approaches for treatment of cancer and in our understanding of cell differentiation.
doi:10.1126/scisignal.3152pe49
PMCID: PMC3171953  PMID: 21156935
18.  TNF/p38 alpha/Polycomb signalling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration 
Cell stem cell  2010;7(4):455-469.
How regeneration cues are converted into the epigenetic information that controls gene expression in adult stem cells is currently unknown. We identified a novel inflammation-activated signalling in muscle stem (satellite) cells, by which the Polycomb Repressive Complex 2 (PRC2) represses Pax7 expression during muscle regeneration. TNF-activated p38alpha kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EzH2, the enzymatic sub-unit of the complex, leading to the formation of repressive chromatin on Pax7 promoter. Anti-TNF antibodies stimulate satellite cell proliferation in regenerating muscles of dystrophic or normal mice. Genetic knockdown or pharmacological inhibition of the enzymatic components of the p38/PRC2 signalling – p38alpha and EzH2 - invariably promote Pax7 expression and expansion of satellite cells that retain their differentiation potential upon signalling resumption. Genetic knockdown of Pax7 impaired satellite cell proliferation in response to p38 inhibition, thereby establishing the biological link between p38/PRC2 signalling to Pax7 and satellite cell decision to proliferate or differentiate.
doi:10.1016/j.stem.2010.08.013
PMCID: PMC2951277  PMID: 20887952
Pax7; p38; muscle stem (satellite) cells; regeneration; chromatin; Polycomb complex
19.  Phosphoryl-EZH-ion 
Cell stem cell  2011;8(3):262-265.
Polycomb group (PcG) proteins regulate gene expression in embryonic and adult stem cells, but the mechanisms responsible for PcG gene targeting and regulation remain largely unknown. Recent evidence shows that EZH2, the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2), is a nuclear phosphoprotein linking cell-cycle-intrinsic or extracellular signals to specific epigenetic signatures.
doi:10.1016/j.stem.2011.02.012
PMCID: PMC3166223  PMID: 21362566
20.  MicroRNA-214 and polycomb group proteins 
Cell cycle (Georgetown, Tex.)  2010;9(8):1445-1446.
PMCID: PMC2903648  PMID: 20372071
microRNA; miR-214; Ezh2; polycomb group; skeletal muscle; embryonic stem cells; regulatory circuits
21.  Mir-214-Dependent Regulation of the Polycomb Protein Ezh2 in Skeletal Muscle and Embryonic Stem Cells 
Molecular cell  2009;36(1):61-74.
Summary
Polycomb group (PcG) proteins exert essential functions in the most disparate biological processes. The contribution of PcG proteins to cell commitment and differentiation relates to their ability to repress transcription of developmental regulators in embryonic stem (ES) cells and in committed cell lineages, including skeletal muscle cells (SMC). PcG proteins are preferentially removed from transcribed regions but the underlying mechanisms remain unclear. Here, PcG proteins are found to occupy and repress transcription from an intronic region containing the microRNA miR-214 in undifferentiated SMC. Cell differentiation coincides with PcG disengagement, recruitment of the developmental regulators MyoD and myogenin, and activation of miR-214 transcription. Once transcribed, miR-214 negatively feeds back on PcG by targeting the Ezh2 3′UTR, the catalytic subunit of the PRC2 complex. miR-214-mediated Ezh2 protein reduction accelerates SMC differentiation and promotes unscheduled transcription of developmental regulators in ES cells. Thus, miR-214 and Ezh2 establish a regulatory loop controlling PcG-dependent gene expression during cell differentiation.
doi:10.1016/j.molcel.2009.08.008
PMCID: PMC2761245  PMID: 19818710
22.  Comparing and Contrasting the Roles of AMPK and SIRT1 in Metabolic Tissues 
Cell cycle (Georgetown, Tex.)  2008;7(23):3669-3679.
The ability to adapt and respond to nutrients is an ancient cellular function, conserved from unicellular to the most complex multicellular organisms, including mammals. Mammals adapt to changes in nutritional status through the modulation of tissue-specific metabolic pathways so as to maintain energy homeostasis. At least two proteins are activated in response to reduced nutrient availability: AMP-activated protein kinase (AMPK) and NAD+-dependent deacetylase SIRT1. AMPK functions as a sensor of cellular energy status and as a master regulator of metabolism. When ATP levels decrease, AMPK is activated to boost ATP production and to inhibit ATP usage, thus restoring energy balance. Similarly, SIRT1 is activated in response to changes in the energy status to promote transcription of genes that mediate the metabolic response to stress, starvation, or calorie restriction. Several observations support a model where, in response to stress and reduced nutrients, a metabolic pathway is activated within which AMPK and SIRT1 concordantly function to ensure an appropriate cellular response and adaptation to environmental modifications. In this perspective, we compare and contrast the roles of SIRT1 and AMPK in several metabolic tissues and propose a working model of how the AMPK-SIRT1 axis may be regulated to control functions relevant to organismal physiology and pathophysiology.
PMCID: PMC2607479  PMID: 19029811
SIRT1; AMPK; Nampt; PGC1-α; Calorie Restriction; Starvation; Gluconeogenesis; Insulin
23.  Glucose Restriction Inhibits Skeletal Myoblast Differentiation by Activating SIRT1 through AMPK-Mediated Regulation of Nampt 
Developmental cell  2008;14(5):661-673.
SUMMARY
It is intuitive to speculate that nutrient availability may influence differentiation of mammalian cells. Nonetheless, a comprehensive complement of the molecular determinants involved in this process has not been elucidated yet. Here, we have investigated how nutrients (glucose) affect skeletal myogenesis. Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK). Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt. Indeed, GR augmented the Nampt activity, which consequently modified the intracellular [NAD+]/[NADH] ratio and nicotinamide levels, and mediated inhibition of skeletal myogenesis. Skeletal myoblasts derived from SIRT1+/− heterozygous mice were resistant to the effects of either GR or AMPK activation. These experiments reveal that AMPK, Nampt, and SIRT1 are the molecular components of a functional signaling pathway that allows skeletal muscle cells to sense and react to nutrient availability.
doi:10.1016/j.devcel.2008.02.004
PMCID: PMC2431467  PMID: 18477450
24.  Mechanisms underlying the transcriptional regulation of skeletal myogenesis 
During skeletal myogenesis, chromatin-modifying enzymes are engaged at discrete genomic regions by transcription factors that recognize sequence-specific DNA motifs located at muscle gene regulatory regions. The composition of the chromatin-bound protein complexes and their temporally and spatially regulated recruitment influence gene expression. Recent findings are consistent with the concept that chromatin modifiers play an important role in regulating skeletal muscle gene expression and cellular differentiation.
doi:10.1016/j.gde.2005.04.015
PMCID: PMC1283108  PMID: 16055324
25.  Fgfr4 is required for effective muscle regeneration in vivo: Delineation of a MyoD-Tead2-Fgfr4 transcriptional pathway 
The Journal of biological chemistry  2005;281(1):429-438.
Fgfr4 has been shown to be important for appropriate muscle development in chick limb buds, however, Fgfr4 null mice show no phenotype. Here, we show that staged induction of muscle regeneration in Fgfr4 null mice becomes highly abnormal at the time point when Fgfr4 is normally expressed. By 7 days of regeneration, differentiation of myotubes became poorly coordinated and delayed by both histology and embryonic myosin heavy chain staining. By 14 days, much of the muscle was replaced by fat and calcifications. To begin to dissect the molecular pathways involving Fgfr4, we queried the promoter sequences for transcriptional factor binding sites, and tested candidate regulators in a 27 time point regeneration series. The Fgfr4 promoter region contained a Tead protein binding site (M-CAT 5′-CATTCCT-3′), and Tead2 showed induction during regeneration commensurate with Fgfr4 regulation. Co-transfection of Tead2 and Fgfr4 promoter reporter constructs into C2C12 myotubes showed Tead2 to activate Fgfr4, and mutation of the M-CAT motif in the Fgfr4 promoter abolished these effects. Immunostaining for Tead2 showed timed expression in myotube nuclei consistent with the mRNA data. Query of the expression timing and genomic sequences of Tead2 suggested direct regulation by MyoD, and, consistent with this, MyoD directly bound to two strong E-boxes in the first intron of Tead2 by chromatin immunoprecipitation assay. Moreover, co-transfection of MyoD and Tead2 intron reporter constructs into 10T1/2 cells activated reporter activity in a dose dependent manner. This activation was greatly reduced when the two E-boxes were mutated. Our data suggest a novel MyoD-Tead2-Fgfr4 pathway important for effective muscle regeneration.
doi:10.1074/jbc.M507440200
PMCID: PMC1892582  PMID: 16267055
Muscle regeneration; Tead; TEF; Fgfr; MyoD; Microarray

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