An epigenetic switch induced by Shh signalling regulates gene activation during development and medulloblastoma growth

Shi, Xuanming; Zhang, Zilai; Zhan, Xiaoming; Cao, Mou; Satoh, Takashi; Akira, Shizuo; Shpargel, Karl B.; Magnuson, Terry; Li, Qingtian; Wang, Rongfu; Wang, Chaochen; Ge, Kai; Wu, Jiang

doi:10.1038/ncomms6425

Cited by 97 publications

(97 citation statements)

References 70 publications

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“…Notably, PcG factors have been reported to be linked with RA, FGFs, SHH and MAP kinase pathways (Schwermann et al, 2009;Shi et al, 2014;van der Velden et al, 2012;Wu et al, 2013;Yokobayashi et al, 2013). By such interactions with signaling pathways, PcG factors may contribute to the compartmentalization of outgrowing or enlarging fetal tissues by regulating the expression of developmental genes.…”

Section: Discussionmentioning

confidence: 99%

RING1 contributes to early proximal-distal specification of the forelimb bud by restricting Meis2 expression

et al. 2015

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Polycomb group (PcG) proteins play a pivotal role in silencing developmental genes and help to maintain various stem and precursor cells and regulate their differentiation. PcG factors also regulate dynamic and complex regional specification, particularly in mammals, but this activity is mechanistically not well understood. In this study, we focused on proximal-distal (PD) patterning of the mouse forelimb bud to elucidate how PcG factors contribute to a regional specification process that depends on developmental signals. Depletion of the RING1 proteins RING1A (RING1) and RING1B (RNF2), which are essential components of Polycomb repressive complex 1 (PRC1), led to severe defects in forelimb formation along the PD axis. We show that preferential defects in early distal specification in Ring1A/B-deficient forelimb buds accompany failures in the repression of proximal signal circuitry bound by RING1B, including Meis1/2, and the activation of distal signal circuitry in the prospective distal region. Additional deletion of Meis2 induced partial restoration of the distal gene expression and limb formation seen in the Ring1A/B-deficient mice, suggesting a crucial role for RING1-dependent repression of Meis2 and likely also Meis1 for distal specification. We suggest that the RING1-MEIS1/2 axis is regulated by early PD signals and contributes to the initiation or maintenance of the distal signal circuitry.

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Section: Discussionmentioning

confidence: 99%

RING1 contributes to early proximal-distal specification of the forelimb bud by restricting Meis2 expression

et al. 2015

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“…The second fundamental prediction from the modeling was that histone-modifying activation and derepression activities would be coupled to generate nonlinear positive feedback to maintain the bistable states (28). Evidence for this has come from the observation that the H3K27 demethylase Jmjd3 recruits the SET1/MLL complex to target loci, hence switching bivalent H3K27me3, H3K4me3 promoters to H3K4me3 only, and thereby activating previously PRC2-silenced gene expression (5). In this report, we provide the experimental validation for physical coupling through analysis of the SDG8-ELF6 interaction that couples H3K36me3 activation with H3K27 demethylation at FLC.…”

Section: Elf6 and Jumonji Domain-containing Protein 13 Are Partiallymentioning

confidence: 99%

“…Transcriptional states are induced by internal developmental signals or triggered by environmental conditions and are then epigenetically maintained through many cell divisions. Considerable evidence suggests that opposing histone modifications mark different transcriptional states (1)(2)(3)(4)(5)(6). However, there is still great debate as to how histone-based transcriptional states are initially established and maintained through development (7,8).…”

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confidence: 99%

Physical coupling of activation and derepression activities to maintain an active transcriptional state at FLC

Yang

Howard

Dean

2016

Proc. Natl. Acad. Sci. U.S.A.

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Establishment and maintenance of gene expression states is central to development and differentiation. Transcriptional and epigenetic mechanisms interconnect in poorly understood ways to determine these states. We explore these mechanisms through dissection of the regulation of Arabidopsis thaliana FLOWERING LOCUS C (FLC). FLC can be present in a transcriptionally active state marked by H3K36me3 or a silent state marked by H3K27me3. Here, we investigate the trans factors modifying these opposing histone states and find a physical coupling in vivo between the H3K36 methyltransferase, SDG8, and the H3K27me3 demethylase, ELF6. Previous modeling has predicted this coupling would exist as it facilitates bistability of opposing histone states. We also find association of SDG8 with the transcription machinery, namely RNA polymerase II and the PAF1 complex. Delivery of the active histone modifications is therefore likely to be through transcription at the locus. SDG8 and ELF6 were found to influence the localization of each other on FLC chromatin, showing the functional importance of the interaction. In addition, both influenced accumulation of the associated H3K27me3 and H3K36me3 histone modifications at FLC. We propose the physical coupling of activation and derepression activities coordinates transcriptional activity and prevents ectopic silencing.epigenetic regulation | histone modifications | histone methyltransferase | histone demethylase | FLOWERING LOCUS C C hromatin-based transcriptional activity is particularly important in multicellular organisms, where cells differentiate into very different developmental states. Transcriptional states are induced by internal developmental signals or triggered by environmental conditions and are then epigenetically maintained through many cell divisions. Considerable evidence suggests that opposing histone modifications mark different transcriptional states (1-6). However, there is still great debate as to how histone-based transcriptional states are initially established and maintained through development (7,8). We used Arabidopsis FLOWERING LOCUS C (FLC) as a model gene to explore histone-based transcriptional regulation and epigenetic memory. Local chromatin states are critical for quantitatively controlling FLC expression (9). Active FLC expression requires functional FRIGIDA (FRI) and a set of histone modifying Trithorax homologs, Complex Proteins Associated with Set1 (COMPASS), RNA polymerase II Associated Factor 1 complex (PAF1C), and SET DOMAIN GROUP 8 (SDG8), the major H3K36 methyltransferase (10-17). Repression of FLC requires either the autonomous pathway, which coordinately influences transcriptional initiation and elongation with associated chromatin modulation, or vernalization, the cold-induced Polycomb silencing (18-21). Both of these involve accumulation of high levels of H3K27me3 at FLC (20-22). A series of FLC antisense transcripts (COOLAIR) contribute to these repression pathways (18,(23)(24)(25)(26) Opposing H3K36me3 and H3K27me3 states are particularly ...

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“…Chromatin immunoprecipitation (ChIP) experiments were performed as described previously (37,42). Tissue disrupted by Dounce homogenization or dissociated cells were cross-linked with PFA and sonicated to fragments (200 to 500 bp).…”

mentioning

confidence: 99%

Autism-Associated Chromatin Regulator Brg1/SmarcA4 Is Required for Synapse Development and Myocyte Enhancer Factor 2-Mediated Synapse Remodeling

Zhang

Cao

Chang

et al. 2016

Molecular and Cellular Biology

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Synapse development requires normal neuronal activities and the precise expression of synapse-related genes. Dysregulation of synaptic genes results in neurological diseases such as autism spectrum disorders (ASD). Mutations in genes encoding chromatin-remodeling factor Brg1/SmarcA4 and its associated proteins are the genetic causes of several developmental diseases with neurological defects and autistic symptoms. Recent large-scale genomic studies predicted Brg1/SmarcA4 as one of the key nodes of the ASD gene network. We report that Brg1 deletion in early postnatal hippocampal neurons led to reduced dendritic spine density and maturation and impaired synapse activities. In developing mice, neuronal Brg1 deletion caused severe neurological defects. Gene expression analyses indicated that Brg1 regulates a significant number of genes known to be involved in synapse function and implicated in ASD. We found that Brg1 is required for dendritic spine/synapse elimination mediated by the ASDassociated transcription factor myocyte enhancer factor 2 (MEF2) and that Brg1 regulates the activity-induced expression of a specific subset of genes that overlap significantly with the targets of MEF2. Our analyses showed that Brg1 interacts with MEF2 and that MEF2 is required for Brg1 recruitment to target genes in response to neuron activation. Thus, Brg1 plays important roles in both synapse development/maturation and MEF2-mediated synapse remodeling. Our study reveals specific functions of the epigenetic regulator Brg1 in synapse development and provides insights into its role in neurological diseases such as ASD. Synapses formed between axons and dendrites connect neurons and generate neural circuits that control brain functions (1). The dysregulation of synapse formation, maturation, or plasticity causes many neurodevelopmental diseases such as autism (2). Autism spectrum disorders (ASDs) are complex diseases characterized by a range of behavior abnormalities and regulated by genetic and epigenetic factors (3-5). In ASDs with various genetic or environmental causes, synaptic dysfunction is a central defect.Many autism risk genes encode transcription factors and epigenetic regulators, which likely function to regulate the expression of synaptic genes (4, 6, 7). A gene network analysis predicted the core subunit of a SWI/SNF-like BRG1-associated factor (BAF) ATP-dependent chromatin remodeling complex, Brg1/SmarcA4, as one of the key nodes in autism pathogenesis (7). BAF complexes containing the ATPase Brg1 or Brm use energy derived from ATP hydrolysis to modulate chromatin structures and regulate transcription (8-10). Mutations in several BAF subunits are the genetic causes of Coffin-Siris syndrome and Nicolaides-Baraitser syndrome with autistic symptoms such as intellectual disability and delayed speech (11-15). In addition, de novo functional mutations of genes encoding several BAF subunits are identified repeatedly in autism patients (7,(16)(17)(18). Mutations in a gene encoding the BAF-associated protein activity-dependent ...

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An epigenetic switch induced by Shh signalling regulates gene activation during development and medulloblastoma growth

Cited by 97 publications

References 70 publications

RING1 contributes to early proximal-distal specification of the forelimb bud by restricting Meis2 expression

RING1 contributes to early proximal-distal specification of the forelimb bud by restricting Meis2 expression

Physical coupling of activation and derepression activities to maintain an active transcriptional state at FLC

Autism-Associated Chromatin Regulator Brg1/SmarcA4 Is Required for Synapse Development and Myocyte Enhancer Factor 2-Mediated Synapse Remodeling

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