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Genetic and epigenetic determinants of neurogenesis and myogenesis [ChIP-seq]

ABSTRACT: The regulatory networks of differentiation programs have been partly characterized; however, the molecular mechanisms of lineage-specific gene regulation by highly similar transcription factors remain largely unknown. Here we compare the genome-wide binding and transcription profiles of NEUROD2-mediated neurogenesis with MYOD-mediated myogenesis. We demonstrate that NEUROD2 and MYOD bind a shared CAGCTG E-box motif and E-box motifs specific for each factor: CAGGTG for MYOD and CAGATG for NEUROD2. Binding at factor-specific motifs is associated with gene transcription, whereas binding at shared sites is associated with regional epigenetic modifications but not as strongly associated with gene transcription. Binding is largely constrained to E-boxes pre-set in an accessible chromatin context that determines the set of target genes activated in each cell type. These findings demonstrate that the differentiation program is genetically determined by E-box sequence whereas cell lineage epigenetically determines the availability of E-boxes for each differentiation program.

ORGANISM(S): Mus musculus

PROVIDER: GSE34906 | GEO | 2012/03/26

SECONDARY ACCESSION(S): PRJNA156259

REPOSITORIES: GEO

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Genetic and epigenetic determinants of neurogenesis and myogenesis [ChIP-seq]

Project description:The regulatory networks of differentiation programs have been partly characterized; however, the molecular mechanisms of lineage-specific gene regulation by highly similar transcription factors remain largely unknown. Here we compare the genome-wide binding and transcription profiles of NEUROD2-mediated neurogenesis with MYOD-mediated myogenesis. We demonstrate that NEUROD2 and MYOD bind a shared CAGCTG E-box motif and E-box motifs specific for each factor: CAGGTG for MYOD and CAGATG for NEUROD2. Binding at factor-specific motifs is associated with gene transcription, whereas binding at shared sites is associated with regional epigenetic modifications but not as strongly associated with gene transcription. Binding is largely constrained to E-boxes pre-set in an accessible chromatin context that determines the set of target genes activated in each cell type. These findings demonstrate that the differentiation program is genetically determined by E-box sequence whereas cell lineage epigenetically determines the availability of E-boxes for each differentiation program. Comparing NeuroD2 induced neurogenesis and MyoD induced myogenesis by examining NeuroD2/MyoD binding sites in fibroblasts and P19 cells and corresponding changes in AcH4 using Chip-Seq. Assess chromatin accessibility using PvuII assay followed by high throughput sequencing.

2012-03-26 | E-GEOD-34906 | biostudies-arrayexpress

Genetic and epigenetic determinants of neurogenesis and myogenesis [expression profiling]

Project description:The regulatory networks of differentiation programs have been partly characterized; however, the molecular mechanisms of lineage-specific gene regulation by highly similar transcription factors remain largely unknown. Here we compare the genome-wide binding and transcription profiles of NEUROD2-mediated neurogenesis with MYOD-mediated myogenesis. We demonstrate that NEUROD2 and MYOD bind a shared CAGCTG E-box motif and E-box motifs specific for each factor: CAGGTG for MYOD and CAGATG for NEUROD2. Binding at factor-specific motifs is associated with gene transcription, whereas binding at shared sites is associated with regional epigenetic modifications but not as strongly associated with gene transcription. Binding is largely constrained to E-boxes pre-set in an accessible chromatin context that determines the set of target genes activated in each cell type. These findings demonstrate that the differentiation program is genetically determined by E-box sequence whereas cell lineage epigenetically determines the availability of E-boxes for each differentiation program. Total RNA samples were collected in triplicate from undifferentiated and differentiated P19 cells and MEFs, and labeled cDNA was made per Affymetrix protocol

2012-03-26 | E-GEOD-34907 | biostudies-arrayexpress

Genetic and epigenetic determinants of neurogenesis and myogenesis [expression profiling]

2012-03-26 | GSE34907 | GEO

Conversion of MyoD to a neurogenic factor: binding site specificity determines lineage [RNA-seq]

Project description:MyoD and NeuroD2 are master regulators of myogenesis and neurogenesis and bind to a "shared" E-box sequence (CAGCTG) and a "private" sequence (CAGGTG or CAGATG, respectively). To determine whether private-site recognition is sufficient to confer lineage-specification, we generated a MyoD-mutant with the DNA binding specificity of NeuroD2. Our results demonstrate that redirecting MyoD binding from MyoD-private sites to NeuroD2-private sites, despite preserved binding to the MyoD/NeuroD2-shared sites, is sufficient to change MyoD from a master regulator of myogenesis to a master regulator of neurogenesis. RNA-seq profiling of mouse P19 cells transfected with MyoD, NeuroD2 and chimera mutants. The chimeric mutants are MyoD with the bHLH domain replaced with the NeuroD2 bHLH domain.

2015-07-31 | E-GEOD-64622 | biostudies-arrayexpress

Conversion of MyoD to a neurogenic factor: binding site specificity determines lineage [ChIP-seq]

Project description:MyoD and NeuroD2 are master regulators of myogenesis and neurogenesis and bind to a "shared" E-box sequence (CAGCTG) and a "private" sequence (CAGGTG or CAGATG, respectively). To determine whether private-site recognition is sufficient to confer lineage-specification, we generated a MyoD-mutant with the DNA binding specificity of NeuroD2. Our results demonstrate that redirecting MyoD binding from MyoD-private sites to NeuroD2-private sites, despite preserved binding to the MyoD/NeuroD2-shared sites, is sufficient to change MyoD from a master regulator of myogenesis to a master regulator of neurogenesis. ChIP-seq profiling of MyoD, NeuroD2 and chimera mutants in mouse P19 cells transfected with these genes. The chimeric mutants are MyoD with the bHLH domain replaced with the NeuroD2 bHLH domain.

2015-07-31 | E-GEOD-64626 | biostudies-arrayexpress

Conversion of MyoD to a neurogenic factor: binding site specificity determines lineage [ChIP-seq]

2015-07-31 | GSE64626 | GEO

Conversion of MyoD to a neurogenic factor: binding site specificity determines lineage [RNA-seq]

2015-07-31 | GSE64622 | GEO

ChIP-Seq of Myf5, MyoD, Snai1, HDAC1, HDAC2, E47 and empty vector controls in mouse skeletal myoblasts or myotubes

Project description:In skeletal myogenesis, the transcription factor MyoD activates distinct transcriptional programs in progenitors compared to terminally differentiated cells. Using ChIP-seq and gene expression analyses, we show that in primary myoblasts, Snail-HDAC1/2 repressive complex bind and exclude MyoD from its targets. Notably, Snail binds E-box motifs that are G/C-rich in their central dinucleotides, and such sites are almost exclusively associated with genes expressed during differentiation. By contrast, Snail does not bind the A/T-rich E-boxes associated with MyoD targets in myoblasts. Thus, Snai1-HDAC1/2 prevents MyoD occupancy on differentiation-specific regulatory elements and the change from Snail- to MyoD-binding often results in enhancer switching during differentiation. Furthermore, we show that a regulatory network involving Myogenic Regulatory Factors (MRFs), Snail/2, miR-30a and miR-206 acts as a molecular switch that controls entry into myogenic differentiation. Together, these results reveal a regulatory paradigm that directs distinct gene expression programs in progenitors versus terminally differentiated cells. Genome wide binding sites of various transcription factors and chromatin modifiers in muscle cells

2012-07-04 | E-GEOD-24852 | biostudies-arrayexpress

Motif Variation Regulates the Affinity Landscape and Epigenetic State of the MyoD Cistrome

Project description:The cis-regulatory code is the cellular lexicon by which the transcriptional machinery converts sequence information within cis-regulatory modules (CRMs) into gene expression output. Tissue-specific transcription factors such as MyoD orchestrate gene expression programs by binding to short DNA motifs called E-boxes within their target CRMs to modulate chromatin state and to fine-tune gene expression output. Despite extensive research, how the relatively short and ubiquitously distributed E-box motifs contribute to binding specificity, assembly and the functional output of the transcriptional machinery remains poorly understood. Here, we have carried out an integrative analysis of the relationship between MyoD occupancy, nucleosome positioning, CRMs-associated histone marks and motif sequences within the myogenic CRMs in differentiating muscle cells. Our data suggests that variant sequences within MyoD-binding motifs and their multiplicity within the CRMs, as well as the spatial arrangement of the motifs, in combination confer binding affinity of MyoD, nucleosome occupancy and the epigenetic state of the myogenic CRMs. Our comparative genomic analysis of single nucleotide polymorphism (SNPs) across publically available data from 17 strains of laboratory mice suggests that variant sequences within MyoD-bound motifs, but not their genome-wide counterparts, are under selection. Taken together, our data suggests that variant sequences within MyoD-binding motifs are retained and have functional role to confer a dynamic range of affinities, enabling MyoD to establish a broad spectrum of activity across myogenic CRMs.

2018-01-02 | GSE80588 | GEO

RNA-seq data of si-Snai1, si-Snai2, si-Snai1/2 and si-Scrambled treated mouse primary myoblasts

Project description:In skeletal myogenesis, the transcription factor MyoD, activates distinct transcriptional programs in progenitors compared to terminally differentiated cells. Using ChIP-seq and gene expression analyses, we show that in primary myoblasts, Snai1/2-HDAC1/2 repressive complex bind and exclude MyoD from its targets. Notably, Snail binds E-box motifs that are G/C-rich in their central dinucleotides, and such sites are almost exclusively associated with genes expressed during differentiation. By contrast, Snai1/2 does not bind the A/T-rich E-boxes associated with MyoD targets in myoblasts. Thus, Snai1/2-HDAC1/2 prevents MyoD occupancy on differentiation-specific regulatory elements and the change from Snail1/2- to MyoD-binding often results in enhancer switching during differentiation. Furthermore, we show that a regulatory network involving Myogenic Regulatory Factors (MRFs), Snail/2, miR-30a and miR-206 acts as a molecular switch that controls entry into myogenic differentiation. Together, these results reveal a regulatory paradigm that directs distinct gene expression programs in progenitors versus terminally differentiated cells. In vivo depletion of transcription factor with siRNA followed by whole transcriptome analysis (RNA-seq) to identify target genes.

2012-07-04 | E-GEOD-38236 | biostudies-arrayexpress

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