Unknown,Transcriptomics,Genomics,Proteomics

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

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. Total RNA samples were collected in triplicate from undifferentiated and differentiated P19 cells and MEFs, and labeled cDNA was made per Affymetrix protocol

ORGANISM(S): Mus musculus

SUBMITTER: Zizhen yao

PROVIDER: E-GEOD-34907 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genetic and epigenetic determinants of neurogenesis and myogenesis.

Fong Abraham P AP Yao Zizhen Z Zhong Jun Wen JW Cao Yi Y Ruzzo Walter L WL Gentleman Robert C RC Tapscott Stephen J SJ

Developmental cell 20120322 4

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 ...[more]

PMID: 22445365

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Project description:Synthetic transcription factors can be applied to many areas of biotechnology, medicine, and basic research.Â Currently, the most common method for engineering synthetic transcription factors has been based on programmable DNA-binding domains of zinc finger proteins, Transcription Activator-Like Effectors (TALEs), and most recently the CRISPR/Cas9 system. These transcription factor platforms consist of the DNA-binding domain fused to potent transcriptional activation domains, most commonly the tetramer of the minimal transactivation domain of the VP16 protein from herpes simplex virus, referred to as VP64. Although many applications are well-suited for the targeted activation of a single gene, genetic reprogramming requires the coordinated regulation of many nodes of natural gene networks as is typically performed by naturally occurring reprogramming factors. Thus we sought to combine principles from each of these approaches by attaching potent transcriptional activation domains to a natural reprogramming factor to increase the efficiency and/or rate of cell fate conversion. In this study, we evaluated the effects of fusing potent activation domains to the transcription factor MyoD, the master regulator of the skeletal myoblast lineage. In certain non-myogenic lineages, MyoD overexpression causes upregulation of the myogenic gene network and conversion to a myoblast phenotype including cell fusion into multinucleated myotubes. Compared to wild-type MyoD, the VP64-MyoD fusion protein induced greater overall reprogramming of global gene expression. This simple approach for increasing the potency of natural reprogramming factors circumvents the need for screening engineered proteins and leads to a more robust cellular reprogramming compared to treatment with the wild type transcription factor. Human dermal fibroblasts were transduced with a single tet inducible lentivirus that expresses either WT-MyoD or VP64-MyoD in response to treatment with doxycycline. Untreated human dermal fibroblast served as the negative control. Gene expression was measured using mRNA-seq, and differential expression was calculated using DESeq. All experiments were performed in biological duplicates.

Dataset Information

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

Publications

Genetic and epigenetic determinants of neurogenesis and myogenesis.

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