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Genome-wide Twist1 occupancy in endocardial cushion cells, embryonic limb buds, and peripheral nerve sheath tumor cells

ABSTRACT: The basic helix-loop-helix transcription factor Twist1 has a well-documented role in mesenchymal populations of the developing embryo, such as endocardial cushion (ECC) mesenchymal cells and limb buds, and during cancer development and progression. Whether Twist1 regulates the same transcriptional targets in different cell types has yet to be investigated. Through chromatin immunoprecipitation followed by sequencing (Chip-seq) analysis, the cell type-specific genome-wide occupancy of Twist1 was investigated in ECCs, limb buds and mouse peripheral nerve sheath tumor (PNST) cells. Twist1 binds mainly in a cell type-specific manner, with very few common genomic regions occupied by Twist1 in different cell types. Genes associated with binding peaks in each cell type are related to known Twist1 cellular functions in ECCs, limb buds, and cancer cells. We found that cell type-specific binding of Twist1 may be influenced by histone modifications or co-factors. Binding regions were located in several Wnt pathway associated genes, supporting a link between Twist1 and Wnt signalling in ECCs, limb buds, and PNST cells. These data suggest that similar functions are regulated by Twist1 in ECCs, limb buds, and PNST cells in a cell type-specific manner, and provide insights into possible mechanisms utilized for cell type-specificity of Twist1 binding.

ORGANISM(S): Mus musculus

PROVIDER: GSE50111 | GEO | 2014/10/02

SECONDARY ACCESSION(S): PRJNA216098

REPOSITORIES: GEO

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Project description:Twist1, a basic helix-loop-helix transcription factor, is expressed in mesenchymal precursor populations during embryogenesis and in metastatic cancer cells. In the developing heart, Twist1 is highly expressed in endocardial cushion (ECC) valve mesenchymal cells and is down regulated during valve differentiation and remodeling. Previous studies demonstrated that Twist1 promotes cell proliferation, migration, and expression of primitive ECM molecules in ECC mesenchymal cells. Furthermore, Twist1 expression is induced in human pediatric and adult diseased heart valves. However, the Twist1 downstream target genes that mediate increased cell proliferation and migration during early heart valve development remain largely unknown. Candidate gene and global gene profiling approaches were used to identify direct transcriptional targets of Twist1 during heart valve development. Candidate target genes were analyzed for evolutionarily conserved regions (ECRs) containing E-box consensus sequences that are potential Twist1 binding sequences. ECRs containing conserved E-box sequences were identified for Twist1 responsive genes Tbx20, Cdh11, Sema3C, Rab39b, and Gadd45a. Twist1 binding to these sequences in vivo was determined by chromatin immunoprecipitation assays, and binding was detected in ECCs but not late stage remodeling valves. In addition identified Twist1 target genes are highly expressed in ECCs and have reduced expression during heart valve remodeling in vivo which is consistent with the expression pattern of Twist1. Together these analyses identify multiple new genes involved in cell proliferation and migration that are differentially expressed in the developing heart valves, are responsive to Twist1 transcriptional function, and contain Twist1 responsive regulatory sequences. Murine MC3T3-E1 preosteoblast cells were treated with siScrambled control or siTwist1 to achieve knockdown of Twist1. Both siScr and siTwist1 were performed in triplicate. Isolated RNA was analyzed with Affymetrix muring MOE 430 2.0 gene chip microarray.

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Genome-wide Twist1 occupancy in endocardial cushion cells, embryonic limb buds, and peripheral nerve sheath tumor cells

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