Abstract
BackgroundThe basic helix-loop-helix transcription factor Twist1 has well-documented roles in progenitor populations of the developing embryo, including endocardial cushions (ECC) and limb buds, and also in cancer. Whether Twist1 regulates the same transcriptional targets in different tissue types is largely unknown.ResultsThe tissue-specificity of Twist1 genomic occupancy was examined in mouse ECCs, limb buds, and peripheral nerve sheath tumor (PNST) cells using chromatin immunoprecipitation followed by sequencing (Chip-seq) analysis. Consistent with known Twist1 functions during development and in cancer cells, Twist1-DNA binding regions associated with genes related to cell migration and adhesion were detected in all three tissues. However, the vast majority of Twist1 binding regions were specific to individual tissue types. Thus, while Twist1 has similar functions in ECCs, limb buds, and PNST cells, the specific genomic sequences occupied by Twist1 were different depending on cellular context. Subgroups of shared genes, also predominantly related to cell adhesion and migration, were identified in pairwise comparisons of ECC, limb buds and PNST cells. Twist1 genomic occupancy was detected for six binding regions in all tissue types, and Twist1-binding sequences associated with Chst11, Litaf, Ror2, and Spata5 also bound the potential Twist1 cofactor RREB1. Pathway analysis of the genes associated with Twist1 binding suggests that Twist1 may regulate genes associated with the Wnt signaling pathway in ECCs and limb buds.ConclusionsTogether, these data indicate that Twist1 interacts with genes that regulate adhesion and migration in different tissues, potentially through distinct sets of target genes. In addition, there is a small subset of genes occupied by Twist1 in all three tissues that may represent a core group of Twist1 target genes in multiple cell types.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-821) contains supplementary material, which is available to authorized users.
Highlights
The basic helix-loop-helix transcription factor Twist1 has well-documented roles in progenitor populations of the developing embryo, including endocardial cushions (ECC) and limb buds, and in cancer
Analysis of Twist1 genomic occupancy in ECCs, limb buds, and peripheral nerve sheath tumor (PNST) cells Twist1 genomic occupancy was assessed by chromatin immunoprecipitation (ChIP) with anti-Twist1 in mouse E12.5 ECCs, E10.5 limb buds, and PNST cells followed by deep sequencing (ChIP-seq)
In order to compare Twist1 genomic occupancy with genes expressed in each tissue, genes associated with binding peaks in each tissue were compared to respective Affymetrix microarray gene expression data for E12.5 ECCs, E10.5 limb buds, and PNST cells [10,16,20]
Summary
The basic helix-loop-helix transcription factor Twist has well-documented roles in progenitor populations of the developing embryo, including endocardial cushions (ECC) and limb buds, and in cancer. Twist is a highly conserved basic-helix-loop-helix (bHLH) transcription factor, which regulates cell migration, proliferation, and differentiation in progenitor populations, such as embryonic neural crest cells, cranial mesoderm, limb buds, and endocardial cushions (ECCs) [1,2,3,4]. Extensive genetic studies have been performed demonstrating an essential role for Twist in limb patterning and morphogenesis, the direct transcriptional targets underlying these functions are only recently being elucidated [12]. It is not known if Twist regulates the same downstream targets in distinct progenitor populations or if there is tissue-specificity to Twist regulatory mechanisms in the developing embryo
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