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The transcriptomics of phenotypic nonspecificity in Drosophila melanogaster

ABSTRACT: Transcription factor (TF) function is redundant as TF phenotypes are frequently rescued by TFs not resident to the TF locus, a phenomenon termed phenotypic nonspecificity. Phenotypic nonspecificity is not dependent on the DNA binding specificity of the TFs and generally due to genetic complementation. Two TF phenotypes (doublesex [dsx] and apterous [ap]) are rescued by multiple TFs, and the rescue and non-rescue by resident and non-resident TFs of these two phenotypes were used to distinguish between three possible outcomes of the comparison of the TF dependent mRNA accumulation in these two systems: first the sets of TF dependent mRNAs are independent and non-overlapping; second the sets of TF dependent mRNAs are independent and overlapping; and third the sets of TF dependent mRNAs are constrained and have extensive overlap. The transcriptomes associated with rescue and non-rescue by resident and non-resident TFs of the two TF phenotypes (dsx and ap) provided many examples of extensive overlap indicating regulation of constrained sets of genes. However, the strength of correlation of transcript accumulation observed between the resident and non-resident TFs was not a strong predictor of the ability of the TFs to rescue the phenotype. The regulation of a constrained set of genes supports the hypothetical assembly of TFs into wolfpacks, and not the hypothetical limited specificity of TF function, as a potential explanation of phenotypic nonspecificity.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE296804 | GEO | 2025/05/12

REPOSITORIES: GEO

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Project description:Eukaryotic transcription factors (TFs) are key determinants of gene activity, yet they bind only a fraction of their corresponding DNA sequence motifs in any given cell type. Chromatin has the potential to restrict accessibility of binding sites; however, in which context chromatin states are instructive for TF binding remains mainly unknown. To explore the contribution of DNA methylation to constrained TF binding, we mapped DNase-I-hypersensitive sites in murine stem cells in the presence and absence of DNA methylation. Methylation-restricted sites are enriched for TF motifs containing CpGs, especially for those of NRF1. In fact, the TF NRF1 occupies several thousand additional sites in the unmethylated genome, resulting in increased transcription. Restoring de novo methyltransferase activity initiates remethylation at these sites and outcompetes NRF1 binding. This suggests that binding of DNA-methylationsensitive TFs relies on additional determinants to induce local hypomethylation. In support of this model, removal of neighbouring motifs in cis or of a TF in trans causes local hypermethylation and subsequent loss of NRF1 binding. This competition between DNA methylation and TFs in vivo reveals a case of cooperativity between TFs that acts indirectly via DNA methylation. Methylation removal by methylation-insensitive factors enables occupancy of methylation-sensitive factors, a principle that rationalizes hypomethylation of regulatory regions. DNase-seq (2 replicates) in mouse embryonic stem cells with (WT) and without DNA methylation (DNMT TKO). RNA-seq (3 replicates) in WT and DNMT TKO cells and in DNMT TKO cells after treatment with control siRNA or siRNA targeting Nrf1. H3K27ac ChIP-seq (2 replicates) in WT and DNMT TKO cells. NRF1 ChIP-seq (2 replicates) in WT and DNMT TKO cells, in WT upon culture in different conditions (adaptation to 2i and back to serum), upon transient overexpression of NRF1 and after differentiation into neuronal progenitor cells (NP). Whole-genome bisulfite sequencing in DNMT TKO cells and in WT upon culture in different conditions (adaptation to 2i and back to serum). NRF1 ChIP-seq (2 replicates) in human HMEC and HCC1954 cells.

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The transcriptomics of phenotypic nonspecificity in Drosophila melanogaster

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