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Developmental and housekeeping transcriptional programs display distinct modes of enhancer-enhancer cooperativity in Drosophila

ABSTRACT: Genomic enhancers are key transcriptional regulators which, upon the binding of sequence-specific transcription factors, can activate their cognate promoter. Although enhancers have been extensively studied in isolation, a substantial number of genes have more than one simultaneously active enhancer, and it remains unclear how these distinct elements cooperate to regulate transcription. In this work, we report that developmental enhancers – that regulate tissue-specific genes – and housekeeping enhancers rely on distinct modes of enhancer-enhancer cooperativity: while developmental enhancers are synergistic, housekeeping enhancers are additive (meaning that their combined activity mirrors the sum of their individual activities). Developmental enhancer synergy is promiscuous in our system and is not associated with specific combinations of transcription factors. However, developmental transcription factors globally contain higher fraction of intrinsically disordered domains, which might support such synergistic interactions.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE245033 | GEO | 2024/09/05

REPOSITORIES: GEO

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Project description:Although technological advances now allow increased tumor profiling, a detailed understanding of the mechanisms leading to the development of different cancers remains elusive. Our approach towards understanding the molecular events that lead to cancer is to characterize changes in transcriptional regulatory networks between normal and tumor tissue. Because enhancer activity is thought to be critical in regulating cell fate decisions, we have focused our studies on distal regulatory elements and transcription factors that bind to these elements. Using DNA methylation data, we identified more than 25,000 enhancers that are differentially activated in breast, prostate, and kidney tumor tissues, as compared to normal tissues. We then developed an analytical approach called TENET (Tracing Enhancer Networks using Epigenetic Traits) that correlates DNA methylation levels at enhancers with gene expression to identify more than 800,000 genome-wide links from enhancers to genes and from genes to enhancers. We found more than 1,200 transcription factors to be involved in these tumor-specific enhancer networks. We further characterized several transcription factors linked to a large number of enhancers in each tumor type, including GATA3 in non-basal breast tumors, HOXC6 and DLX1 in prostate tumors, and ZNF395 in kidney tumors. We showed that HOXC6 and DLX1 are associated with different clusters of prostate tumor-specific enhancers and confer distinct transcriptomic changes upon knockdown in C42B prostate cancer cells. We also discovered de novo motifs enriched in enhancers linked to ZNF395 in kidney tumors. Our studies characterized tumor-specific enhancers and revealed key transcription factors involved in enhancer networks for specific tumor types and subgroups. Our findings, which include a large set of identified enhancers and transcription factors linked to those enhancers in breast, prostate, and kidney cancers, will facilitate understanding of enhancer networks and mechanisms leading to the development of these cancers. Examination of FAIRE and ChIP assays in prostate and breast epithelial cells. RNA-seq assays in C42B, prostate cancer cell line after knocking down of TFs (HOXC6, DLX1).

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Developmental and housekeeping transcriptional programs display distinct modes of enhancer-enhancer cooperativity in Drosophila

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