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An epigenetic switch of let‐7 targeted oncofetal genes
Author(s) -
Jnbaptiste Courtney,
Gurtan Allan,
Lu Victoria,
Bhutkar Arjun,
Sharp Phillip
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.562.24
Subject(s) - dicer , microrna , epigenetics , biology , chromatin , psychological repression , regulation of gene expression , gene silencing , transcriptional regulation , gene , gene expression , transcription (linguistics) , genetics , transcription factor , microbiology and biotechnology , computational biology , rna , rna interference , linguistics , philosophy
MicroRNAs (miRNAs) are post‐transcriptional regulators that fine‐tune gene expression. Despite the modest 2‐fold repression that miRNA activity generally confers on a target, miRNAs are critical for many biological processes. By regulating core transcription factors and their downstream effectors, miRNAs modify transcriptional networks. However, description of the interactions between miRNAs and transcriptional networks has been limited, and the magnitude of these interactions has not been investigated. We sought to investigate the transcriptional programs regulated by miRNAs in adult murine fibroblasts. We previously reported that Dicer deletion results in up‐regulation of let‐7 targets. For some targets, the magnitude of up‐regulation is 50‐100 fold, much greater than that typically reported for miRNA‐mRNA interactions, suggesting effects additional to the loss of post‐transcriptional repression by miRNAs. The activation of these let‐7 targets upon Dicer loss correlated with H3K4me3 and H3K36me3 chromatin marks, indicating enhanced transcription. Further studies indicate that despite complete restoration of the expression and post‐transcriptional activity of miRNAs, the transcriptionally activated let‐7 targets fail to revert to their original wildtype expression levels. Furthermore, these genes maintain a chromatin signature consistent with enhanced transcription. Thus in fibroblasts, global miRNA loss leads to epigenetic changes of an oncofetal gene network, that continue in the absence of the initiating event. Ongoing studies involve experimental and computational strategies to identify mediators of the observed transcriptional effect. This work was funded by USA Public Health Service grant RO1‐CA133404 from the NIH to Dr. Phillip Sharp.