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TFII-I-mediated polymerase pausing antagonizes GLI2 induction by TGFβ

Angela L McCleary-Wheeler1,2, Brooke D Paradise1,2, Luciana L Almada1

  • 1Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.

Nucleic Acids Research
|June 17, 2020
PubMed

Insights

Transcription factor TFII-I represses GLI2 expression by regulating RNA polymerase II pausing. This mechanism impacts cancer-related genes and is influenced by TGFβ signaling.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Cancer Biology

Background:

  • GLI2, an oncogenic transcription factor, is often upregulated in cancer through non-genetic mechanisms.
  • The specific molecular events driving GLI2 dysregulation are largely unknown.

Purpose of the Study:

  • To identify novel regulators of GLI2 expression.
  • To elucidate the mechanism by which TFII-I modulates GLI2.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) assays to assess protein binding to the GLI2 promoter.
  • RNA polymerase II (RNAPII) phosphorylation analysis.
  • Immunoprecipitation studies to identify protein interactions.
  • Gene expression analysis in response to TFII-I modulation and TGFβ treatment.

Main Results:

  • TFII-I was identified as a novel repressor of GLI2 expression, binding to the GLI2 promoter's INR region.
  • TFII-I regulates RNAPII pausing at the GLI2 gene, influencing transcription.
  • TFII-I overexpression antagonizes TGFβ-induced GLI2 activation.
  • This mechanism extends to other TGFβ-responsive genes.

Conclusions:

  • TFII-I acts as a repressor of GLI2 and other TGFβ-responsive genes.
  • Regulation occurs via modulation of RNAPII pausing at the promoter.
  • Identifies a novel pathway for controlling oncogenic transcription factor expression in cancer.

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