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

Abstract:

:The modulation of GLI2, an oncogenic transcription factor commonly upregulated in cancer, is in many cases not due to genetic defects, suggesting dysregulation through alternative mechanisms. The identity of these molecular events remains for the most part unknown. Here, we identified TFII-I as a novel repressor of GLI2 expression. Mapping experiments suggest that the INR region of the GLI2 promoter is necessary for GLI2 repression. ChIP studies showed that TFII-I binds to this INR. TFII-I knockdown decreased the binding of NELF-A, a component of the promoter-proximal pausing complex at this site, and enriched phosphorylated RNAPII serine 2 in the GLI2 gene body. Immunoprecipitation studies demonstrate TFII-I interaction with SPT5, another pausing complex component. TFII-I overexpression antagonized GLI2 induction by TGFβ, a known activator of GLI2 in cancer cells. TGFβ reduced endogenous TFII-I binding to the INR and increased RNAPII SerP2 in the gene body. We demonstrate that this regulatory mechanism is not exclusive of GLI2. TGFβ-induced genes CCR7, TGFβ1 and EGR3 showed similar decreased TFII-I and NELF-A INR binding and increased RNAPII SerP2 in the gene body post-TGFβ treatment. Together these results identify TFII-I as a novel repressor of a subset of TGFβ-responsive genes through the regulation of RNAPII pausing.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

McCleary-Wheeler AL,Paradise BD,Almada LL,Carlson AJ,Marks DL,Vrabel A,Vera RE,Sigafoos AN,Olson RL,Fernandez-Zapico ME

doi

10.1093/nar/gkaa476

subject

Has Abstract

pub_date

2020-07-27 00:00:00

pages

7169-7181

issue

13

eissn

0305-1048

issn

1362-4962

pii

5858115

journal_volume

48

pub_type

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