Enhancer recruitment of transcription repressors RUNX1 and TLE3 by mis-expressed FOXC1 blocks differentiation in acute myeloid leukemia

Simeoni, Fabrizio; Romero-Camarero, Isabel; Camera, Francesco; Amaral, Fabio; Sinclair, Oliver; Papachristou, Evangelia K.; Spencer, Gary J.; Lie-A-Ling, Michael; Lacaud, Georges; Carroll, Jason S.; Somervaille, Tim C. P.

doi:10.1016/j.celrep.2021.109725

Cited by 20 publications

(15 citation statements)

References 55 publications

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“…In addition, RUNX1 can serve as transcription repressor by recruiting corepressors to target genes. For example, RUNX1 binds to corepressor SIN3A complex [ 63 ] and the Groucho/TLE repressor complex [ 64 , 65 ]. Whether RUNX1 active or suppress gene expression, it depends on the cellular and promoter context.…”

Section: Discussionmentioning

confidence: 99%

RUNX1 inhibits the antiviral immune response against influenza A virus through attenuating type I interferon signaling

Pan

Zhou

et al. 2022

Virol J

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Background Influenza A viruses (IAVs) are zoonotic, segmented negative-stranded RNA viruses. The rapid mutation of IAVs results in host immune response escape and antiviral drug and vaccine resistance. RUNX1 is a transcription factor that not only plays essential roles in hematopoiesis, but also functions as a regulator in inflammation. However, its role in the innate immunity to IAV infection has not been well studied. Methods To investigate the effects of RUNX1 on IAV infection and explore the mechanisms that RUNX1 uses during IAV infection. We infected the human alveolar epithelial cell line (A549) with influenza virus A/Puerto Rico/8/34 (H1N1) (PR8) and examined RUNX1 expression by Western blot and qRT-PCR. We also knocked down or overexpressed RUNX1 in A549 cells, then evaluated viral replication by Western blot, qRT-PCR, and viral titration. Results We found RUNX1 expression is induced by IAV H1N1 PR8 infection, but not by poly(I:C) treatment, in the human alveolar epithelial cell line A549. Knockdown of RUNX1 significantly inhibited IAV infection. Conversely, overexpression of RUNX1 efficiently promoted production of progeny viruses. Additionally, RUNX1 knockdown increased IFN-β and ISGs production while RUNX1 overexpression compromised IFN-β and ISGs production upon PR8 infection in A549 cells. We further showed that RUNX1 may attenuate the interferon signaling transduction by hampering the expression of IRF3 and STAT1 during IAV infection. Conclusions Taken together, we found RUNX1 attenuates type I interferon signaling to facilitate IAV infection in A549 cells.

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Section: Discussionmentioning

confidence: 99%

RUNX1 inhibits the antiviral immune response against influenza A virus through attenuating type I interferon signaling

Pan

Zhou

et al. 2022

Virol J

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“…To ensure the transcriptional changes observed in the KO cells were specific to the predicted target genes, we tested three canonical GR target genes ( FKBP5, SGK1, TSC22D3 ) and did not observe differences in their dex-inducibility in the KO and WT cells, except for TSC22D3 in the rs12206258 KO (Figure S4 A-B) , possibly due to FOXC1’s role as a transcription factor, which has been shown to bind at TSC22D3 . 87 H , Using homology-directed repair and a template, we edited SNP rs12206258. I , By generating homozygously edited (C/C) cells we observed a significant blunting of the transcriptional response to dex when compared to the homozygous wild type (T/T) cells (p-value = 0.040 ) .…”

Section: Resultsmentioning

confidence: 99%

Assessment of glucocorticoid-induced enhancer activity of eSNP regions using STARR-seq reveals novel molecular mechanisms in psychiatric disorders

Penner-Goeke

Bothe

Kappelmann

et al. 2022

Preprint

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Exposure to stressful events increases risk for psychiatric disorders. Mechanistic insight into genetic factors moderating the impact of stress can increase our understanding of disease processes. Here, we test 3662 SNPs from preselected expression quantitative trait loci in massively parallel reporter assays to identify genetic variants that modulate the activity of regulatory elements sensitive to glucocorticoids, important mediators of the stress response. Of the tested SNP sequences, 547 were located in glucocorticoid-responsive regulatory elements of which 233 showed allele-dependent activity. Transcripts regulated by these variants were enriched for those differentially expressed in psychiatric disorders in postmortem brain. Phenome-wide Mendelian randomization analysis in 4,439 phenotypes revealed potentially causal associations specifically in neuro-behavioral traits, including psychiatric disorders. Finally, functional gene scores derived from these variants were significantly associated with differences in physiological stress measures, suggesting that these may alter disease risk by moderating the individual set point of the stress response.

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“…Furthermore, FOXA1 has a wide impact on TLE3, since its protein levels and genome-wide chromatin occupancy are decreased upon FOXA1 depletion. Beyond GR and FOXA1 in PCa, TLE3 has been shown to restrict estrogen receptor signaling (75), and FOXC1-mediated recruitment of TLE3 limits monocyte enhancer activity (76). This suggests an extensive role of TLE3 in restricting steroid receptor signaling, whereas FOX-family members could be involved in the mediation of TLE3’s chromatin activity.…”

Section: Discussionmentioning

confidence: 99%

Chromatin Accessibility and Pioneer Factor FOXA1 Shape Glucocorticoid Receptor Action in Prostate Cancer

Helminen

Huttunen

Aaltonen

et al. 2023

Preprint

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Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the antiandrogen therapies, the cancer often develops resistance to the AR blockade. One mechanism of the resistance is glucocorticoid receptor (GR)-mediated replacement of AR function. Nevertheless, the mechanistic ways and means how the GR-mediated antiandrogen resistance occurs have remained elusive. Here, we have discovered several crucial features of GR action in prostate cancer cells through genome-wide techniques. We detected that the replacement of AR by GR in enzalutamide-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying FOXA1 occupancy. Counterintuitively to the classical pioneer factor model, silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of theNR3C1(gene encoding GR) expressionviathe corepressor TLE3. Moreover, the small-molecule inhibition of coactivator p300’s enzymatic activity efficiently restricted GR-mediated gene regulation and cell proliferation. Overall, we identified chromatin pre-accessibility and FOXA1-mediated repression as important regulators of GR action in prostate cancer, pointing out new avenues to oppose steroid receptor-mediated antiandrogen resistance.

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Enhancer recruitment of transcription repressors RUNX1 and TLE3 by mis-expressed FOXC1 blocks differentiation in acute myeloid leukemia

Cited by 20 publications

References 55 publications

RUNX1 inhibits the antiviral immune response against influenza A virus through attenuating type I interferon signaling

RUNX1 inhibits the antiviral immune response against influenza A virus through attenuating type I interferon signaling

Assessment of glucocorticoid-induced enhancer activity of eSNP regions using STARR-seq reveals novel molecular mechanisms in psychiatric disorders

Chromatin Accessibility and Pioneer Factor FOXA1 Shape Glucocorticoid Receptor Action in Prostate Cancer

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