Transient upregulation of IRF1 during exit from naive pluripotency confers viral protection

Romeike, Merrit; Spach, Stephanie; Huber, Martin; Feng, Songjie; Vainorius, Gintautas; Elling, Ulrich; Versteeg, Gjis A; Buecker, Christa

doi:10.15252/embr.202255375

Cited by 11 publications

(6 citation statements)

References 68 publications

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“…Next, we asked how the loss of MLL3/4 impacted H3K4me1 and H3K27ac at well-known functionally validated enhancers regulating genes important for pluripotent cell identity including Sox2, Nanog, Fgf5, and Oct6 (28,(30)(31)(32)(33)(34). Sox2 and Nanog expression normally decrease, while Fgf5 and Oct6 expression increase during the naive to formative transition.…”

Section: Enhancer Activation Can Occur Independently Of Mll3/4mentioning

confidence: 99%

Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation during ESC differentiation

Boileau

Chen

Blelloch

2022

Preprint

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Enhancers are essential in defining cell fates through the control of cell type specific gene expression. Enhancer activation is a multi-step process involving chromatin remodelers and histone modifiers including the monomethylation of H3K4 (H3K4me1) by MLL3 (KMT2C) and MLL4 (KMT2D). MLL3/4 are thought to be critical for enhancer activation and cognate gene expression including through the recruitment of acetyltransferases for H3K27. Here we test this model by evaluating the impact of MLL3/4 loss on chromatin and transcription during early embryonic stem cell differentiation. We find that MLL3/4 activity is required at most if not all sites that gain or lose H3K4me1 but is largely dispensable at sites that remain stably methylated during this transition. This requirement extends to H3K27 acetylation (H3K27ac) at most transitional sites. However, many sites gain H3K27ac independent of MLL3/4 or H3K4me1 including enhancers regulating key factors in early differentiation. Furthermore, despite the failure to gain active histone marks at thousands of enhancers, transcriptional activation of nearby genes is largely unaffected, thus uncoupling the regulation of these chromatin events from transcriptional changes during this transition. These data challenge current models of enhancer activation and imply distinct mechanisms between stable and dynamically changing enhancers. Collectively, our study highlights gaps in knowledge about the steps and epistatic relationships of enzymes necessary for enhancer activation and cognate gene transcription.

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Section: Enhancer Activation Can Occur Independently Of Mll3/4mentioning

confidence: 99%

Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation during ESC differentiation

Boileau

Chen

Blelloch

2022

Preprint

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“…In agreement with the enrichment of CSCs in our resistant lines, Hey1 and Notch1 were downregulated in the resistant cell lines ( Figure 4 D). To further examine the role of ID4 in cancer stemness, we knocked down ID4 in MDA-MB-468 breast tumor cells using SMARTpool siRNAs ( Figure 4 E), and tested the expression of a panel of stemness genes including Twist1, Twist2 [ 27 ], Snail, Slug [ 24 ], BMP2 [ 28 ], IRF1 [ 29 ], SOX4 [ 30 ], Foxk1 [ 31 ] and Notch3 [ 27 ]. Depletion of ID4 resulted in downregulation of most stemness-related genes we tested, including Twist2, Slug, BMP2, IRF1, SOX4, Twist1 and Notch3 ( Figure 4 F).…”

Section: Resultsmentioning

confidence: 99%

Upregulation of Receptor Tyrosine Kinase Activity and Stemness as Resistance Mechanisms to Akt Inhibitors in Breast Cancer

Tsang

Cohen

et al. 2022

Cancers

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The PI3K/Akt pathway is frequently deregulated in human cancers, and multiple Akt inhibitors are currently under clinical evaluation. Based on the experience from other molecular targeted therapies, however, it is likely that acquired resistance will be developed in patients treated with Akt inhibitors. We established breast cancer models of acquired resistance by prolonged treatment of cells with allosteric or ATP-competitive Akt inhibitors. Phospho-Receptor tyrosine kinase (Phospho-RTK) arrays revealed hyper-phosphorylation of multiple RTKS, including EGFR, Her2, HFGR, EhpB3 and ROR1, in Akt-inhibitor-resistant cells. Importantly, resistance can be overcome by treatment with an EGFR inhibitor. We further showed that cancer stem cells (CSCs) are enriched in breast tumor cells that have developed resistance to Akt inhibitors. Several candidates of CSC regulators, such as ID4, are identified by RNA sequencing. Cosmic analysis indicated that sensitivity of tumor cells to Akt inhibitors can be predicted by ID4 and stem cell/epithelial–mesenchymal transition pathway targets. These findings indicate the potential of targeting the EGFR pathway and CSC program to circumvent Akt inhibitor resistance in breast cancer.

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“…Type 1 interferon pathway becomes mature coincident with mESC differentiation. Although intrinsic low expression of interferon-stimulated genes independent of viral infection was recently reported in mESCs, this was shown to be dependent on the TF, IRF9 ( 21 ). We did not observe a change in IRF9 transcript level in the absence of ARID4B, suggesting other mechanisms that include ARID4B in ISG regulation might be at play.…”

Section: Discussionmentioning

confidence: 96%

ARID4B loss leads to activated STAT1-dependent interferon pathway in mouse embryonic stem cells and during meso/endodermal differentiation

Terzi Çizmecioğlu

2023

J Turkish German Gynecol Assoc

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Objective: Proper deactivation of the pluripotency network and activation of a lineage-specific gene expression program are critical for mouse embryonic stem cell (mESC) differentiation. This is achieved by the coordinated action of transcription and chromatin factors. Our previous work identified ARID4B as a critical chromatin factor for mesoderm and endoderm differentiation. As part of a histone deacetylase complex, ARID4B plays a role in transcriptional suppression of its direct targets. Here, we investigated the mechanism of ARID4B function in mESC differentiation by focusing on genes and pathways that are upregulated in its absence. Material and Methods: We analyzed transcriptomic results of wild-type and arid4bΔ endoderm or mesoderm differentiated cells through integrative genomics viewer and ingenuity pathway analysis. We performed real-time quantitative polymerase chain reaction for selected genes. To understand pathway activation, we performed Western blot for candidate proteins during the time-course of differentiation. We also analyzed H3K4me3, H3K27me3 and H3K27Ac ChIP-seq results to understand changes in the chromatin environment. Results: Interferon-related genes were activated in arid4bΔ mESCs and endoderm or mesoderm directed cells. Consistent with this, higher phosphorylated STAT1 levels were found in arid4bΔ mESCs while a related phosphorylated STAT3 was unchanged. Finally, we observed a significant increase in H3K4me3 around interferon-related distal gene regulatory regions with a combination of either upregulation of H3K27Ac level or downregulation of H3K27me3 level. Conclusion: These results provide evidence that ARID4B is involved in the suppression of interferon-related genes in mESCs and during meso/endoderm differentiation through modulation, mainly of H3K4me3. This regulation might be important for successful mESC differentiation.

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Transient upregulation of IRF1 during exit from naive pluripotency confers viral protection

Cited by 11 publications

References 68 publications

Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation during ESC differentiation

Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation during ESC differentiation

Upregulation of Receptor Tyrosine Kinase Activity and Stemness as Resistance Mechanisms to Akt Inhibitors in Breast Cancer

ARID4B loss leads to activated STAT1-dependent interferon pathway in mouse embryonic stem cells and during meso/endodermal differentiation

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