Control of Embryonic Stem Cell Identity by BRD4-Dependent Transcriptional Elongation of Super-Enhancer-Associated Pluripotency Genes

Micco, Raffaella Di; Fontanals-Cirera, Bárbara; Low, Vivien; Ntziachristos, Panagiotis; Yuen, Stephanie K.; Lovell, Claudia D.; Dolgalev, Igor; Yonekubo, Yoshiya; Zhang, Guangtao; Rusinova, E. V.; Gerona‐Navarro, Guillermo; Cañamero, Marta; Ohlmeyer, Michael; Aifantis, Iannis; Zhou, Ming; Tsirigos, Aristotelis; Hernando, Eva

doi:10.1016/j.celrep.2014.08.055

Cited by 184 publications

(210 citation statements)

References 47 publications

(71 reference statements)

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“…They are also required for mesenchymal to epithelial transition during induced reprogramming of human fibroblasts into stem-like cells (96,97). BRD4 is an important factor of self-renewal ability and pluripotency in ESCs (98). The reduced H3K4me3 peaks at genes encoding these important factors could be established during germline reprogramming, as these factors are required earlier in development.…”

Section: Resultsmentioning

confidence: 99%

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

et al. 2016

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The epigenetic events imposed during germline reprogramming and affected by harmful exposure can be inherited and transferred to subsequent generations via gametes inheritance. In this study, we examine the transgenerational effects promoted by widely used herbicide atrazine (ATZ). We exposed pregnant outbred CD1 female mice and the male progeny was crossed for three generations with untreated females. We demonstrate here that exposure to ATZ affects meiosis, spermiogenesis and reduces the spermatozoa number in the third generation (F3) male mice. We suggest that changes in testis cell types originate from modified transcriptional network in undifferentiated spermatogonia. Importantly, exposure to ATZ dramatically increases the number of transcripts with novel transcription initiation sites, spliced variants and alternative polyadenylation sites. We found the global decrease in H3K4me3 occupancy in the third generation males. The regions with altered H3K4me3 occupancy in F3 ATZ-derived males correspond to altered H3K4me3 occupancy of F1 generation and 74% of changed peaks in F3 generation are associated with enhancers. The regions with altered H3K4me3 occupancy are enriched in SP family and WT1 transcription factor binding sites. Our data suggest that the embryonic exposure to ATZ affects the development and the changes induced by ATZ are transferred up to three generations.

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Section: Resultsmentioning

confidence: 99%

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

et al. 2016

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“…Indeed, BR-DIM has been shown to inhibit both AR variants and stem cell and EMT markers in PCa (Kong et al 2015). In addition, although the use of bromodomain inhibitors, such as JQ1, clearly have shown efficacy in reducing AR activity (Asangani et al 2014), the close association between BRD4 and the genes that control stem cell properties and NEPC, such as MYC (Di Micco et al 2014, Rodriguez et al 2014, may mean that bromodomain inhibitors could simultaneously prevent AR signaling and the emergence of cell types that are associated with a loss of AR activity. Importantly however, we are unaware of any potential adverse side effects that targeting multiple tumor cell populations may have, such as putting strong selective pressure on various signaling pathways, which could lead to emergent mechanisms of resistance.…”

Section: Tumor Cell Plasticity: Overlap In Aggressive Cell Phenotypesmentioning

confidence: 99%

Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

Bishop¹,

Davies

Ketola

et al. 2015

Endocrine-Related Cancer

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Prostate cancer (PCa) has become the most common form of cancer in men in the developed world, and it ranks second in cancer-related deaths. Men that succumb to PCa have a disease that is resistant to hormonal therapies that suppress androgen receptor (AR) signaling, which plays a central role in tumor development and progression. Although AR continues to be a clinically relevant therapeutic target in PCa, selection pressures imposed by androgendeprivation therapies promote the emergence of heterogeneous cell populations within tumors that dictate the severity of disease. This cellular plasticity, which is induced by androgen deprivation, is the focus of this review. More specifically, we address the emergence of cancer stem-like cells, epithelial-mesenchymal or myeloid plasticity, and neuroendocrine transdifferentiation as well as evidence that demonstrates how each is regulated by the AR. Importantly, because all of these cell phenotypes are associated with aggressive PCa, we examine novel therapeutic approaches for targeting therapy-induced cellular plasticity as a way of preventing PCa progression.

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“…BRD4 has been implicated in maintaining cell identity through its interaction with gene regulatory regions (Dey et al 2003(Dey et al , 2009Di Micco et al 2014). In part, the maintenance of cell identity is postulated to occur through stable interaction of BRD4 with chromosomes during mitosis (Dey et al 2000).…”

Section: A Shortcut To Epithelial Cancermentioning

confidence: 99%

The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains

et al. 2015

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NUT midline carcinoma (NMC), a subtype of squamous cell cancer, is one of the most aggressive human solid malignancies known. NMC is driven by the creation of a translocation oncoprotein, BRD4-NUT, which blocks differentiation and drives growth of NMC cells. BRD4-NUT forms distinctive nuclear foci in patient tumors, which we found correlate with ∼100 unprecedented, hyperacetylated expanses of chromatin that reach up to 2 Mb in size. These "megadomains" appear to be the result of aberrant, feed-forward loops of acetylation and binding of acetylated histones that drive transcription of underlying DNA in NMC patient cells and naïve cells induced to express BRD4-NUT. Megadomain locations are typically cell lineage-specific; however, the cMYC and TP63 regions are targeted in all NMCs tested and play functional roles in tumor growth. Megadomains appear to originate from select pre-existing enhancers that progressively broaden but are ultimately delimited by topologically associating domain (TAD) boundaries. Therefore, our findings establish a basis for understanding the powerful role played by large-scale chromatin organization in normal and aberrant lineage-specific gene transcription.

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Control of Embryonic Stem Cell Identity by BRD4-Dependent Transcriptional Elongation of Super-Enhancer-Associated Pluripotency Genes

Cited by 184 publications

References 47 publications

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains

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