Recent studies suggest a hierarchical model in which lineage-determining factors act in a collaborative manner to select and prime cell-specific enhancers, thereby enabling signal-dependent ...transcription factors to bind and function in a cell-type-specific manner. Consistent with this model, TLR4 signaling primarily regulates macrophage gene expression through a pre-existing enhancer landscape. However, TLR4 signaling also induces priming of ∼3,000 enhancer-like regions de novo, enabling visualization of intermediates in enhancer selection and activation. Unexpectedly, we find that enhancer transcription precedes local mono- and dimethylation of histone H3 lysine 4 (H3K4me1/2). H3K4 methylation at de novo enhancers is primarily dependent on the histone methyltransferases Mll1, Mll2/4, and Mll3 and is significantly reduced by inhibition of RNA polymerase II elongation. Collectively, these findings suggest an essential role of enhancer transcription in H3K4me1/2 deposition at de novo enhancers that is independent of potential functions of the resulting eRNA transcripts.
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•TLR4 signaling substantially remodels the macrophage enhancer landscape•Intermediates in enhancer selection and activation can be visualized•Signal-dependent enhancer transcription is linked to H3K4 methylation•Enhancer H3K4 methylation is primarily dependent on Mll1, Mll2/4, and Mll3
Humans carry trillions of viruses that thrive because of their ability to exploit the host. In this exploitation, viruses promote their own replication by suppressing the host antiviral response and ...by inducing changes in host biosynthetic processes, often with extremely small genomes of their own. In the review, we discuss the phenomenon of histone mimicry by viral proteins and how this mimicry allows the virus to dial in to the cell's transcriptional processes and establish a cell state that promotes infection. We suggest that histone mimicry is part of a broader viral strategy to use intrinsic protein disorder as a means to overcome the size limitations of its own genome and to maximize its impact on host protein networks. In particular, we discuss how intrinsic protein disorder may enable viral proteins to interfere with phase-separated host protein condensates, including those that contribute to chromatin-mediated control of gene expression.
The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown ...efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.
Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb ...repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.
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•PRC2 maintains bivalency at MHC-I antigen-processing genes silencing MHC-I expression•Cancer cells co-opt this conserved, lineage-specific PRC2 function to evade T cells•Pharmacological inhibition of PRC2 in MHC-I low cancers restores anti-tumor immunity•Immunotherapy resistance may arise via non-genomic routes that exploit PRC2 activity
Burr et al. show that cancer cells co-opt PRC2 to evade immune surveillance. PRC2 maintains bivalency at the promoters of MHC-I antigen-processing pathway (MHC-I APP) genes to repress their basal and cytokine-activated expression. Inhibition of PRC2 restores the MHC-I APP and T cell-mediated anti-tumor immunity.
BET family proteins are epigenetic regulators known to control expression of genes involved in cell growth and oncogenesis. Selective inhibitors of BET proteins exhibit potent anti-proliferative ...activity in a number of hematologic cancer models, in part through suppression of the MYC oncogene and downstream Myc-driven pathways. However, little is currently known about the activity of BET inhibitors in solid tumor models, and whether down-regulation of MYC family genes contributes to sensitivity. Here we provide evidence for potent BET inhibitor activity in neuroblastoma, a pediatric solid tumor associated with a high frequency of MYCN amplifications. We treated a panel of neuroblastoma cell lines with a novel small molecule inhibitor of BET proteins, GSK1324726A (I-BET726), and observed potent growth inhibition and cytotoxicity in most cell lines irrespective of MYCN copy number or expression level. Gene expression analyses in neuroblastoma cell lines suggest a role of BET inhibition in apoptosis, signaling, and N-Myc-driven pathways, including the direct suppression of BCL2 and MYCN. Reversal of MYCN or BCL2 suppression reduces the potency of I-BET726-induced cytotoxicity in a cell line-specific manner; however, neither factor fully accounts for I-BET726 sensitivity. Oral administration of I-BET726 to mouse xenograft models of human neuroblastoma results in tumor growth inhibition and down-regulation MYCN and BCL2 expression, suggesting a potential role for these genes in tumor growth. Taken together, our data highlight the potential of BET inhibitors as novel therapeutics for neuroblastoma, and suggest that sensitivity is driven by pleiotropic effects on cell growth and apoptotic pathways in a context-specific manner.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immune-mediated diseases are clinically heterogeneous but they share genetic and pathogenic mechanisms. These diseases may develop from the interplay of genetic factors and environmental or lifestyle ...factors. Exposure to such factors, including infectious agents, is associated with coordinated changes in gene transcription owing to epigenetic alterations. A growing understanding of how epigenetic mechanisms control gene expression patterns and cell function has been aided by the development of small-molecule inhibitors that target these processes. These chemical tools have helped to reveal the importance of epigenetics in guiding cell fate decisions during immune responses and have also highlighted the potential for targeting epigenetic mechanisms for the treatment of inflammation and immune-mediated diseases. In this Review, we discuss the most advanced areas of epigenetic drug development for autoimmune and inflammatory diseases and summarize the promising preclinical data in this exciting and evolving field. These agents will inevitably begin to move into clinical trials for use in patients with immune-mediated diseases.
The success of new therapies hinges on our ability to understand their molecular and cellular mechanisms of action. We modified BET bromodomain inhibitors, an epigenetic-based therapy, to create ...functionally conserved compounds that are amenable to click chemistry and can be used as molecular probes in vitro and in vivo. We used click proteomics and click sequencing to explore the gene regulatory function of BRD4 (bromodomain containing protein 4) and the transcriptional changes induced by BET inhibitors. In our studies of mouse models of acute leukemia, we used high-resolution microscopy and flow cytometry to highlight the heterogeneity of drug activity within tumor cells located in different tissue compartments. We also demonstrate the differential distribution and effects of BET inhibitors in normal and malignant cells in vivo. This study provides a potential framework for the preclinical assessment of a wide range of drugs.
Memory T cells possess functional differences from naïve T cells that powerfully contribute to the efficiency of secondary immune responses. These abilities are imprinted during the primary response, ...linked to the acquisition of novel patterns of gene expression. Underlying this are alterations at the chromatin level (epigenetic modifications) that regulate constitutive and inducible gene transcription. T cell epigenetic memory can persist long-term, contributing to long-lasting immunity after infection or vaccination. However, acquired epigenetic states can also hinder effective tumor immunity or contribute to autoimmunity. The growing understanding of epigenetic gene regulation as it relates to both the stability and malleability of T cell memory may offer the potential to selectively modify T cell memory in disease by targeting epigenetic mechanisms.
Precise control of gene expression is achieved by epigenetic mechanisms involving covalent modifications to DNA and histones that alter chromatin structure.T cell activation and differentiation into effector cells is accompanied by widespread epigenetic modifications and marked changes in gene expression.Memory T cells retain a long-term epigenetic imprint that confers constitutive and inducible gene expression associated with a rapid recall response capacity.Exhausted T cells generated in response to chronic antigen exposure are functionally defective and epigenetically distinct from both effector and memory T cells. Blocking inhibitory receptors on Tex cells transiently restores function but has little effect on the epigenetic memory of these cells.Epigenetic mediators have been identified that can modulate T cell differentiation into effector, memory, and exhausted cells.
PAD4 has been strongly implicated in the pathogenesis of autoimmune, cardiovascular and oncological diseases through clinical genetics and gene disruption in mice. New selective PAD4 inhibitors ...binding a calcium-deficient form of the PAD4 enzyme have validated the critical enzymatic role of human and mouse PAD4 in both histone citrullination and neutrophil extracellular trap formation for, to our knowledge, the first time. The therapeutic potential of PAD4 inhibitors can now be explored.
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