Immune evasion is linked to histone variation malfunction. Gene therapy could provide tools for targeting histone variant deposition as a critical part of its pharmacology

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Immune Evasion ◽  
Patient Survival ◽  
Immune Therapy ◽  
Treatment Resistance ◽  
Histone Variants ◽  
Histone Variant ◽  
Histone Chaperones ◽  
Evolutionary Trajectory ◽  
Core Histones

For a range of cancer-related processes, histone variants play a function. MacroH2A1.1's ADP ribose-binding properties have emerged as a connection between metabolites and the epigenome that must be studied further in vivo. Based on the data we have discovered thus far, we think that altered histone variant functions are co-opted by transformed cells with varying outcomes over the evolutionary trajectory of the tumor. However, our current understanding of histone variations in tumor dormancy and treatment resistance is insufficient. H3 mutations are most common in solid tumors, but they have also been found in hematological malignancies.In addition, a study of over 3,000 patient samples from various cancer types found that all core histones are mutated in 4% of cancers, but the role of these newly formed mutations is unknown.However, an ongoing study is investigating how to better characterize tumor response, as well as how to better predict patient survival in difficult-to-treat cancers. Based on many studies, we hypothesize that altered gene expression levels in tumor cells or tumor-associated cells can change the immunological microenvironment. Histone variation dysfunction influences the genes associated with immune evasion, which in turn affects immune-therapy responsiveness.The success of our goal depends on developing unique, pharmacologically practical ways to target histone variant deposition. Since histone chaperones lack enzymatic capabilities and possess large surfaces without deep pockets where small-molecule inhibitors may act, this has proven problematic thus far. Since cell identity is dependent on histone variants and chaperones, it is reasonable to ponder if cell destiny is lost due to histone variant and chaperone regulation. Histone variants may still be utilized to predict therapeutic response while we wait for these data, helping to personalize treatments and enhancing patient survival and quality of life.

scholarly journals Intrinsic elasticity of nucleosomes is encoded by histone variants and calibrated by their binding partners

2019 ◽  
Vol 116 (48) ◽  
pp. 24066-24074 ◽  
Author(s):  
Daniël P. Melters ◽  
Mary Pitman ◽  
Tatini Rakshit ◽  
Emilios K. Dimitriadis ◽  
Minh Bui ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Chromosome Segregation ◽  
Binding Proteins ◽  
Histone Variants ◽  
Histone Variant ◽  
Binding Partners ◽  
Damage Repair ◽  
Fine Tune

Histone variants fine-tune transcription, replication, DNA damage repair, and faithful chromosome segregation. Whether and how nucleosome variants encode unique mechanical properties to their cognate chromatin structures remains elusive. Here, using in silico and in vitro nanoindentation methods, extending to in vivo dissections, we report that histone variant nucleosomes are intrinsically more elastic than their canonical counterparts. Furthermore, binding proteins, which discriminate between histone variant nucleosomes, suppress this innate elasticity and also compact chromatin. Interestingly, when we overexpress the binding proteins in vivo, we also observe increased compaction of chromatin enriched for histone variant nucleosomes, correlating with diminished access. Taken together, these data suggest a plausible link between innate mechanical properties possessed by histone variant nucleosomes, the adaptability of chromatin states in vivo, and the epigenetic plasticity of the underlying locus.

258. Differential expression of H2A and H3 variant histones in mouse preimplantation embryos and R1 ES cells

2008 ◽  
Vol 20 (9) ◽  
pp. 58
Author(s):  
G. R. Kafer ◽  
SA Lehnert ◽  
P. L. Kaye ◽  
R. J. Moser
Keyword(s):  
Messenger Rna ◽  
Expression Profiles ◽  
Es Cells ◽  
Expression Patterns ◽  
Embryonic Stem ◽  
Histone Variants ◽  
Histone Variant ◽  
Preimplantation Embryos ◽  
Es Cell

Histone variants replace canonical histones in nucleosomes to serve numerous biological processes. This integration alters DNA properties to ultimately regulate gene expression. Previous mouse studies have indicated that some variants (H2AZ and H3.3) are essential for survival, but here we document and correlate histone expression patterns with key developmental events. Using quantitative reverse-transcribed PCR (qRT–PCR) we investigated the expression of 7 genes coding for H2A variants and 4 genes coding for H3 variants in mouse preimplantation embryos and in pluripotent R1 ES cells. Messenger RNA was extracted from pools of 3 embryos flushed from superovulated mice. Embryos were collected at five stages, zygotes, 2-cell embryos, morulae, blastocysts and hatching blastocysts (20 h, 44 h, 68 h, 92 h and 116 h post hCG respectively). The expression of H2A variant genes typically peaked within blastocysts. H2AZ and H2AX expression was 80 – 95% higher in blastocysts than other stages. Conversely, genes coding for H3 variants showed elevated expression in zygotes, where H3.3 expression was 85 – 95% higher and CENPA was ~75% higher than in later preimplantation stages. The expression profiles of histone remodellers SWI/SNF and CAF-1 correlated with the variants they are known to remodel (H2A and H3 variants respectively), suggesting an increased integration of those variants into nucleosomes. We also compared blastocyst and embryonic stem cell (ES cell) expression patterns. R1 ES cells express all histone variants, including H2A.Bbd, H3.1 and H3.2 which were not expressed in preimplantation embryos. Further, expression levels of every histone variant investigated differed significantly between R1 ES cells and hatching blastocysts (ANOVA, P < 0.05, n = 3 experiments). We conclude that histone variant expression reflects preimplantation developmental demands. Further, histone code expression profiles show significant change upon extended cell culture and maintenance of pluripotency as indicated by comparing in vivo hatching blastocysts to the R1 ES cell line.

scholarly journals Human Histone Chaperone Nucleophosmin Enhances Acetylation-Dependent Chromatin Transcription

2005 ◽  
Vol 25 (17) ◽  
pp. 7534-7545 ◽  
Author(s):  
V. Swaminathan ◽  
A. Hari Kishore ◽  
K. K. Febitha ◽  
Tapas K. Kundu
Keyword(s):  
Transcriptional Activation ◽  
Histone Chaperone ◽  
Dependent Manner ◽  
Histone Chaperones ◽  
Cellular Processes ◽  
The Core ◽  
Core Histones ◽  
Nucleosomal Structure

ABSTRACT Histone chaperones are a group of proteins that aid in the dynamic chromatin organization during different cellular processes. Here, we report that the human histone chaperone nucleophosmin interacts with the core histones H3, H2B, and H4 but that this histone interaction is not sufficient to confer the chaperone activity. Significantly, nucleophosmin enhances the acetylation-dependent chromatin transcription and it becomes acetylated both in vitro and in vivo. Acetylation of nucleophosmin and the core histones was found to be essential for the enhancement of chromatin transcription. The acetylated NPM1 not only shows an increased affinity toward acetylated histones but also shows enhanced histone transfer ability. Presumably, nucleophosmin disrupts the nucleosomal structure in an acetylation-dependent manner, resulting in the transcriptional activation. These results establish nucleophosmin (NPM1) as a human histone chaperone that becomes acetylated, resulting in the enhancement of chromatin transcription.

scholarly journals Histone variant H2A.Z regulates nucleosome unwrapping and CTCF binding in mouse ES cells

2020 ◽  
Vol 48 (11) ◽  
pp. 5939-5952
Author(s):  
Zengqi Wen ◽  
Liwei Zhang ◽  
Haihe Ruan ◽  
Guohong Li
Keyword(s):  
Es Cells ◽  
Embryonic Stem ◽  
Histone Variants ◽  
Histone Variant ◽  
Micrococcal Nuclease ◽  
Ctcf Binding ◽  
Mouse Es Cells ◽  
Nucleosome Structure ◽  
Paired End Sequencing

Abstract Nucleosome is the basic structural unit of chromatin, and its dynamics plays critical roles in the regulation of genome functions. However, how the nucleosome structure is regulated by histone variants in vivo is still largely uncharacterized. Here, by employing Micrococcal nuclease (MNase) digestion of crosslinked chromatin followed by chromatin immunoprecipitation (ChIP) and paired-end sequencing (MNase-X-ChIP-seq), we mapped unwrapping states of nucleosomes containing histone variant H2A.Z in mouse embryonic stem (ES) cells. We found that H2A.Z nucleosomes are more enriched with unwrapping states compared with canonical nucleosomes. Interestingly, +1 H2A.Z nucleosomes with 30–80 bp DNA is correlated with less active genes compared with +1 H2A.Z nucleosomes with 120–140 bp DNA. We confirmed the unwrapping of H2A.Z nucleosomes under native condition by re-ChIP of H2A.Z and H2A after CTCF CUT&RUN in mouse ES cells. Importantly, we found that depletion of H2A.Z results in decreased unwrapping of H3.3 nucleosomes and increased CTCF binding. Taken together, through MNase-X-ChIP-seq, we showed that histone variant H2A.Z regulates nucleosome unwrapping in vivo and that its function in regulating transcription or CTCF binding is correlated with unwrapping states of H2A.Z nucleosomes.

scholarly journals Intrinsic elasticity of nucleosomes is encoded by histone variants and calibrated by their binding partners

2018 ◽  
Author(s):  
Daniël P. Melters ◽  
Mary Pitman ◽  
Tatini Rakshit ◽  
Emilios K Dimitriadis ◽  
Minh Bui ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Dna Damage ◽  
Chromosome Segregation ◽  
Binding Proteins ◽  
Histone Variants ◽  
Histone Variant ◽  
Chromatin State ◽  
Damage Repair ◽  
Fine Tune

AbstractHistone variants fine-tune transcription, replication, DNA damage repair, and faithful chromosome segregation. Whether and how nucleosome variants encode unique mechanical properties to their cognate chromatin structures remains elusive. Here, using novel in silico and in vitro nanoindentation methods, extending to in vivo dissections, we report that histone variant nucleosomes are intrinsically more elastic than their canonical counterparts. Furthermore, binding proteins which discriminate between histone variant nucleosomes suppress this innate elasticity and also compact chromatin. Interestingly, when we overexpress the binding proteins in vivo, we also observe increased compaction of chromatin enriched for histone variant nucleosomes, correlating with diminished access. Together, these data suggest a plausible link between innate mechanical properties possessed by histone variant nucleosomes, the adaptability of chromatin states in vivo, and the epigenetic plasticity of the underlying locus.SignificanceNucleosomes are the base unit which organize eukaryotic genomes. Besides the canonical histone, histone variants create unique local chromatin domains that fine-tune transcription, replication, DNA damage repair, and faithful chromosome segregation. We developed computational and single-molecule nanoindentation tools to determine mechanical properties of histone variant nucleosomes. We found that the CENP-A nucleosome variant is more elastic than the canonical H3 nucleosome but becomes stiffer when bound to its partner CENP-C. In addition, CENP-C induces cross-array clustering, creating a chromatin state that less accessible. These data suggest that innate material properties of nucleosomes can influence the ultimate chromatin state, thereby influence biological outcomes.

750 Malat1 lncRNA controls metastatic reactivation of dormant breast cancer by immune evasion

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A799-A799
Author(s):  
Dhiraj Kumar ◽  
Sreeharsha Gurrapu ◽  
Hyunho Han ◽  
Yan Wang ◽  
Seongyeon Bae ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Single Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Breast Cancer Cells ◽  
Metastatic Potential ◽  
Rna Seq

BackgroundLong non-coding RNAs (lncRNAs) are involved in various biological processes and diseases. Malat1 (metastasis-associated lung adenocarcinoma transcript 1), also known as Neat2, is one of the most abundant and highly conserved nuclear lncRNAs. Several studies have shown that the expression of lncRNA Malat1 is associated with metastasis and serving as a predictive marker for various tumor progression. Metastatic relapse often develops years after primary tumor removal as a result of disseminated tumor cells undergoing a period of latency in the target organ.1–4 However, the correlation of tumor intrinsic lncRNA in regulation of tumor dormancy and immune evasion is largely unknown.MethodsUsing an in vivo screening platform for the isolation of genetic entities involved in either dormancy or reactivation of breast cancer tumor cells, we have identified Malat1 as a positive mediator of metastatic reactivation. To functionally uncover the role of Malat1 in metastatic reactivation, we have developed a knock out (KO) model by using paired gRNA CRISPR-Cas9 deletion approach in metastatic breast and other cancer types, including lung, colon and melanoma. As proof of concept we also used inducible knockdown system under in vivo models. To delineate the immune micro-environment, we have used 10X genomics single cell RNA-seq, ChIRP-seq, multi-color flowcytometry, RNA-FISH and immunofluorescence.ResultsOur results reveal that the deletion of Malat1 abrogates the tumorigenic and metastatic potential of these tumors and supports long-term survival without affecting their ploidy, proliferation, and nuclear speckles formation. In contrast, overexpression of Malat1 leads to metastatic reactivation of dormant breast cancer cells. Moreover, the loss of Malat1 in metastatic cells induces dormancy features and inhibits cancer stemness. Our RNA-seq and ChIRP-seq data indicate that Malat1 KO downregulates several immune evasion and stemness associated genes. Strikingly, Malat1 KO cells exhibit metastatic outgrowth when injected in T cells defective mice. Our single-cell RNA-seq cluster analysis and multi-color flow cytometry data show a greater proportion of T cells and reduce Neutrophils infiltration in KO mice which indicate that the immune microenvironment playing an important role in Malat1-dependent immune evasion. Mechanistically, loss of Malat1 is associated with reduced expression of Serpinb6b, which protects the tumor cells from cytotoxic killing by the T cells. Indeed, overexpression of Serpinb6b rescued the metastatic potential of Malat1 KO cells by protecting against cytotoxic T cells.ConclusionsCollectively, our data indicate that targeting this novel cancer-cell-initiated domino effect within the immune system represents a new strategy to inhibit tumor metastatic reactivation.Trial RegistrationN/AEthics ApprovalFor all the animal studies in the present study, the study protocols were approved by the Institutional Animal Care and Use Committee(IACUC) of UT MD Anderson Cancer Center.ConsentN/AReferencesArun G, Diermeier S, Akerman M, et al., Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss. Genes Dev 2016 Jan 1;30(1):34–51.Filippo G. Giancotti, mechanisms governing metastatic dormancy and reactivation. Cell 2013 Nov 7;155(4):750–764.Gao H, Chakraborty G, Lee-Lim AP, et al., The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 2012b;150:764–779.Gao H, Chakraborty G, Lee-Lim AP, et al., Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation. Proc Natl Acad Sci U S A 2014 Nov 18; 111(46): 16532–16537.

scholarly journals Differential effects of chronic immunosuppression on behavioral, epigenetic, and Alzheimer’s disease-associated markers in 3xTg-AD mice

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Minesh Kapadia ◽  
M. Firoz Mian ◽  
Donglai Ma ◽  
Craig P. Hutton ◽  
Amber Azam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Emotional Reactivity ◽  
Histone Variant ◽  
In Vivo Model ◽  
Adult Males ◽  
Bdnf Expression ◽  
Systemic Autoimmunity ◽  
Circulating Autoantibodies

Abstract Background Circulating autoantibodies and sex-dependent discrepancy in prevalence are unexplained phenomena of Alzheimer’s disease (AD). Using the 3xTg-AD mouse model, we reported that adult males show early manifestations of systemic autoimmunity, increased emotional reactivity, enhanced expression of the histone variant macroH2A1 in the cerebral cortex, and loss of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain their AD-like phenotype. This study examines the link between immunity and other traits of the current 3xTg-AD model. Methods Young 3xTg-AD and wild-type mice drank a sucrose-laced 0.4 mg/ml solution of the immunosuppressant cyclophosphamide on weekends for 5 months. After behavioral phenotyping at 2 and 6 months of age, we assessed organ mass, serologic markers of autoimmunity, molecular markers of early AD pathology, and expression of genes associated with neurodegeneration. Results Chronic immunosuppression prevented hematocrit drop and reduced soluble Aβ in 3xTg-AD males while normalizing the expression of histone variant macroH2A1 in 3xTg-AD females. This treatment also reduced hepatosplenomegaly, lowered autoantibody levels, and increased the effector T cell population while decreasing the proportion of regulatory T cells in both sexes. Exposure to cyclophosphamide, however, neither prevented reduced brain mass and BDNF expression nor normalized increased tau and anxiety-related behaviors. Conclusion The results suggest that systemic autoimmunity increases soluble Aβ production and affects transcriptional regulation of macroH2A1 in a sex-related manner. Despite the complexity of multisystem interactions, 3xTg-AD mice can be a useful in vivo model for exploring the regulatory role of autoimmunity in the etiology of AD-like neurodegenerative disorders.

scholarly journals Slow viral propagation during initial phase of infection leads to viral persistence in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Haifeng C. Xu ◽  
Ruifeng Wang ◽  
Prashant V. Shinde ◽  
Lara Walotka ◽  
Anfei Huang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Evasion ◽  
Protein Transport ◽  
Adaptive Immune System ◽  
Viral Persistence ◽  
Lymphocytic Choriomeningitis ◽  
Type I ◽  
Viral Propagation

AbstractImmune evasion of pathogens can modify the course of infection and impact viral persistence and pathology. Here, using different strains of the lymphocytic choriomeningitis virus (LCMV) model system, we show that slower propagation results in limited type I interferon (IFN-I) production and viral persistence. Specifically, cells infected with LCMV-Docile exhibited reduced viral replication when compared to LCMV-WE and as a consequence, infection with LCMV-Docile resulted in reduced activation of bone marrow derived dendritic cells (BMDCs) and IFN-I production in vitro in comparison with LCMV-WE. In vivo, we observed a reduction of IFN-I, T cell exhaustion and viral persistence following infection of LCMV-Docile but not LCMV-WE. Mechanistically, block of intracellular protein transport uncovered reduced propagation of LCMV-Docile when compared to LCMV-WE. This reduced propagation was critical in blunting the activation of the innate and adaptive immune system. When mice were simultaneously infected with LCMV-Docile and LCMV-WE, immune function was restored and IFN-I production, T cell effector functions as well as viral loads were similar to that of mice infected with LCMV-WE alone. Taken together, this study suggests that reduced viral propagation can result in immune evasion and viral persistence.

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