Leveraging epigenetics to enhance the efficacy of immunotherapy

Abstract Background Epigenetic mechanisms regulate chromatin accessibility patterns that govern interaction of transcription machinery with genes and their cis-regulatory elements. Mutations that affect epigenetic mechanisms are common in cancer. Because epigenetic modifications are reversible many anticancer strategies targeting these mechanisms are currently under development and in clinical trials. Main body Here we review evidence suggesting that epigenetic therapeutics can deactivate immunosuppressive gene expression or reprogram tumor cells to activate antigen presentation mechanisms. In addition, the dysregulation of epigenetic mechanisms commonly observed in cancer may alter the immunogenicity of tumor cells and effectiveness of immunotherapies. Conclusions Therapeutics targeting epigenetic mechanisms may be helpful to counter immune evasion and improve the effectiveness of immunotherapies.

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Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas

Nature Communications ◽

10.1038/s41467-021-23922-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Karolina Stępniak ◽

Magdalena A. Machnicka ◽

Jakub Mieczkowski ◽

Anna Macioszek ◽

Bartosz Wojtaś ◽

...

Keyword(s):

Gene Expression ◽

Chromatin Structure ◽

Molecular Mechanisms ◽

Genome Mapping ◽

Malignant Gliomas ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Multiple Tumor ◽

Genes Encoding ◽

Methylation Patterns

AbstractChromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.

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The regulatory genome of the malaria vector Anopheles gambiae: integrating chromatin accessibility and gene expression

NAR Genomics and Bioinformatics ◽

10.1093/nargab/lqaa113 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

José L Ruiz ◽

Lisa C Ranford-Cartwright ◽

Elena Gómez-Díaz

Keyword(s):

Gene Expression ◽

Transcriptional Regulation ◽

Anopheles Gambiae ◽

Mosquito Control ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Malaria Vectors ◽

Specific Gene ◽

Mosquito Vector ◽

Human Malaria

Abstract Anopheles gambiae mosquitoes are primary human malaria vectors, but we know very little about their mechanisms of transcriptional regulation. We profiled chromatin accessibility by the assay for transposase-accessible chromatin by sequencing (ATAC-seq) in laboratory-reared A. gambiae mosquitoes experimentally infected with the human malaria parasite Plasmodium falciparum. By integrating ATAC-seq, RNA-seq and ChIP-seq data, we showed a positive correlation between accessibility at promoters and introns, gene expression and active histone marks. By comparing expression and chromatin structure patterns in different tissues, we were able to infer cis-regulatory elements controlling tissue-specific gene expression and to predict the in vivo binding sites of relevant transcription factors. The ATAC-seq assay also allowed the precise mapping of active regulatory regions, including novel transcription start sites and enhancers that were annotated to mosquito immune-related genes. Not only is this study important for advancing our understanding of mechanisms of transcriptional regulation in the mosquito vector of human malaria, but the information we produced also has great potential for developing new mosquito-control and anti-malaria strategies.

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BIOM-16. IMMUNOMIC ANALYSIS OF GLIOBLASTOMA (GBM) USING GENE EXPRESSION PROFILING

Neuro-Oncology ◽

10.1093/neuonc/noaa215.016 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii5-ii5

Author(s):

Michael Castro ◽

Nilofar Badra-Azar ◽

Thomas Kessler ◽

Moritz Schütte ◽

Bodo Lange ◽

...

Keyword(s):

Gene Expression ◽

Antigen Presentation ◽

Hierarchical Clustering ◽

Immune Evasion ◽

Human Cancer ◽

Progression Free Survival ◽

Immune Checkpoints ◽

Successful Implementation ◽

Cell Trafficking ◽

Box Plots

Abstract BACKGROUND Despite the success of immunotherapy across the spectrum of human cancer, a successful strategy has not emerged for GBM. While PD-L1 IHC and TMB have demonstrated some utility as predictors of immunotherapy benefit, responsiveness is complexly determined by factors affecting T cell trafficking, antigen presentation, other immune checkpoints, and mediators of immune exhaustion. Thus, we set out to to characterize mediators of immune resistance and their diversity in a population of GBM patients utilizing quantitative gene expression. METHODS A set of 54 immunotherapy and checkpoint relevant genes and seven genes related to immune failure were selected from the literature. RNA gene counts for TCGA glioblastoma multiforme samples (N=163) were downloaded from https://portal.gdc.cancer.gov/. Annotation on subtypes and PFS values were obtained from PMID: 24120142. Gene expression normalization as FPKM, hierarchical clustering and box-plots were performed using R-3.6.0. Statistical differences of gene expression between subtypes were quantified using a TurkeyHSD test. RESULTS A heatmap with hierarchical clustering for immune related genes for the TCGA GBM cohort was generated including colored annotation for the subtype and progression free survival. The graph shows a rough separation into two groups, where one group of the genes is tentatively associated with mesenchymal subtype and shorter survival and showing higher expression for most immune evasion genes. However, a heterogeneity of immune evasion signatures was identified within and across subtypes. Transcripts related to antigen presentation, EZH2, and LDHA varied significantly between GBM subtypes (p < 0.05). CONCLUSION Gene expression analysis has utility to identify specific mediators of immune evasion and to inform the selection of combination therapies for discrete subsets of patients. A Bayesian approach to patient selection for specific immunotherapy strategies may enhance the likelihood of successful implementation of immunotherapy in the clinic.

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Epigenetic mechanisms in sexual differentiation of the brain and behaviour

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2015.0114 ◽

2016 ◽

Vol 371 (1688) ◽

pp. 20150114 ◽

Cited By ~ 34

Author(s):

Nancy G. Forger

Keyword(s):

Gene Expression ◽

Sex Differences ◽

Sexual Differentiation ◽

Wide Distribution ◽

Epigenetic Modifications ◽

Epigenetic Mechanism ◽

Epigenetic Mechanisms ◽

Genome Wide ◽

The Brain

Circumstantial evidence alone argues that the establishment and maintenance of sex differences in the brain depend on epigenetic modifications of chromatin structure. More direct evidence has recently been obtained from two types of studies: those manipulating a particular epigenetic mechanism, and those examining the genome-wide distribution of specific epigenetic marks. The manipulation of histone acetylation or DNA methylation disrupts the development of several neural sex differences in rodents. Taken together, however, the evidence suggests there is unlikely to be a simple formula for masculine or feminine development of the brain and behaviour; instead, underlying epigenetic mechanisms may vary by brain region or even by dependent variable within a region. Whole-genome studies related to sex differences in the brain have only very recently been reported, but suggest that males and females may use different combinations of epigenetic modifications to control gene expression, even in cases where gene expression does not differ between the sexes. Finally, recent findings are discussed that are likely to direct future studies on the role of epigenetic mechanisms in sexual differentiation of the brain and behaviour.

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Epigenetic Research in Stem Cell Bioengineering—Anti-Cancer Therapy, Regenerative and Reconstructive Medicine in Human Clinical Trials

Cancers ◽

10.3390/cancers12041016 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1016 ◽

Cited By ~ 1

Author(s):

Claudia Dompe ◽

Krzysztof Janowicz ◽

Greg Hutchings ◽

Lisa Moncrieff ◽

Maurycy Jankowski ◽

...

Keyword(s):

Gene Expression ◽

Clinical Trials ◽

Stem Cell ◽

Cancer Therapy ◽

Regulation Of Gene Expression ◽

Epigenetic Modifications ◽

Transcriptional Level ◽

Cancer Therapies ◽

Stem Cell Engineering ◽

Anti Cancer

The epigenome denotes all the information related to gene expression that is not contained in the DNA sequence but rather results from chemical changes to histones and DNA. Epigenetic modifications act in a cooperative way towards the regulation of gene expression, working at the transcriptional or post-transcriptional level, and play a key role in the determination of phenotypic variations in cells containing the same genotype. Epigenetic modifications are important considerations in relation to anti-cancer therapy and regenerative/reconstructive medicine. Moreover, a range of clinical trials have been performed, exploiting the potential of epigenetics in stem cell engineering towards application in disease treatments and diagnostics. Epigenetic studies will most likely be the basis of future cancer therapies, as epigenetic modifications play major roles in tumour formation, malignancy and metastasis. In fact, a large number of currently designed or tested clinical approaches, based on compounds regulating epigenetic pathways in various types of tumours, employ these mechanisms in stem cell bioengineering.

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Modeling gene regulation from paired expression and chromatin accessibility data

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1704553114 ◽

2017 ◽

Vol 114 (25) ◽

pp. E4914-E4923 ◽

Cited By ~ 76

Author(s):

Zhana Duren ◽

Xi Chen ◽

Rui Jiang ◽

Yong Wang ◽

Wing Hung Wong

Keyword(s):

Gene Expression ◽

Target Genes ◽

Transcriptional Regulatory Network ◽

Joint Modeling ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Exciting Opportunity ◽

Transcriptional Regulatory ◽

Dna Elements ◽

Context Specific

The rapid increase of genome-wide datasets on gene expression, chromatin states, and transcription factor (TF) binding locations offers an exciting opportunity to interpret the information encoded in genomes and epigenomes. This task can be challenging as it requires joint modeling of context-specific activation of cis-regulatory elements (REs) and the effects on transcription of associated regulatory factors. To meet this challenge, we propose a statistical approach based on paired expression and chromatin accessibility (PECA) data across diverse cellular contexts. In our approach, we model (i) the localization to REs of chromatin regulators (CRs) based on their interaction with sequence-specific TFs, (ii) the activation of REs due to CRs that are localized to them, and (iii) the effect of TFs bound to activated REs on the transcription of target genes (TGs). The transcriptional regulatory network inferred by PECA provides a detailed view of how trans- and cis-regulatory elements work together to affect gene expression in a context-specific manner. We illustrate the feasibility of this approach by analyzing paired expression and accessibility data from the mouse Encyclopedia of DNA Elements (ENCODE) and explore various applications of the resulting model.

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The regulatory genome of the malaria vector Anopheles gambiae: integrating chromatin accessibility and gene expression

10.1101/2020.06.22.164228 ◽

2020 ◽

Cited By ~ 2

Author(s):

José L. Ruiz ◽

Lisa C. Ranford-Cartwright ◽

Elena Gómez-Díaz

Keyword(s):

Gene Expression ◽

Transcriptional Regulation ◽

Anopheles Gambiae ◽

Mosquito Control ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Malaria Vectors ◽

Specific Gene ◽

Mosquito Vector ◽

Human Malaria

ABSTRACTAnopheles gambiae mosquitoes are primary human malaria vectors, but we know very little about mechanisms of transcriptional regulation. We profiled chromatin accessibility by ATAC-seq in laboratory-reared An. gambiae mosquitoes experimentally infected with the human malaria parasite Plasmodium falciparum. By integrating ATAC-seq, RNA-seq and ChIP-seq data we showed a positive correlation between accessibility at promoters and introns, gene expression and active histone marks. By comparing expression and chromatin structure patterns in different tissues, we were able to infer cis-regulatory elements controlling tissue specific gene expression and to predict the in vivo binding sites of relevant transcription factors. The ATAC-seq assay also allowed the precise mapping of active regulatory regions, including novel transcription start sites and enhancers that annotate to mosquito immune-response genes. This study is important not only for advancing our understanding of mechanisms of transcriptional regulation in the mosquito vector of human malaria, but the information is of great potential for developing new mosquito-control and anti-malaria strategies.

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Identification of enhancer regulatory elements that direct epicardial gene expression during zebrafish heart regeneration

10.1101/2021.08.23.457406 ◽

2021 ◽

Author(s):

Yingxi Cao ◽

Yu Xia ◽

Joseph B Balowski ◽

jianhong ou ◽

Lingyun Song ◽

...

Keyword(s):

Gene Expression ◽

Cardiac Injury ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Heart Regeneration ◽

Epicardial Cells ◽

Transgenic Lines ◽

Functional Features ◽

Multiple Trees ◽

Regulatory Controls

The epicardium is a mesothelial tissue layer that envelops the heart. Cardiac injury activates dynamic gene expression programs in epicardial tissue, which in the case of zebrafish enables subsequent regeneration through paracrine and vascularizing effects. To identify tissue regeneration enhancer elements (TREEs) that control injury-induced epicardial gene expression during heart regeneration, we profiled transcriptomes and chromatin accessibility in epicardial cells purified from regenerating zebrafish hearts. We identified hundreds of candidate TREEs, defined by increased chromatin accessibility of non-coding elements near genes with increased expression during regeneration. Several of these candidate TREEs were incorporated into stable transgenic lines, with 5 of 6 elements directing injury-induced epicardial expression but not ontogenetic epicardial expression in hearts of larval animals. Whereas two independent TREEs linked to the gene gnai3 showed similar functional features of gene regulation in transgenic lines, two independent ncam1a-linked TREEs directed distinct spatiotemporal domains of epicardial gene expression. Thus, multiple TREEs linked to a regeneration gene can possess either matching or complementary regulatory controls. Our study provides a new resource and principles for understanding the regulation of epicardial genetic programs during heart regeneration.

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Comparative chromatin accessibility upon BDNF-induced neuronal activity delineates neuronal regulatory elements

10.1101/2021.05.28.446128 ◽

2021 ◽

Author(s):

Ignacio L. Ibarra ◽

Vikram S. Ratnu ◽

Lucia Gordillo ◽

In-Young Hwang ◽

Luca Mariani ◽

...

Keyword(s):

Gene Expression ◽

Synaptic Plasticity ◽

Neuronal Activity ◽

Cortical Neurons ◽

Complex Traits ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Regulatory Control ◽

Comparative Genomic ◽

Regulatory Sequences

Neuronal activity induced by brain-derived neurotrophic factor (BDNF) triggers gene expression, which is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. However, its role in chromatin regulation is unclear. Here, using temporal profiling of chromatin accessibility and transcription in mouse primary cortical neurons upon either BDNF stimulation or depolarization (KCl), we identify features that define BDNF-specific chromatin-to-gene expression programs. Enhancer activation is an early event in the regulatory control of BDNF-treated neurons, where the bZIP motif-binding Fos protein pioneered chromatin opening and cooperated with co-regulatory transcription factors (Homeobox, EGRs, and CTCF) to induce transcription. Deleting cis-regulatory sequences decreased BDNF-mediated Arc expression, a regulator of synaptic plasticity. BDNF-induced accessible regions are linked to preferential exon usage by neurodevelopmental disorder-related genes and heritability of neuronal complex traits, which were validated in human iPSC-derived neurons. Thus, we provide a comprehensive view of BDNF-mediated genome regulatory features using comparative genomic approaches to dissect mammalian neuronal activity.

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Functional Inference of Gene Regulation using Single-Cell Multi-Omics

10.1101/2021.07.28.453784 ◽

2021 ◽

Author(s):

Vinay K Kartha ◽

Fabiana M Duarte ◽

Yan Hu ◽

Sai Ma ◽

Jennifer G Chew ◽

...

Keyword(s):

Gene Expression ◽

Single Cell ◽

Regulatory Networks ◽

Immunological Response ◽

Cell Types ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Human Blood Cells ◽

Functional Inference ◽

Omic Data

Cells require coordinated control over gene expression when responding to environmental stimuli. Here, we apply scATAC-seq and scRNA-seq in resting and stimulated human blood cells. Collectively, we generate ~91,000 single-cell profiles, allowing us to probe the cis -regulatory landscape of immunological response across cell types, stimuli and time. Advancing tools to integrate multi-omic data, we develop FigR - a framework to computationally pair scATAC-seq with scRNA-seq cells, connect distal cis -regulatory elements to genes, and infer gene regulatory networks (GRNs) to identify candidate TF regulators. Utilizing these paired multi-omic data, we define Domains of Regulatory Chromatin (DORCs) of immune stimulation and find that cells alter chromatin accessibility prior to production of gene expression at time scales of minutes. Further, the construction of the stimulation GRN elucidates TF activity at disease-associated DORCs. Overall, FigR enables the elucidation of regulatory interactions across single-cell data, providing new opportunities to understand the function of cells within tissues.

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