Targeting Histone Modifications Research Articles

Histone modifications in hypoxic ischemic encephalopathy: Implications for therapeutic interventions.

Hypoxic-ischemic encephalopathy (HIE) is a brain injury induced by many causes of cerebral tissue ischemia and hypoxia. Although HIE may occur at many ages, its impact on the neonatal brain is greater because it occurs during the formative stage. Recent research suggests that histone modifications may occur in the human brain in response to acute stress events, resulting in transcriptional changes and HIE development. Because there are no safe and effective therapies for HIE, researchers have focused on HIE treatments that target histone modifications. In this review, four main histone modifications are explored, histone methylation, acetylation, phosphorylation, and crotonylation, as well as their relevance to HIE. The efficacy of histone deacetylase inhibitors in the treatment of HIE is also explored. In conclusion, targeting histone modifications may be a novel strategy for elucidating the mechanism of HIE, as well as a novel approach to HIE treatment.

Histone modifications in head and neck squamous cell carcinoma.

Head and neck cancer is the main cause of cancer death worldwide, with squamous cell carcinoma (HNSCC) being the second most frequent subtype. HNSCC poses significant health threats due to its high incidence and poor prognosis, underscoring the urgent need for advanced research. Histone modifications play a crucial role in the regulation of gene expression and influencing various biological processes. In the context of HNSCC, aberrant histone modifications are increasingly recognized as critical contributors to its development and pathologic progression. This review demonstrates the molecular mechanisms, by which histone modifications such as acetylation, methylation, phosphorylation, and ubiquitination, impact the pathogenesis of HNSCC. The dysregulation of histone-modifying enzymes, including histone acetyltransferases (HATs), histone deacetylases (HDACs), and histone methyltransferases (HMTs), is discussed for its role in altering chromatin structure and gene expression in HNSCC. Moreover, we will explore the potential of targeting histone modifications as a therapeutic strategy, highlighting current preclinical and clinical studies that investigate histone deacetylase inhibitors (HDIs) and other epigenetic drugs, referring to the completed and ongoing clinical trials on those medications.

To Erase or Not to Erase: Non-Canonical Catalytic Functions and Non-Catalytic Functions of Members of Histone Lysine Demethylase Families.

Histone lysine demethylases (KDMs) play an essential role in biological processes such as transcription regulation, RNA maturation, transposable element control, and genome damage sensing and repair. In most cases, their action requires catalytic activities, but non-catalytic functions have also been shown in some KDMs. Indeed, some strictly KDM-related proteins and some KDM isoforms do not act as histone demethylase but show other enzymatic activities or relevant non-enzymatic functions in different cell types. Moreover, many studies have reported on functions potentially supported by catalytically dead mutant KDMs. This is probably due to the versatility of the catalytical core, which can adapt to assume different molecular functions, and to the complex multi-domain structure of these proteins which encompasses functional modules for targeting histone modifications, promoting protein-protein interactions, or recognizing nucleic acid structural motifs. This rich modularity and the availability of multiple isoforms in the various classes produced variants with enzymatic functions aside from histone demethylation or variants with non-catalytical functions during the evolution. In this review we will catalog the proteins with null or questionable demethylase activity and predicted or validated inactive isoforms, summarizing what is known about their alternative functions. We will then go through some experimental evidence for the non-catalytical functions of active KDMs.

Noval advance of histone modification in inflammatory skin diseases and related treatment methods.

Inflammatory skin diseases are a group of diseases caused by the disruption of skin tissue due to immune system disorders. Histone modification plays a pivotal role in the pathogenesis and treatment of chronic inflammatory skin diseases, encompassing a wide range of conditions, including psoriasis, atopic dermatitis, lupus, systemic sclerosis, contact dermatitis, lichen planus, and alopecia areata. Analyzing histone modification as a significant epigenetic regulatory approach holds great promise for advancing our understanding and managing these complex disorders. Additionally, therapeutic interventions targeting histone modifications have emerged as promising strategies for effectively managing inflammatory skin disorders. This comprehensive review provides an overview of the diverse types of histone modification. We discuss the intricate association between histone modification and prevalent chronic inflammatory skin diseases. We also review current and potential therapeutic approaches that revolve around modulating histone modifications. Finally, we investigated the prospects of research on histone modifications in the context of chronic inflammatory skin diseases, paving the way for innovative therapeutic interventions and improved patient outcomes.

Elovanoids are Neural Resiliency Epigenomic Regulators Targeting Histone Modifications, DNA Methylation, Tau Phosphorylation, Telomere Integrity, Senescence Programming, and Dendrite Integrity

Cellular identity, developmental reorganization, genomic structure modulation, and susceptibility to neurodegenerative diseases involve epigenomic regulation engaging multiple signaling interplay. Here we demonstrate that elovanoids (ELVs), mediators derived from very-long-chain polyunsaturated fatty acids (VLC-PUFAs, n-3, C >28), and their precursors in human neurons/astrocytes in culture overcome the damage triggered by oligomeric amyloid-β (OAβ), erastin (ferroptosis-dependent cell death), or other insults like uncompensated oxidative stress (UOS), NMDA mediated cellular excitotoxicity, or oxygen-glucose deprivation (OGD), that target epigenomic signaling. We uncover that ELVs counteract damage targeting histones H3K9 and H3K27 methylation and acetylation; tau hyperphosphorylation (pThr181, pThr217, pThr231, and pSer202/pThr205 (AT8)); senescence gene programming (p16INK4a, p27KIP, p21CIP1, and p53); and DNA methylation (DNAm) modifying enzymes: TET (DNA hydroxymethylase), DNA methyltransferase, DNA demethylase, and DNA methylation (5mC) phenotype. Moreover, ELVs revert OAβ-triggered telomere length (TL) attrition as well as upregulation of telomerase reverse transcriptase (TERT) expression fostering dendrite protection and neuronal survival. Thus, ELVs modulate epigenomic resiliency by pleiotropic interrelated signaling.

BIOM-08. SINGLE-MOLECULE SYSTEMS FOR DETECTION OF PLASMA CIRCULATING ONCOPROTEINS IN DIFFUSE MIDLINE GLIOMA

Abstract Diffuse midline glioma (DMG) is a high-risk pediatric brain tumor that has primarily been diagnosed and monitored via medical imaging (MRI) due to risks associated with re-biopsying midline brain structures. Recent advances in molecular diagnostics have improved classification and molecular characterization of DMG; these tumors are in dire need of non-invasive, molecular-based diagnostic tools to supplement serial assessments of radiographic response. Our group recently developed a single-molecule imaging platform, Epigenetics of Plasma Isolated Nucleosomes (EPINUC), to profile histone modification patterns in cell-free tumor DNA (ctDNA) from plasma of cancer patients. We developed a novel strategy for single-molecule detection of the histone mutation H3K27M, a key DMG genetic driver, by capturing mutant nucleosomes on a PEG-streptavidin coated surface and detecting them with fluorescently labeled antibodies targeting histone modifications enriched on these mutant nucleosomes. We applied this method to 46 H3K27M and 10 H3 wildtype DMG samples and found significantly higher signal in K27M samples. Using this data, we generated a predictive model of H3 status with an AUC of 0.81, sensitivity 90%, specificity 71%, and precision 73%. This test was found to be highly reproducible and rapid (60 minutes) and required less than 100 uL of plasma. We also analyzed mutant p53 protein in plasma samples from 11 p53-mutant and 4 p53-wildtype DMG patients, seeing significant separation between the two groups. We overlayed H3K27M and p53 cell-free protein results with H3.3K27M and TP53 ctDNA variant allele fraction (VAF) by digital droplet PCR (ddPCR) in serial plasma samples from n = 3 DMG patients undergoing experimental therapy. These data highlighted unique patterns of disease response by (1) MRI, (2) plasma tumor protein, and (3) plasma ctDNA. Overall, these results demonstrate the clinical potential of our platform for non-invasive and accurate detection and monitoring of levels of key oncoproteins in plasma of DMG patients.

Increased histone acetylation is the signature of repressed state on the genes transcribed by RNA polymerase III

Several covalent modifications are found associated with the transcriptionally active chromatin regions constituted by the genes transcribed by RNA polymerase (pol) II. Pol III-transcribed genes code for the small, stable RNA species, which participate in many cellular processes, essential for survival. Pol III transcription is repressed under most of the stress conditions by its negative regulator Maf1. We found that most of the histone acetylations increase with starvation-induced repression on several genes transcribed by the yeast pol III. On one of these genes, SNR6 (coding for the U6snRNA), a strongly positioned nucleosome in the gene upstream region plays regulatory role under repression. On this nucleosome, the changes in H3K9 and H3K14 acetylations show different dynamics. During repression, acetylation levels on H3K9 show steady increase whereas H3K14 acetylation increases with a peak at 40 min after which levels reduce. Both the levels settle by 2 hr to a level higher than the active state, which revert to normal levels with nutrient repletion. The increase in H3 acetylations is seen in the mutants reported to show reduced SNR6 transcription but not in the maf1Δ cells. This increase on a regulatory nucleosome may be part of the signaling mechanisms, which prepare cells for the stress-related quick repression as well as reactivation. The contrasting association of the histone acetylations with pol II and pol III transcription may be an important consideration to make in research studies focused on drug developments targeting histone modifications.

Liquid biopsy epigenomic profiling for cancer subtyping

Although circulating tumor DNA (ctDNA) assays are increasingly used to inform clinical decisions in cancer care, they have limited ability to identify the transcriptional programs that govern cancer phenotypes and their dynamic changes during the course of disease. To address these limitations, we developed a method for comprehensive epigenomic profiling of cancer from 1 ml of patient plasma. Using an immunoprecipitation-based approach targeting histone modifications and DNA methylation, we measured 1,268 epigenomic profiles in plasma from 433 individuals with one of 15 cancers. Our assay provided a robust proxy for transcriptional activity, allowing us to infer the expression levels of diagnostic markers and drug targets, measure the activity of therapeutically targetable transcription factors and detect epigenetic mechanisms of resistance. This proof-of-concept study in advanced cancers shows how plasma epigenomic profiling has the potential to unlock clinically actionable information that is currently accessible only via direct tissue sampling.

Targeting epigenetic crosstalk that restrains the responses of exhausted T cells to immune checkpoint blockade therapy

Abstract Epigenetic scarring of exhausted CD8 T (TEX) cells during chronic virus infections or cancer remains a major cell-intrinsic barrier to T cell immunotherapies, including immune checkpoint blockade (ICB). For successful epigenetic reprogramming of TEX cells, it is crucial to identify and target the molecular mechanisms underlying terminal exhaustion. Previous work revealed that de novo DNA methylation enforces silencing of T cell function and restrains their responses to ICB therapy. Yet, it remains largely unknown whether post-translational histone modifications crosstalk with de novo DNA methylation during the progression to terminal exhaustion. To better understand the interplay between these epigenetic mechanisms in chronically stimulated CD8 T cells, we employed our novel in vitro model of human T cell dysfunction, as well as preclinical models of T cell exhaustion including chronic LCMV infection. We found a significant relationship between dynamic histone changes and de novo DNA methylation in TEX cells. Importantly, targeting a key histone-modifying enzyme in dysfunctional human T cells improved their effector function and cytotoxicity in vitro. In addition, during chronic LCMV infection, combined treatment by a selective inhibitor and anti-PD-L1 significantly enhanced the ICB responses of stem-like and cytolytic subsets of TEX cells. We further explored the impact of targeting histone modifications on DNA methylation programming in CD8 T cells. These findings provide important mechanistic insights for developing novel therapeutic approaches to epigenetically reprogram TEX cells and enhance T cell immunotherapies. Supported by the Ohio State University College of Medicine and the OSU Comprehensive Cancer Center.

Screening of an epigenetic compound library identifies BRD4 as a potential antiviral target for hepatitis B virus covalently closed circular DNA transcription

HBV cccDNA is the persistent form of viral genome, which exists in host cell nucleus as an episomal minichromosome decorated with histone and non-histone proteins. cccDNA is the authentic viral transcription template and resistant to current antivirals. Growing evidence shows that the transcriptional activity of cccDNA minichromosome undergoes epigenetic regulations, suggesting a new perspective for anti-cccDNA drug development through targeting histone modifications. In this study, we screened an epigenetic compound library in the cccDNA reporter cell line HepBHAe82, which produces the HA-tagged HBeAg in a cccDNA-dependent manner. Among the obtained hits, a bromodomain-containing protein 4 (BRD4) inhibitor MS436 exhibited marked inhibition of cccDNA transcription in both HBV stable cell line HepAD38 and HepG2-NTCP or primary human hepatocyte infection system under noncytotoxic concentrations. Chromatin immunoprecipitation (ChIP) assay demonstrated that MS436 dramatically reduced the enrichment of H3K27ac, an activating histone modification pattern, on cccDNA minichromosome. RNAseq differential analysis showed that MS436 does not drastically change host transcriptome or induce any known anti-HBV factors/pathways, indicating a direct antiviral effect of MS436 on cccDNA minichromosome. Interestingly, the MS436-mediated inhibition of cccDNA transcription is accompanied by cccDNA destabilization in HBV infection and a recombinant cccDNA system, indicating that BRD4 activity may also play a role in cccDNA maintenance. Furthermore, depletion of BRD4 by siRNA knockdown or PROTAC degrader resulted in cccDNA inhibition in HBV-infected HepG2-NTCP cells, further validating BRD4 as an antiviral target. Taken together, our study has demonstrated the practicability of HepBHAe82-based anti-HBV drug screening system and provided a proof-of-concept for targeting HBV cccDNA with epigenetic compounds.

Inhibition of Heat Shock-Induced H3K9ac Reduction Sensitizes Cancer Cells to Hyperthermia.

Heat stress, clinically known as hyperthermia, is a promising adjunctive modality in cancer treatment. However, the efficacy of hyperthermia as a monotherapy is limited and the underlying mechanism remains poorly understood. Targeting histone modifications is an emerging strategy for cancer therapy, but little is known regarding the role of heat stress in altering these modifications. Here, we report that heat shock inhibits H3K9 acetylation (H3K9ac) via histone deacetylase 6 (HDAC6) regulation. Heat shock inhibits the interaction between HDAC6 and heat shock protein 90 (HSP90), enhances nuclear localization of HDAC6, and promotes HDAC6 phosphorylation, which is regulated by protein phosphatase 2A (PP2A). Combining hyperthermia with HDAC inhibitors vorinostat or panobinostat leads to better anti-cancer effects compared to monotherapy. KEAP1 and DPP7 as genes affected by heat-induced inhibition of H3K9ac, and combining them with hyperthermia can better induce apoptosis in tumor cells. This study reveals previously unknown mechanisms of H3K9ac decreased by heat shock in cancer cells and highlights a potential combinational therapy involving hyperthermia and targeting of these new mechanisms.

DNA and histone modifications as potent diagnostic and therapeutic targets to advance non-small cell lung cancer management from the perspective of 3P medicine.

Lung cancer has a very high mortality in females and males. Most (~ 85%) of lung cancers are non-small cell lung cancers (NSCLC). When lung cancer is diagnosed, most of them have either local or distant metastasis, with a poor prognosis. In order to achieve better outcomes, it is imperative to identify the molecular signature based on genetic and epigenetic variations for different NSCLC subgroups. We hypothesize that DNA and histone modifications play significant roles in the framework of predictive, preventive, and personalized medicine (PPPM; 3P medicine). Epigenetics has a significant impact on tumorigenicity, tumor heterogeneity, and tumor resistance to chemotherapy, targeted therapy, and immunotherapy. An increasing interest is that epigenomic regulation is recognized as a potential treatment option for NSCLC. Most attention has been paid to the epigenetic alteration patterns of DNA and histones. This article aims to review the roles DNA and histone modifications play in tumorigenesis, early detection and diagnosis, and advancements and therapies of NSCLC, and also explore the connection between DNA and histone modifications and PPPM, which may provide an important contribution to improve the prognosis of NSCLC. We found that the success of targeting DNA and histone modifications is limited in the clinic, and how to combine the therapies to improve patient outcomes is necessary in further studies, especially for predictive diagnostics, targeted prevention, and personalization of medical services in the 3P medicine approach. It is concluded that DNA and histone modifications are potent diagnostic and therapeutic targets to advance non-small cell lung cancer management from the perspective of 3P medicine.

P-526 Targeting histone modifications: H3K27 acetylation regulates the expression of genes involved in key processes of uterine leiomyoma pathogenesis

Abstract Study question Does histone mark H3K27ac regulate the expression of genes involved in uterine leiomyoma (UL) pathogenesis, and can histone deacetylation inhibition be a new therapeutic approach? Summary answer H3K27ac regulates genes implicated in UL pathogenesis through angiogenesis and extracellular matrix (ECM), and histone deacetylation reversion could offer a therapeutic approach to treat UL. What is known already UL is a benign tumor arising from myometrium (MM). Women present symptoms such as pelvic pain and infertility. There is no fully effective treatment with minimal side effects. Available medical options focus on the relief of symptoms and not in mechanisms implicated in UL development. Histone modifications are altered in tumors, particularly via histone acetylation which is correlated with gene activation. Herein, we aimed to identify if the modification H3K27ac is involved in UL pathogenesis, determining the relationship between H3K27ac and gene expression in UL versus MM and if its reversion may be a therapeutic option to treat UL. Study design, size, duration Prospective study comparing transcriptome (GEO:GSE192354 and GSE142332) by RNA sequencing (RNA-seq) (n = 48) and H3K27ac profile (GEO:GSE142332) by Chromatin Immunoprecipitation Sequencing (CHIP-seq) (n = 19) in UL versus adjacent MM tissue. Human uterine leiomyoma primary (HULP) cells obtained from individual patients (n = 10) were treated with 0.01% DMSO (control) and 10 µM SAHA, a histone deacetylases inhibitor, for 48 hours. Participants/materials, setting, methods Samples were collected from 48 women aged 31-54 years. Bioinformatics analysis were performed within the R/Bioconductor (4.1.1.). Differential expressed genes (DEGs) were analysed using three methods: DESeq2, edgeR and limma. Common DEGs (FDR<0.01,log2FC>1 or <-1) were considered for further analysis. Differential H2K27ac peak enrichment analysis of selected genes was performed with limma and functional enrichment analysis (FDR<0.05) with Shiny Go (version 0.741). SAHA effect on hypoacetylated/downregulated genes was assessed in HULP cells by qRT-PCR. Main results and the role of chance CHIP-seq analysis showed a lower amount of global H3K27ac peak enrichment level in UL versus MM (p-value<2.2e-16). RNA-seq showed 922 common DEGs in UL versus MM, being 559 up-regulated and 363 down-regulated (FDR<0.01, log2FC>1 or <-1). Integration of CHIP-seq and RNA-seq data showed that among 922 selected genes, 482 also presented the histone mark H3K27ac. Differential peak enrichment analysis demonstrated that 82 of them presented differential acetylation (FDR<0.05) in UL versus MM, being 29 hyper-acetylated/up-regulated and 53 hypo-acetylated/down-regulated. Functional enrichment analysis of 82 DEGs regulated by H3K27ac showed biological processes deregulated in UL that were related to angiogenesis. Additionally, we found cellular components enriched in UL, which were related to an alteration of ECM, one of the key features of UL. We studied further these 82 genes controlled by H3K27ac and found hyperacetylation/upregulation of oncogenes (NDP, TFAP2C, HOXA13, COL24A1 and IGFL3) and hypoacetylation/downregulation of tumor suppressor genes (CD40, GIMAP8, IL15, GPX3 and DPT) in UL, which are related to immune system, angiogenesis, invasion, metabolism, ECM, TGFβ3 and Wnt/β-catenin pathway dysregulation. Finally, SAHA treatment in HULP cells significantly increased expression of the tumor suppressor genes that were hypoacetylated/downregulated in UL versus MM (CD40, GIMAP8, IL15, GPX3 and DPT) (p < 0.05). Limitations, reasons for caution This is a preliminary study including only 19 participants in ChIP-seq analysis, thereby we should be cautious extrapolating our results to the general population. Further studies are necessary to determine the effectiveness of histone deacetylases inhibition, SAHA dose and adverse effects on UL in vivo. Wider implications of the findings H3K27 acetylation regulates the expression of oncogenes and tumor suppressor genes involved in key processes of UL pathogenesis, such as angiogenesis and ECM formation. Histone deacetylation reversion by SAHA upregulated the expression of tumor suppressor genes in HULP cells, suggesting histone deacetylation as a potential therapeutic approach for UL patients. Trial registration number Not applicable

Deciphering the Role of Histone Modifications in Uterine Leiomyoma: Acetylation of H3K27 Regulates the Expression of Genes Involved in Proliferation, Cell Signaling, Cell Transport, Angiogenesis and Extracellular Matrix Formation.

Uterine leiomyoma (UL) is a benign tumor arising from myometrium (MM) with a high prevalence and unclear pathology. Histone modifications are altered in tumors, particularly via histone acetylation which is correlated with gene activation. To identify if the acetylation of H3K27 is involved in UL pathogenesis and if its reversion may be a therapeutic option, we performed a prospective study integrating RNA-seq (n = 48) and CHIP-seq for H3K27ac (n = 19) in UL vs MM tissue, together with qRT-PCR of SAHA-treated UL cells (n = 10). CHIP-seq showed lower levels of H3K27ac in UL versus MM (p-value < 2.2 × 10−16). From 922 DEGs found in UL vs. MM (FDR < 0.01), 482 presented H3K27ac. A differential acetylation (FDR < 0.05) was discovered in 82 of these genes (29 hyperacetylated/upregulated, 53 hypoacetylated/downregulated). Hyperacetylation/upregulation of oncogenes (NDP,HOXA13,COL24A1,IGFL3) and hypoacetylation/downregulation of tumor suppressor genes (CD40,GIMAP8,IL15,GPX3,DPT) altered the immune system, the metabolism, TGFβ3 and the Wnt/β-catenin pathway. Functional enrichment analysis revealed deregulation of proliferation, cell signaling, transport, angiogenesis and extracellular matrix. Inhibition of histone deacetylases by SAHA increased expression of hypoacetylated/downregulated genes in UL cells (p < 0.05). Conclusively, H3K27ac regulates genes involved in UL onset and maintenance. Histone deacetylation reversion upregulates the expression of tumor suppressor genes in UL cells, suggesting targeting histone modifications as a therapeutic approach for UL.

Redistribution of Histone Marks on Inflammatory Genes Associated With Intracerebral Hemorrhage-Induced Acute Brain Injury in Aging Rats.

The contribution of histone mark redistribution to the age-induced decline of endogenous neuroprotection remains unclear. In this study, we used an intracerebral hemorrhage (ICH)-induced acute brain injury rat model to study the transcriptional and chromatin responses in 13- and 22-month-old rats. Transcriptome analysis (RNA-seq) revealed that the expression of neuroinflammation-associated genes was systematically upregulated in ICH rat brains, irrespective of age. Further, we found that interferon-γ (IFN-γ) response genes were activated in both 13- and 22-month-old rats. Anti-IFN-γ treatment markedly reduced ICH-induced acute brain injury in 22-month-old rats. At the chromatin level, ICH induced the redistribution of histone modifications in the promoter regions, especially H3K4me3 and H3K27me3, in neuroinflammation-associated genes in 13- and 22-month-old rats, respectively. Moreover, ICH-induced histone mark redistribution and gene expression were found to be correlated. Collectively, these findings demonstrate that histone modifications related to gene expression are extensively regulated in 13- and 22-month-old rats and that anti-IFN-γ is effective for ICH treatment, highlighting the potential of developing therapies targeting histone modifications to cure age-related diseases, including brain injury and neuroinflammation.

Mechanism and Therapeutic Opportunities of Histone Modifications in Chronic Liver Disease.

Chronic liver disease (CLD) represents a global health problem, accounting for the heavy burden of disability and increased health care utilization. Epigenome alterations play an important role in the occurrence and progression of CLD. Histone modifications, which include acetylation, methylation, and phosphorylation, represent an essential part of epigenetic modifications that affect the transcriptional activity of genes. Different from genetic mutations, histone modifications are plastic and reversible. They can be modulated pharmacologically without changing the DNA sequence. Thus, there might be chances to establish interventional solutions by targeting histone modifications to reverse CLD. Here we summarized the roles of histone modifications in the context of alcoholic liver disease (ALD), metabolic associated fatty liver disease (MAFLD), viral hepatitis, autoimmune liver disease, drug-induced liver injury (DILI), and liver fibrosis or cirrhosis. The potential targets of histone modifications for translation into therapeutics were also investigated. In prospect, high efficacy and low toxicity drugs that are selectively targeting histone modifications are required to completely reverse CLD and prevent the development of liver cirrhosis and malignancy.

Targeting Histone Modifications in Breast Cancer: A Precise Weapon on the Way.

Histone modifications (HMs) contribute to maintaining genomic stability, transcription, DNA repair, and modulating chromatin in cancer cells. Furthermore, HMs are dynamic and reversible processes that involve interactions between numerous enzymes and molecular components. Aberrant HMs are strongly associated with tumorigenesis and progression of breast cancer (BC), although the specific mechanisms are not completely understood. Moreover, there is no comprehensive overview of abnormal HMs in BC, and BC therapies that target HMs are still in their infancy. Therefore, this review summarizes the existing evidence regarding HMs that are involved in BC and the potential mechanisms that are related to aberrant HMs. Moreover, this review examines the currently available agents and approved drugs that have been tested in pre-clinical and clinical studies to evaluate their effects on HMs. Finally, this review covers the barriers to the clinical application of therapies that target HMs, and possible strategies that could help overcome these barriers and accelerate the use of these therapies to cure patients.

Inhibition of Epigenetic Modifiers LSD1 and HDAC1 Blocks Rod Photoreceptor Death in Mouse Models of Retinitis Pigmentosa

Epigenetic modifiers are increasingly being investigated as potential therapeutics to modify and overcome disease phenotypes. Diseases of the nervous system present a particular problem as neurons are postmitotic and demonstrate relatively stable gene expression patterns and chromatin organization. We have explored the ability of epigenetic modifiers to prevent degeneration of rod photoreceptors in a mouse model of retinitis pigmentosa (RP), using rd10 mice of both sexes. The histone modification eraser enzymes lysine demethylase 1 (LSD1) and histone deacetylase 1 (HDAC1) are known to have dramatic effects on the development of rod photoreceptors. In the RP mouse model, inhibitors of these enzymes blocked rod degeneration, preserved vision, and affected the expression of multiple genes including maintenance of rod-specific transcripts and downregulation of those involved in inflammation, gliosis, and cell death. The neuroprotective activity of LSD1 inhibitors includes two pathways. First, through targeting histone modifications, they increase accessibility of chromatin and upregulate neuroprotective genes, such as from the Wnt pathway. We propose that this process is going in rod photoreceptors. Second, through nonhistone targets, they inhibit transcription of inflammatory genes and inflammation. This process is going in microglia, and lack of inflammation keeps rod photoreceptors alive.SIGNIFICANCE STATEMENT Retinal degenerations are a leading cause of vision loss. RP is genetically very heterogeneous, and the multiple pathways leading to cell death are one reason for the slow progress in identifying suitable treatments for patients. Here we demonstrate that inhibition of LSD1and HDAC1 in a mouse model of RP leads to preservation of rod photoreceptors and visual function, retaining of expression of rod-specific genes, and with decreased inflammation, cell death, and Müller cell gliosis. We propose that these epigenetic inhibitors cause more open and accessible chromatin, allowing expression of neuroprotective genes. A second mechanism that allows rod photoreceptor survival is suppression of inflammation by epigenetic inhibitors in microglia. Manipulation of epigenetic modifiers is a new strategy to fight neurodegeneration in RP.

Genome-wide mapping of histone modifications during axenic growth in two species of Leptosphaeria maculans showing contrasting genomic organization

Leptosphaeria maculans ‘brassicae’ (Lmb) and Leptosphaeria maculans ‘lepidii’ (Lml) are closely related phytopathogenic species that exhibit a large macrosynteny but contrasting genome structure. Lmb has more than 30% of repeats clustered in large repeat-rich regions, while the Lml genome has only a small amount of evenly distributed repeats. Repeat-rich regions of Lmb are enriched in effector genes, expressed during plant infection. The distinct genome structures of Lmb and Lml provide an excellent model for comparing the organization of pathogenicity genes in relation to the chromatin landscape in two closely related phytopathogenic fungi. Here, we performed chromatin immunoprecipitation (ChIP) during axenic culture, targeting histone modifications typical for heterochromatin or euchromatin, combined with transcriptomic analysis to analyze the influence of chromatin organization on gene expression. In both species, we found that facultative heterochromatin is enriched with genes lacking functional annotation, including numerous effector and species-specific genes. Notably, orthologous genes located in H3K27me3 domains are enriched with effector genes. Compared to other fungal species, including Lml, Lmb is distinct in having large H3K9me3 domains associated with repeat-rich regions that contain numerous species-specific effector genes. Discovery of these two distinctive heterochromatin landscapes now raises questions about their involvement in the regulation of pathogenicity, the dynamics of these domains during plant infection and the selective advantage to the fungus to host effector genes in H3K9me3 or H3K27me3 domains.

Targeting Histone Modifications in Bone and Lung Metastatic Cancers.

Breast cancer frequently metastasizes to the bone and lung, but the ability to treat metastatic tumor cells remains a pressing clinical challenge. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) have emerged as promising targets since these enzymes are aberrantly expressed in numerous cancers and regulate the expression of genes that drive tumorigenesis and metastasis. This review focuses on the abnormal expression of histone-modifying enzymes in cancers that have a high tropism for the bone and lung and explores the clinical use of histone deacetylase inhibitors for the treatment and prevention of metastasis to these sites. Preclinical studies have demonstrated that the role for HDACs is highly dependent on tumor type and stage of disease progression. HDAC inhibitors can induce apoptosis, senescence, cell differentiation, and tumor dormancy genes and inhibit angiogenesis, making these promising therapeutics for the treatment of metastatic disease. HDAC inhibitors are already FDA approved for hematologic malignancies and are in clinical trials with standard-of-care chemotherapies and targeted agents for several solid tumors, including cases of metastatic disease. However, these drugs can negatively impact bone homeostasis. Although HDAC inhibitors are not currently administered for the treatment of bone and lung metastatic disease, preclinical studies have shown that these drugs can reduce distant metastasis by targeting molecular factors and signaling pathways that drive tumor cell dissemination to these sites. Thus, HDAC inhibitors in combination with bone protective therapies may be beneficial in the treatment of bone metastatic cancers.