Genome-wide Epigenetic Changes Research Articles

Genome-wide epigenetic profiling and transcriptome analysis in pediatric Obstructive Sleep Apnea: A focus on Black female children

Obstructive Sleep Apnea (OSA) is a common sleep-related breathing disorder characterized by airway obstruction during sleep. Diagnosing pediatric OSA is challenging, particularly in underrepresented populations, leading to disparities in treatment and long-term negative health outcomes. Our study aimed to identify alternative diagnostic tools by investigating genome-wide epigenetic changes and associated transcriptomic alterations in Black female, pediatric patients with OSA. Whole-genome bisulfite sequencing and RNA sequencing were performed on saliva samples from healthy controls and children with OSA. Analysis of differential methylation and gene expression patterns revealed dysregulated inflammation and metabolism pathways in children with OSA. Chromosomes 19 and 22 exhibited elevated methylation signatures in this patient population. Integration of methylation and gene expression data identified specific molecular markers, including NAP1L4, CCR1, and LIF. The study emphasizes the need to consider both genetic and environmental factors in pediatric OSA, and the identified markers may offer avenues for further research.

Genome-wide epigenetic changes in compartments of genetically unbalanced human blastocysts

BACKGROUND: Epigenetic genome reprogramming is an important determinant of human embryo development. However, its mechanisms remain poorly elucidated, especially in genetically unbalanced embryos. AIM: The aim of this study is the analysis of DNA methylation and hydroxymethylation levels in trophectoderm and inner cell mass of genetically balanced and unbalanced human blastocysts. MATERIALS AND METHODS: Twenty-two IVF-derived human blastocysts were enrolled in the study; of these blastocysts, 15 were genetically unbalanced and 7 — genetically balanced. Detection of 5-methylcytosine and 5-hydroxymethylcytosine was performed on trophectoderm and inner cell mass nuclei by indirect immunofluorescence. RESULTS: In genetically unbalanced blastocysts, the DNA methylation level was elevated in both compartments. The DNA hydroxymethylation level, in contrast, was elevated only in inner cell mass, whereas trophectoderm cells retained the same level as in genetically balanced embryos. These changes equalized the inner cell mass and trophectoderm DNA hydroxymethylation levels in genetically unbalanced blastocysts, while in genetically balanced ones the 5-hydroxymethylcytosine content in inner cell mass lagged behind that in trophectoderm. CONCLUSIONS: Genetic imbalance is associated with differential epigenetic changes in trophectoderm and inner cell mass cells of human blastocysts: DNA methylation level increases in both compartments while DNA hydroxymethylation level increases only in inner cell mass. The trophectoderm cells in genetically unbalanced blastocysts retain the same hydroxymethylation level as in genetically balanced ones, suggesting a possible explanation of the ability of karyotypically abnormal embryos to implant.

DNA Methylation Profiles Are Stable in H3 K27M-Mutant Diffuse Midline Glioma Neurosphere Cell Lines.

Diffuse midline gliomas are among the deadliest human cancers and have had little progress in treatment in the last 50 years. Cell cultures of these tumors have been developed recently, but the degree to which such cultures retain the characteristics of the source tumors is unknown. DNA methylation profiling offers a powerful tool to look at genome-wide epigenetic changes that are biologically meaningful and can help assess the similarity of cultured tumor cells to their in vivo progenitors. Paraffinized diagnostic tissue from three diffuse intrinsic pontine gliomas with H3 K27M mutations was compared with subsequent passages of neurosphere cell cultures from those tumors. Each cell line was passaged 3-4 times and analyzed with DNA methylation arrays and standard algorithms that provided a comparison of diagnostic classification and cluster analysis. All samples tested maintained high classifier scores and clustered within the reference group of H3 K27M-mutant diffuse midline gliomas. There was a gain of 1q in all cell lines, with two cell lines initially manifesting the gain of 1q only during culture. In vitro cell cultures of H3 K27M-mutant gliomas maintain high degrees of similarity in DNA methylation profiles to their source tumor, confirming their fidelity even with some chromosomal changes.

Epigenetic signature of ionizing radiation in therapy-related AML patients

Therapy-related acute myeloid leukaemia (t-AML) is a late side effect of previous chemotherapy (ct-AML) and/or radiotherapy (rt-AML) or immunosuppressive treatment. t-AMLs, which account for ∼10–20 % of all AML cases, are extremely aggressive and have a poor prognosis compared to de novo AML. Our hypothesis is that exposure to radiation causes genome-wide epigenetic changes in rt-AML. An epigenome-wide association study was undertaken, measuring over 850K methylation sites across the genome from fifteen donors (five healthy, five de novo, and five t-AMLs). The study predominantly focussed on 94K sites that lie in CpG-rich gene promoter regions. Genome-wide hypomethylation was discovered in AML, primarily in intergenic regions. Additionally, genes specific to AML were identified with promoter hypermethylation. A two-step validation was conducted, both internally, using pyrosequencing to measure methylation levels in specific regions across fifteen primary samples, and externally, with an additional eight AML samples. We demonstrated that the MEST and GATA5 gene promoters, which were previously identified as tumour suppressors, were noticeably hypermethylated in rt-AML, as opposed to other subtypes of AML and control samples. These may indicate the epigenetic involvement in the development of rt-AML at the molecular level and could serve as potential targets for drug therapy in rt-AML.

Genome-wide neonatal epigenetic changes associated with maternal exposure to the COVID-19 pandemic

BackgroundDuring gestation, stressors to the fetus, including viral exposure or maternal psychological distress, can fundamentally alter the neonatal epigenome, and may be associated with long-term impaired developmental outcomes. The impact of in utero exposure to the COVID-19 pandemic on the newborn epigenome has yet to be described.MethodsThis study aimed to determine whether there are unique epigenetic signatures in newborns who experienced otherwise healthy pregnancies that occurred during the COVID-19 pandemic (Project RESCUE). The pre-pandemic control and pandemic cohorts (Project RESCUE) included in this study are part of a prospective observational and longitudinal cohort study that evaluates the impact of elevated prenatal maternal stress during the COVID-19 pandemic on early childhood neurodevelopment.Using buccal swabs collected at birth, differential DNA methylation analysis was performed using the Infinium MethylationEPIC arrays and linear regression analysis. Pathway analysis and gene ontology enrichment were performed on resultant gene lists.ResultsWidespread differential methylation was found between neonates exposed in utero to the pandemic and pre-pandemic neonates. In contrast, there were no apparent epigenetic differences associated with maternal COVID-19 infection during pregnancy. Differential methylation was observed among genomic sites that underpin important neurological pathways that have been previously reported in the literature to be differentially methylated because of prenatal stress, such as NR3C1.ConclusionsThe present study reveals potential associations between exposure to the COVID-19 pandemic during pregnancy and subsequent changes in the newborn epigenome. While this finding warrants further investigation, it is a point that should be considered in any study assessing newborn DNA methylation studies obtained during this period, even in otherwise healthy pregnancies.

Epigenomics in stress tolerance of plants under the climate change.

Epigenomics in stress tolerance of plants under the climate change.

Docosahexaenoic Acid Alters Lipid Metabolism Processes via H3K9ac Epigenetic Modification in Dairy Goat.

Goat milk is increasingly recognized by consumers due to its high nutritional value, richness in short- and medium-chain fatty acids, and richness in polyunsaturated fatty acids (PUFA). Exogenous supplementation of docosahexaenoic acid (DHA) is an important approach to increasing the content of PUFA in goat milk. Several studies have reported benefits of dietary DHA in terms of human health, including potential against chronic diseases and tumors. However, the mechanisms whereby an increased supply of DHA regulates mammary cell function is unknown. In this study, we investigated the effect of DHA on lipid metabolism processes in goat mammary epithelial cells (GMEC) and the function of H3K9ac epigenetic modifications in this process. Supplementation of DHA promoted lipid droplet accumulation increased the DHA content and altered fatty acid composition in GMEC. Lipid metabolism processes were altered by DHA supplementation through transcriptional programs in GMEC. ChIP-seq analysis revealed that DHA induced genome-wide H3K9ac epigenetic changes in GMEC. Multiomics analyses (H3K9ac genome-wide screening and RNA-seq) revealed that DHA-induced expression of lipid metabolism genes (FASN, SCD1, FADS1, FADS2, LPIN1, DGAT1, MBOAT2), which were closely related with changes in lipid metabolism processes and fatty acid profiles, were regulated by modification of H3K9ac. In particular, DHA increased the enrichment of H3K9ac in the promoter region of PDK4 and promoted its transcription, while PDK4 inhibited lipid synthesis and activated AMPK signaling in GMEC. The activation of the expression of fatty acid metabolism-related genes FASN, FADS2, and SCD1 and their upstream transcription factor SREBP1 by the AMPK inhibitor was attenuated in PDK4-overexpressing GMEC. In conclusion, DHA alters lipid metabolism processes via H3K9ac modifications and the PDK4-AMPK-SREBP1 signaling axis in goat mammary epithelial cells, providing new insights into the mechanism through which DHA affects mammary cell function and regulates milk fat metabolism.

Genome-wide DNA methylation predicts environmentally driven life history variation in a marine fish.

Epigenetic modifications are thought to be one of the molecular mechanisms involved in plastic adaptive responses to environmental variation. However, studies reporting associations between genome-wide epigenetic changes and habitat-specific variations in life history traits (e.g., lifespan, reproduction) are still scarce, likely due to the recent application of methylome resequencing methods to non-model species. In this study, we examined associations between whole genome DNA methylation and environmentally driven life history variation in 2 lineages of a marine fish, the capelin (Mallotus villosus), from North America and Europe. In both lineages, capelin harbor 2 contrasting life history tactics (demersal vs. beach-spawning). Performing whole genome and methylome sequencing, we showed that life history tactics are associated with epigenetic changes in both lineages, though the effect was stronger in European capelin. Genetic differentiation between the capelin harboring different life history tactics was negligible, but we found genome-wide methylation changes in both lineages. We identified 9,125 European and 199 North American differentially methylated regions (DMRs) due to life history. Gene ontology (GO) enrichment analysis for both lineages revealed an excess of terms related to neural function. Our results suggest that environmental variation causes important epigenetic changes that are associated with contrasting life history tactics in lineages with divergent genetic backgrounds, with variable importance of genetic variation in driving epigenetic variation. Our study emphasizes the potential role of genome-wide epigenetic variation in adaptation to environmental variation.

Abstract 3763: Detection of tumor-associated gene inactivation in clinical blood draws via cell-free DNA methylation profiling

Abstract Introduction: The ability to detect genome-wide epigenetic changes, such as DNA methylation, has expanded translational applications in oncology settings. Because these changes occur early in carcinogenesis, they can be used for early cancer detection when genomic technologies fall short due to lower sensitivity, and in the early and late-stage cancer setting for minimal residual disease detection, disease monitoring and therapy selection. In this analysis, we demonstrated our detection of differential methylations that classify cancer from healthy normals, as well as the quantification of promoter methylation, using a highly sensitive targeted assay that simultaneously captures both genomic alterations and methylation signatures in cell-free DNA (cfDNA). Methods: Methylation signals were profiled with a broad genomic panel (15.2 Mb) targeting regions that are unmethylated in plasma cfDNA from cancer-free donors. The panel covers the promoter regions of 925 out of 1,217 known tumor suppressor genes (TSGs) (e.g. TP53, APC, RB1, PTEN), homologous recombination and repair (HRR) genes (e.g. ATM, BRCA1/2, CDK12, RAD51C/D). We applied our genomic and epigenomic assay on cfDNA from 1,968 colorectal cancer (CRC) patients, 480 patients with other 6 common cancers, and 2,037 cancer-free donors. To test the sensitivity of our epigenomic assay, we generated an in-silico dataset by computationally mixing reads from the cancer patients with those from cancer-free donors at a low tumor fraction (TF) of 0.1%. Results: Among 62 clinically relevant TSG and HRR genes, 56 (90%) were differentially methylated (Wilcoxon p<0.05) between the 2,448 cancer vs. 2,037 cancer-free donor samples. In the in-silico dataset, 51 of the 56 differentially methylated genes remained statistically significant (Wilcoxon p<0.05) at 0.1% TF. In the 1,968 CRC patients, we observed a significant association (Fisher’s p<1e-05) between MLH1 promoter methylation and microsatellite instability (MSI-H): 70% of MSI-H samples has MLH1 promoter methylation above a predefined “high methylation” threshold, while only 7% of microsatellite-stable samples has MLH1 promoter methylation above this threshold. Our result is consistent with previous studies that 54-100% of CRC patients with MSI-H tumors harbor MLH1 promoter methylation. Conclusion: We demonstrate that our assay can accurately detect cancer-driven DNA methylation across the genome in clinical plasma samples. Detection of differential methylation in cancerous versus non-cancerous tissues could allow for early cancer detection, leading to better survival and prediction of recurrence prior to imaging. The highly sensitive detection of promoter methylation shown with TSG, HRR, and MLH1 genes may provide orthogonal information to oncologists in therapeutic selection with high confidence. Citation Format: Sai Chen, Shile Zhang, Tingting Jiang, Jennifer Yen, Yupeng He, Ariel Jaimovich, Yvonne Kim, Dustin Ma, Giao Tran, Daniel P. Gaile, Rebecca J. Nagy, Elena Helman, Han-Yu Chuang. Detection of tumor-associated gene inactivation in clinical blood draws via cell-free DNA methylation profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3763.

Epigenome-Wide Histone Acetylation Changes in Peripheral Blood Mononuclear Cells in Patients with Type 2 Diabetes and Atherosclerotic Disease.

There is emerging evidence of an association between epigenetic modifications, glycemic control and atherosclerosis risk. In this study, we mapped genome-wide epigenetic changes in patients with type 2 diabetes (T2D) and advanced atherosclerotic disease. We performed chromatin immunoprecipitation sequencing (ChIP-seq) using a histone 3 lysine 9 acetylation (H3K9ac) mark in peripheral blood mononuclear cells from patients with atherosclerosis with T2D (n = 8) or without T2D (ND, n = 10). We mapped epigenome changes and identified 23,394 and 13,133 peaks in ND and T2D individuals, respectively. Out of all the peaks, 753 domains near the transcription start site (TSS) were unique to T2D. We found that T2D in atherosclerosis leads to an H3K9ac increase in 118, and loss in 63 genomic regions. Furthermore, we discovered an association between the genomic locations of significant H3K9ac changes with genetic variants identified in previous T2D GWAS. The transcription factor 7-like 2 (TCF7L2) rs7903146, together with several human leukocyte antigen (HLA) variants, were among the domains with the most dramatic changes of H3K9ac enrichments. Pathway analysis revealed multiple activated pathways involved in immunity, including type 1 diabetes. Our results present novel evidence on the interaction between genetics and epigenetics, as well as epigenetic changes related to immunity in patients with T2D and advanced atherosclerotic disease.

A Review of Recent Developments in Turner Syndrome Research

Turner syndrome is a rare disorder resulting from complete or partial loss of the second sex chromosome. Common manifestations include delayed growth, premature ovarian failure, congenital heart defects, endocrine disorders, lymphedema, and webbed neck. People with Turner syndrome have significantly increased mortality risk primarily due to cardiovascular abnormalities. The mechanisms that lead to these defects are not completely understood and are obscured by the significant variability of both karyotype and phenotype without consistent correlation between the two. This paper presents a review of the recent literature surrounding the symptoms, mechanisms, diagnosis, and treatment of Turner syndrome with a focus on cardiovascular manifestations. With technological advancements in genetics, the molecular processes of Turner syndrome have begun to be dissected. Certain genes on the X chromosome that typically escape inactivation have been implicated in both specific manifestations and broader risk categories. Recently identified genome-wide epigenetic changes may help explain the variability in presentation. It remains unclear as to how the combination of these factors results in the overall clinical picture, but advances in genomic, genetic, epigenetic, and -omics technology hold promise for providing insights that will improve the medical management of individuals with Turner syndrome.

Genome-Wide DNA Methylation Changes Associated With High-Altitude Acclimatization During an Everest Base Camp Trek.

The individual physiological response to high-altitude hypoxia involves both genetic and non-genetic factors, including epigenetic modifications. Epigenetic changes in hypoxia factor pathway (HIF) genes are associated with high-altitude acclimatization. However, genome-wide epigenetic changes that are associated with short-term hypoxia exposure remain largely unknown. We collected a series of DNA samples from 15 participants of European ancestry trekking to Everest Base Camp to identify DNA methylation changes associated with incremental altitude ascent. We determined genome-wide DNA methylation levels using the Illumina MethylationEPIC chip comparing two altitudes: baseline 1,400 m (day 0) and elevation 4,240 m (day 7). The results of our epigenome-wide association study revealed 2,873 significant differentially methylated positions (DMPs) and 361 significant differentially methylated regions (DMRs), including significant positions and regions in hypoxia inducible factor (HIF) and the renin–angiotensin system (RAS) pathways. Our pathway enrichment analysis identified 95 significant pathways including regulation of glycolytic process (GO:0006110), regulation of hematopoietic stem cell differentiation (GO:1902036), and regulation of angiogenesis (GO:0045765). Lastly, we identified an association between the ACE gene insertion/deletion (I/D) polymorphism and oxygen saturation, as well as average ACE methylation. These findings shed light on the genes and pathways experiencing the most epigenetic change associated with short-term exposure to hypoxia.

Nitric Oxide Increases Mitomycin-C Cytotoxicity by Generation of Reactive Oxygen Species and Induces Cell Death by Apoptosis in FancC-/- Cells

Fanconi Anemia (FA) is a rare genetic disorder and patients of FA exhibit progressive bone marrow failure, developmental defects and cancer predisposition. Mitochondrial dysfunction due to oxidative stress and higher levels of Reactive Oxygen Species (ROS) has been well documented in FA. Increase in the levels of Reactive Nitrogen Species (RNS) and Nitric Oxide Synthase (NOS) activity is often correlated with OS- related disorders which have altered mitochondrial function. Biological effects of Nitric Oxide (NO) and nitrosative stress depend on the cell type, concentration of NO, the time of incubation and cellular homeostasis. NO is known to have both prooncogenic as well as tumour -suppressing effects which are a result of regulation of S- nitrosylation, genome wide epigenetic changes and posttranslational modification of protein. NO plays strategic roles in metabolic and signalling pathways, making NO metabolism a key mediator in pathways that are responsible for supporting tumorigenesis. NO is also known to have important regulatory roles in the process of autophagy, which is an important mediator in the cross-talk with ROS and RNS. In the present study, we examined the interaction between ROS and NO, induction of apoptosis by NO and the possible role of NO in the pathogenesis of FA. Investigating the involvement of NO and NS and their interactions with the known hallmarks of FA will give a more comprehensive understanding of pathogenesis of FA.

Applications of Deep Mutational Scanning in Virology.

Several recently developed high-throughput techniques have changed the field of molecular virology. For example, proteomics studies reveal complete interactomes of a viral protein, genome-wide CRISPR knockout and activation screens probe the importance of every single human gene in aiding or fighting a virus, and ChIP-seq experiments reveal genome-wide epigenetic changes in response to infection. Deep mutational scanning is a relatively novel form of protein science which allows the in-depth functional analysis of every nucleotide within a viral gene or genome, revealing regions of importance, flexibility, and mutational potential. In this review, we discuss the application of this technique to RNA viruses including members of the Flaviviridae family, Influenza A Virus and Severe Acute Respiratory Syndrome Coronavirus 2. We also briefly discuss the reverse genetics systems which allow for analysis of viral replication cycles, next-generation sequencing technologies and the bioinformatics tools that facilitate this research.

Oncohistones: a roadmap to stalled development.

Since the discovery of recurrent mutations in histone H3 variants in paediatric brain tumours, so-called 'oncohistones' have been identified in various cancers. While their mechanism of action remains under active investigation, several studies have shed light on how they promote genome-wide epigenetic perturbations. These findings converge on altered post-translational modifications on two key lysine (K) residues of the H3 tail, K27 and K36, which regulate several cellular processes, including those linked to cell differentiation during development. We will review how these oncohistones affect the methylation of cognate residues, but also disrupt the distribution of opposing chromatin marks, creating genome-wide epigenetic changes which participate in the oncogenic process. Ultimately, tumorigenesis is promoted through the maintenance of a progenitor state at the expense of differentiation in defined cellular and developmental contexts. As these epigenetic disruptions are reversible, improved understanding of oncohistone pathogenicity can result in needed alternative therapies.

Multiplexed and Ultralow-Input ChIP-seq Enabled by Tagmentation-Based Indexing and Facile Microfluidics

Epigenome constitutes an important layer that regulates gene expression and dynamics during development and diseases. Extensive efforts have been made to develop epigenome profiling methods using a low number of cells and with high throughput. Chromatin immunoprecipitation (ChIP) is the most important approach for profiling genome-wide epigenetic changes such as histone modifications. In this report, we demonstrate microfluidic ChIPmentation (mu-CM), a microfluidic technology that enables profiling cell samples that individually do not generate enough ChIP DNA for sequencing library preparation. We used a simple microfluidic device to allow eight samples to be processed simultaneously. The samples were indexed differently using a tagmentation-based approach (ChIPmentation) and then merged for library preparation. A histone modification profile for each individual sample was obtained by demultiplexing the sequencing reads based on the indexes. Our technology allowed profiling 20 cells and is well suited for cell-type-specific studies using low-abundance tissues.

Social defeat stress in adult mice causes alterations in gene expression, alternative splicing, and the epigenetic landscape of H3K4me3 in the prefrontal cortex: An impact of early-life stress

Chronic stress is the leading risk factor of a broad range of severe psychopathologies. Nonetheless, the molecular mechanisms triggering these pathological processes are not well understood. In our study, we investigated the effects of 15-day social defeat stress (SDS) on the genome-wide landscape of trimethylation at the 4th lysine residue of histone H3 (H3K4me3) and on the transcriptome in the prefrontal cortex of mice that were reared normally (group SDS) or subjected to maternal separation early in life (group MS+SDS). The mice with the history of stress early in life showed increased susceptibility to SDS in adulthood and demonstrated long-lasting genome-wide alterations in gene expression and splicing as well as in the H3K4me3 epigenetic landscape in the prefrontal cortex. Thus, the high-throughput techniques applied here allowed us to simultaneously detect, for the first time, genome-wide epigenetic and transcriptional changes in the murine prefrontal cortex that are associated with both chronic SDS and increased susceptibility to this stressor.

Metabolism-associated genome-wide epigenetic changes in bovine oocytes during early lactation

Dietary intake in early lactating cows is outmatched by milk production. These cows experience a negative energy balance, resulting in a distinct blood metabolism and poor reproductive function due to impaired ovulation and increased embryo loss. We hypothesize that oocytes from lactating cows undergoing transient metabolic stress exhibit a different epigenetic profile crucial for developmental competence. To investigate this, we collected oocytes from metabolically-profiled cows at early- and mid-postpartum stages and characterized their epigenetic landscape compared with control heifers using whole-genome bisulfite sequencing. Early-postpartum cows were metabolically deficient with a significantly lower energy balance and significantly higher concentrations of non-esterified fatty acids and beta-hydroxybutyrate than mid-postpartum animals and control heifers. Accordingly, 32,990 early-postpartum-specific differentially methylated regions (DMRs) were found in genes involved in metabolic pathways, carbon metabolism, and fatty acid metabolism, likely descriptive of the epigenetic regulation of metabolism in early-postpartum oocytes. DMRs found overlapping CpG islands and exons of imprinted genes such as MEST and GNAS in early-postpartum oocytes suggest that early lactation metabolic stress may affect imprint acquisition, which could explain the embryo loss. This whole-genome approach introduces potential candidate genes governing the link between metabolic stress and the reproductive outcome of oocytes.

Role of GFI1 in Epigenetic Regulation of MDS and AML Pathogenesis: Mechanisms and Therapeutic Implications.

Growth factor independence 1 (GFI1) is a DNA binding zinc finger protein, which can mediate transcriptional repression mainly by recruiting histone-modifying enzymes to its target genes. GFI1 plays important roles in hematopoiesis, in particular by regulating both the function of hematopoietic stem- and precursor cells and differentiation along myeloid and lymphoid lineages. In recent years, a number of publications have provided evidence that GFI1 is involved in the pathogenesis of acute myeloid leukemia (AML), its proposed precursor, myelodysplastic syndrome (MDS), and possibly also in the progression from MDS to AML. For instance, expression levels of the GFI1 gene correlate with patient survival and treatment response in both AML and MDS and can influence disease progression and maintenance in experimental animal models. Also, a non-synonymous single nucleotide polymorphism (SNP) of GFI1, GFI1-36N, which encodes a variant GFI1 protein with a decreased efficiency to act as a transcriptional repressor, was found to be a prognostic factor for the development of AML and MDS. Both the GFI1-36N variant as well as reduced expression of the GFI1 gene lead to genome-wide epigenetic changes at sites where GFI1 occupies target gene promoters and enhancers. These epigenetic changes alter the response of leukemic cells to epigenetic drugs such as HDAC- or HAT inhibitors, indicating that GFI1 expression levels and genetic variants of GFI1 are of clinical relevance. Based on these and other findings, specific therapeutic approaches have been proposed to treat AML by targeting some of the epigenetic changes that occur as a consequence of GFI1 expression. Here, we will review the well-known role of Gfi1 as a transcription factor and describe the more recently discovered functions of GFI1 that are independent of DNA binding and how these might affect disease progression and the choice of epigenetic drugs for therapeutic regimens of AML and MDS.

Loss of Msh2 and a single-radiation hit induce common, genome-wide, and persistent epigenetic changes in the intestine

BackgroundMismatch repair (MMR)-deficiency increases the risk of colorectal tumorigenesis. To determine whether the tumors develop on a normal or disturbed epigenetic background and how radiation affects this, we quantified genome-wide histone H3 methylation profiles in macroscopic normal intestinal tissue of young radiated and untreated MMR-deficient VCMsh2LoxP/LoxP (Msh2−/−) mice months before tumor onset.ResultsHistone H3 methylation increases in Msh2−/− compared to control Msh2+/+ mice. Activating H3K4me3 and H3K36me3 histone marks frequently accumulate at genes that are H3K27me3 or H3K4me3 modified in Msh2+/+ mice, respectively. The genes recruiting H3K36me3 enrich in gene sets associated with DNA repair, RNA processing, and ribosome biogenesis that become transcriptionally upregulated in the developing tumors. A similar epigenetic effect is present in Msh2+/+ mice 4 weeks after a single-radiation hit, whereas radiation of Msh2−/− mice left their histone methylation profiles almost unchanged.ConclusionsMMR deficiency results in genome-wide changes in histone H3 methylation profiles preceding tumor development. Similar changes constitute a persistent epigenetic signature of radiation-induced DNA damage.