Epigenetic Environment Research Articles

Modeling Malignant Mesothelioma in Genetically Engineered Mice.

Mesothelioma is a lethal cancer of the serosal lining of the body cavities. Risk factors include environmental and genetic factors. Asbestos exposure is considered the principal environmental risk factor, but other carcinogenic mineral fibers, such as erionite, also have a causal role. Pathogenic germline (heritable) mutations of specific genes, especially BAP1, are thought to predispose the individual to mesothelioma in about 10% of cases. Somatic mutations and deletions of specific tumor suppressor genes, particularly BAP1, CDKN2A/B, and NF2, occur frequently in human mesothelioma, and asbestos-exposed mice with heterozygous deletions of any one of these genes have been shown to develop mesothelioma more often and at an accelerated rate than in control animals. Autochthonous mesothelioma mouse models, which are genetically engineered to carry multiple genetic lesions matching those observed in the human disease counterpart, closely resemble the disease phenotype and the extensive inflammatory responses that characterize human mesothelioma. Because autochthonous mice do not require asbestos exposure and form tumors rapidly, these models are invaluable for assessing novel therapeutic strategies in an immunocompetent setting. The overlapping genetic, epigenetic, and immune environments of the tumors observed in these genetically engineered mouse models (GEMMs) and human primary mesothelioma specimens support the clinical relevance of these preclinical models. This article presents protocols for studies of asbestos-induced mesothelioma in GEMMs and non-carcinogenic conditional knockout models of mesothelioma, including an example of a preclinical application. These models are invaluable for understanding the biological underpinnings of mesothelioma and for testing new therapeutics and chemoprevention or interception agents. © 2025 Wiley Periodicals LLC. Basic Protocol 1: Generation of a genetically engineered mouse model (GEMM) with a germline Bap1 knockout allele Basic Protocol 2: Generation of GEMMs with germline Bap1 knock-in alleles Basic Protocol 3: Asbestos carcinogenicity investigations with GEMMs Basic Protocol 4: Preclinical chemoprevention and chemotherapy studies using a GEMM with asbestos-induced mesothelioma Basic Protocol 5: Generation of a GEMM with conditional knockout of Bap1 Basic Protocol 6: Generation of a conditional knockout model of mesothelioma.

Golcadomide-Mediated Degradation of Aiolos/Ikaros Synergizes with BET Inhibitors through Bidirectional Restructuring of the Directly Regulated Epigenetic Environment in DLBCL

Golcadomide-Mediated Degradation of Aiolos/Ikaros Synergizes with BET Inhibitors through Bidirectional Restructuring of the Directly Regulated Epigenetic Environment in DLBCL

Antimony stable isotope fractionation during adsorption onto birnessite: A molecular perspective from X-ray absorption spectroscopy and density functional theory

Sorption of antimony (Sb) onto birnessite significantly influences the fate of Sb in oceanic and terrestrial environments and fractionates Sb isotopes. Nevertheless, little is known about Sb isotopic fractionation during its adsorption on birnessite. Here, we show the value of Δ123Sbadsorbed-aqueous increases from −0.398 to −0.332 ‰ in 1 h and then decreases and stabilizes at −0.384 ‰ in 72 h. The enrichment of the light Sb isotope is predominantly due to the distortion of the octahedral symmetry. X-ray absorption spectroscopy results indicate Sb first forms a double-corner-sharing complex on birnessite and then transforms to a double-edge-sharing complex during adsorption. The optimized bond distances for double-corner-sharing (3.37 Å) and double-edge-sharing (2.90 Å) complexes calculated using density functional theory (DFT) fits well with the structure (3.41 and 3.00 Å) revealed by X-ray absorption spectroscopy, respectively. The fractionation derived from reduced partition function ratios calculated using DFT aligns well with the experimental results. Therefore, the variation in Sb isotopic fractionation during adsorption is attributed to the evolving structure of Sb complexes on birnessite. Our results demonstrate the isotopic fractionation of Sb during adsorption on birnessite and provide a molecular-scale understanding of Sb behavior, contributing to the correct reconstruction of the Sb isotope composition of ancient seawater using ferromanganese crusts and nodules, and efforts to trace Sb migration in epigenetic mining environments.

ΔNp63 bookmarks and creates an accessible epigenetic environment for TGFβ-induced cancer cell stemness and invasiveness

Backgroundp63 is a transcription factor with intrinsic pioneer factor activity and pleiotropic functions. Transforming growth factor β (TGFβ) signaling via activation and cooperative action of canonical, SMAD, and non-canonical, MAP-kinase (MAPK) pathways, elicits both anti- and pro-tumorigenic properties, including cell stemness and invasiveness. TGFβ activates the ΔNp63 transcriptional program in cancer cells; however, the link between TGFβ and p63 in unmasking the epigenetic landscape during tumor progression allowing chromatin accessibility and gene transcription, is not yet reported.MethodsSmall molecule inhibitors, including protein kinase inhibitors and RNA-silencing, provided loss of function analyses. Sphere formation assays in cancer cells, chromatin immunoprecipitation and mRNA expression assays were utilized in order to gain mechanistic evidence. Mass spectrometry analysis coupled to co-immunoprecipitation assays revealed novel p63 interactors and their involvement in p63-dependent transcription.ResultsThe sphere-forming capacity of breast cancer cells was enhanced upon TGFβ stimulation and significantly decreased upon ΔNp63 depletion. Activation of TGFβ signaling via p38 MAPK signaling induced ΔNp63 phosphorylation at Ser 66/68 resulting in stabilized ΔNp63 protein with enhanced DNA binding properties. TGFβ stimulation altered the ratio of H3K27ac and H3K27me3 histone modification marks, pointing towards higher H3K27ac and increased p300 acetyltransferase recruitment to chromatin. By silencing the expression of ΔNp63, the TGFβ effect on chromatin remodeling was abrogated. Inhibition of H3K27me3, revealed the important role of TGFβ as the upstream signal for guiding ΔNp63 to the TGFβ/SMAD gene loci, as well as the indispensable role of ΔNp63 in recruiting histone modifying enzymes, such as p300, to these genomic regions, regulating chromatin accessibility and gene transcription. Mechanistically, TGFβ through SMAD activation induced dissociation of ΔNp63 from NURD or NCOR/SMRT histone deacetylation complexes, while promoted the assembly of ΔNp63-p300 complexes, affecting the levels of histone acetylation and the outcome of ΔNp63-dependent transcription.ConclusionsΔNp63, phosphorylated and recruited by TGFβ to the TGFβ/SMAD/ΔNp63 gene loci, promotes chromatin accessibility and transcription of target genes related to stemness and cell invasion.

A climate change from icehouse to greenhouse following Huronian glaciation: Evidence from long-term storm deposits of the Paleoproterozoic Hutuo Group in the North China Craton

The Hutuo Group was deposited from 2.14 to 2.0 Ga in Wutai Mountain, North China Craton. This group is composed of the Doucun and Dongye subgroups, which are likely contemporaneous heterotopic facies. The Hutuo Group displays well-known positive to negative drifts of inorganic carbon isotopes, large-scale stromatolitic carbonates, and red beds in epigenetic environments. Twelve storm-deposited lithofacies were identified in the Dongye Subgroup, which changes from sandstones, siltstones, and mudstones of the Qingshicun and lower Wenshan formations to carbonates of the upper Wenshan, Hebiancun, Jian’ancun, Daguanshan, Huaiyincun, Beidaxing, and Tianpengnao formations from bottom to top. The above sedimentary sequence transformation indicates a gradual transformation from terrigenous storm deposits in the Qingshicun and Wenshan formations to endogenous or mixed-source storm deposits in the Hebiancun, Jian’ancun, Daguanshan, and Huaiyincun formations. Additionally, coastal and shallow-marine storm deposits are revealed from sedimentary structures, including hummocky cross-stratification, intraclasts or boulder clays exhibiting radial or chrysanthemum-shaped stacking, and sinuous or torn stromatolites. These storm deposits, occurring with oolitic and stromatolitic carbonates of mid-low latitudes or tropical-subtropical zones, are characterized as tropical storm deposits. Based on reported ages, we propose that such tropical storms started from ca. 2.1 Ga and lasted for over 40 Myr. The long-term storm deposits indicate high temperatures and intense water circulation during the greenhouse climate. A climate change from icehouse to greenhouse is also evident by the extensive distribution of carbonates, evaporates, and organic-rich shales above the glacial diamictites in multi-cratons, and was probably driven by the transformative evolution of the atmosphere.

Adsorption Behaviors of Lanthanum (III) and Yttrium (III) Ions on Gibbsite

The enrichment process of rare earth elements in ion-adsorbed rare earth ores and bauxite is potentially related to the adsorption of rare earth elements by gibbsite. In this paper, lanthanum and yttrium were selected as surrogates of light rare earth elements and heavy rare earth elements, respectively. The effects of adsorption time, solution pH, and background electrolyte concentration on the adsorption of rare earth ions by gibbsite were investigated through batch adsorption experiments. The results showed that the adsorption of rare earth ions by gibbsite can approach equilibrium in 72 h. There is mainly electrostatic repulsion between gibbsite and rare earth ions at pH 4–7, and the adsorption efficiency increases with the increase in solution pH value and background electrolyte concentration. The adsorption process of rare earth ions by gibbsite is more consistent with the pseudo-second-order kinetic and Langmuir single-layer adsorption models. Moreover, based on the structural correlation between clay minerals and gibbsite, the causes for the differences in the adsorption behaviors of rare earth elements on the minerals are discussed. The results of this study help to understand the role of aluminum hydroxide in the migration and fate of rare earth elements in epigenetic environments.

Interchromosomal Colocalization with Parental Genes Is Linked to the Function and Evolution of Mammalian Retrocopies.

Retrocopies are gene duplicates arising from reverse transcription of mature mRNA transcripts and their insertion back into the genome. While long being regarded as processed pseudogenes, more and more functional retrocopies have been discovered. How the stripped-down retrocopies recover expression capability and become functional paralogs continually intrigues evolutionary biologists. Here, we investigated the function and evolution of retrocopies in the context of 3D genome organization. By mapping retrocopy-parent pairs onto sequencing-based and imaging-based chromatin contact maps in human and mouse cell lines and onto Hi-C interaction maps in 5 other mammals, we found that retrocopies and their parental genes show a higher-than-expected interchromosomal colocalization frequency. The spatial interactions between retrocopies and parental genes occur frequently at loci in active subcompartments and near nuclear speckles. Accordingly, colocalized retrocopies are more actively transcribed and translated and are more evolutionarily conserved than noncolocalized ones. The active transcription of colocalized retrocopies may result from their permissive epigenetic environment and shared regulatory elements with parental genes. Population genetic analysis of retroposed gene copy number variants in human populations revealed that retrocopy insertions are not entirely random in regard to interchromosomal interactions and that colocalized retroposed gene copy number variants are more likely to reach high frequencies, suggesting that both insertion bias and natural selection contribute to the colocalization of retrocopy-parent pairs. Further dissection implies that reduced selection efficacy, rather than positive selection, contributes to the elevated allele frequency of colocalized retroposed gene copy number variants. Overall, our results hint a role of interchromosomal colocalization in the "resurrection" of initially neutral retrocopies.

Brain Tumor Autophagy: A New Breakthrough in Cancer Research

Autophagy is the inherent, preserved cell breakdown that removes undesirable or imperfect factors through a lysosome- correspondent definite media. It slows down necrosis in cancer cells, which in ramble slows down the inflammation that comes before necrosis, which is understood to speed up neoplasm growth but whose exact cause is intimately unclear. Hence, autophagy is nowadays noted as a pivotal element since it stops the advancement of tumor by precluding cancer cells from ageing and turning on cell death. Yet, some autophagic pathways, alike the PI3K- AKT- mTOR pathway, also amplify tumor production. This pathway has steps like inauguration, nucleation, extension and conformation of double membrane vesicles understood as autophagosomes, which fuse with lysosomes in mammals and vacuoles in yeast and plants, for the degeneration of the intravascular cargo. Because, autophagy contributes to both tumorigenesis and tumor suppression, it isn’t easy to distinguish if it results in a positive or negative stasis for cell survival. So, autophagy should be acclimated in the molecular, cellular and epigenetic environment, to deduce variety of tumor cells, in high- grade gliomas. In this review, we talk over the aim of pathways, modulators and genes of autophagy in brain neoplasms.

The HIV-2 OGH double reporter virus shows that HIV-2 is less cytotoxic and less sensitive to reactivation from latency than HIV-1 in cell culture

A better understanding of HIV-1 latency is a research priority in HIV cure research. Conversely, little is known about the latency characteristics of HIV-2, the closely related human lentivirus. Though both viruses cause AIDS, HIV-2 infection progresses more slowly with significantly lower viral loads, even when corrected for CD4+ T cell counts. Hence a direct comparison of latency characteristics between HIV-1 and HIV-2 could provide important clues towards a functional cure.Transduction of SupT1 cells with single-round HIV-1 and HIV-2 viruses with an enhanced green fluorescent protein (eGFP) reporter showed higher levels of eGFP expression for HIV-2 than HIV-1, while HIV-1 expression appeared more cytotoxic. To compare HIV-1 and HIV-2 gene expression, latency and reactivation in more detail, we have generated HIV-2 OGH, a replication deficient, near full- length, double reporter virus that discriminates latently and productively infected cells in cell culture. This construct is based on HIV-1 OGH, and to our knowledge, first of its kind for HIV-2. Using this construct we have observed a higher eGFP expression for HIV-2, but higher losses of HIV-1 transduced cells in SupT1 and Jurkat cells and a reduced sensitivity of HIV-2 for reactivation with TNF-α. In addition, we have analysed HIV-2 integration sites and their epigenetic environment. HIV-1 and HIV-2 share a preference for actively transcribed genes in gene-dense regions and favor active chromatin marks while disfavoring methylation markers associated with heterochromatin. In conclusion the HIV-2 OGH construct provides an interesting tool for studying HIV-2 expression, latency and reactivation. As simian immunodeficiency virus (SIV) and HIV-2 have been proposed to model a functional HIV cure, a better understanding of the mechanisms governing HIV-2 and SIV latency will be important to move forward. Further research is needed to investigate if HIV-2 uses similar mechanisms as HIV-1 to achieve its integration site selectivity.

The Role of Circadian Rhythm in Autism Spectrum Disorder

With the development of technology and gradual enrichment in life, there is a significant increase in attention towards neurodevelopment and child health. Autism Spectrum Disorder (ASD) is defined as a neurological and developmental disorder that affects how people speak, behave, and interact with others. Communication and social interaction issues, sensory abnormalities, repetitive habits, and varying degrees of intellectual disability are some of the symptoms of autism. ASDs influences about 1 in 44 children in the USA, with the number of incidents sharply increasing over the years. Epigenetic neurobiology factors and environment related factors should both be considered when interpreting the pathophysiology that lies behind ASD. The 24-hour physiological cycle that displays an endogenous and entrainable oscillation is known as the circadian rhythm, which is generated by a molecular clock system. Mounting evidence are linking circadian rhythm disorder and autism. This includes sleep chaos as a common epiphenomenon of ASD, melatonin level disorder in ASD and circadian gene dysfunction in ASD. This article revolves around three perspectives: 1) Sleep Disorder in ASD 2) Role of Circadian Biomarkers in ASD 3) Variants and deficiency of circadian genes in ASD. In conclusion, the article reveals the important role circadian rhythm plays in neurodevelopmental processes. Through examining the circadian rhythm not only as an epiphenomenon but also as a possible indicator for ASD, the article anticipates the implication of circadian rhythm in novel treatments of ASD as a conclusion.

Epigenetics as a mediator of genetic risk in osteoarthritis: role during development, homeostasis, aging, and disease progression.

The identification of genomic loci that are associated with osteoarthritis (OA) has provided a starting point for understanding how genetic variation activates catabolic processes in the joint. However, genetic variants can only alter gene expression and cellular function when the epigenetic environment is permissive to these effects. In this review, we provide examples of how epigenetic shifts at distinct life stages can alter the risk for OA, which we posit is critical for the proper interpretation of genome-wide association studies (GWAS). During development, intensive work on the growth and differentiation factor 5 (GDF5) locus has revealed the importance of tissue-specific enhancer activity in controlling both joint development and the subsequent risk for OA. During homeostasis in adults, underlying genetic risk factors may help establish beneficial or catabolic "set points" that dictate tissue function, with a strong cumulative effect on OA risk. During aging, methylation changes and the reorganization of chromatin can "unmask" the effects of genetic variants. The destructive function of variants that alter aging would only mediate effects after reproductive competence and thus avoid any evolutionary selection pressure, as consistent with larger frameworks of biological aging and its relationship to disease. A similar "unmasking" may occur during OA progression, which is supported by the finding of distinct expression quantitative trait loci (eQTLs) in chondrocytes depending on the degree of tissue degradation. Finally, we propose that massively parallel reporter assays (MPRAs) will be a valuable tool to test the function of putative OA GWAS variants in chondrocytes from different life stages.

Epigenetic reprogramming of cancer stem cells to tumor cells using ultrasmall gold nanoparticle

Epigenetic reprogramming of cancer stem-like cells (CSC) is crucial to the clinical implementation of efficient tumor management. Groups of methylation on genomic DNA are a relatively stable epigenetic component. They are key drivers in the formation and maintenance of CSCs. Hence, reprogramming the DNA methylation epigenetics can provide new insights into cancer therapeutic approaches. Nanoprobes can influence CSC epigenetics; however, existing nanoprobes induce epigenetic alterations in an unregulated manner, which might result in undesirable mutation accumulation, which can hinder the reprogramming process. Here we report an epigenetic reprogramming approach with an ultrasmall Au NP, which can demethylate the genomic DNA, thereby causing the reprogramming of CSCs to cancer cells. In vitro bench top verification on preclinical models of non-metastatic and metastatic lung CSC showed a significant decrease in genetic, phenotypic stemness, and cell cycle quiescence, validated with biological assays. Furthermore, the ultrasmall Au NP was shown to interact with the epigenetic environment of CSCs through gold-DNA affinity spectral analysis. The pilot clinical validation study established the potential of our approach for clinical implementation. To the best of our knowledge, this is the first study to demonstrate a CSC epigenetic reprogramming using nanoparticles. In summary, this paper demonstrated that the nanoprobe could actively modify epigenetics and, as a result, can be employed to mitigate CSC stemness. Our findings might pave the path for more effective anti-cancer treatments and precision nanomedicine in the future.

ODP403 Diversity of Estrogen-Responsive Genes in Endometriotic Lesions

Abstract Background Endometriosis has been accepted as an estrogen-dependent disease for more than two decades. So far, estrogen modulators that targeting estrogen depletion in endometriotic lesions have been expected as the first option of treatments to improve the symptoms associated with endometriosis. However, the limits of treatment are becoming apparent. Objective As the background of limits, we hypothesized the heterogeneity of genetic and/or epigenetic environments in endometriotic lesions (1). To test our hypothesis, we examined the expression profile of estrogen-responsive genes using endometriotic stromal cells as a model. Patients: Institutional Review Boards approved this project. We obtained informed consent from all patients. The chocolate cyst lining in the ovaries of patients with endometriosis was the source of endometriotic tissue. As a control, the eutopic endometrial tissues were obtained from uteri of premenopausal women who had uterine leiomyoma. Methods Stromal cells were prepared from endometriotic and endometrial tissues. ESR1 and ESR2 expression were evaluated using RT-PCR (2). For RNA-seq analysis of estrogen-responsive genes, total cellular RNAs from endometriotic cells treated with or without 10nM estradiol for 8hr were prepared. Following the quality control (concentration>50ng/ul, RIN>9), RNA samples were used for polyA+ selected library preparation and the strand-specific RNA-seq (NovaSeq, DNBSEQ-G400, 20M paired- end (PE) reads and 2×150bp PE/sample). Estrogen-responsive genes were extracted using RNA-seq bioinformatics analysis. Genes with adjusted p-values < 0. 05 and absolute log2 fold changes > 1 were extracted as estrogen-responsive genes (DESeq2 BP). Principal component analysis (PCA) was used to visualize sample-to-sample distances. Differential gene GO enrichment analysis was performed (GOseq. v1.34.1). Results 1) wild type ERα mRNA expression in endometriotic cells was one-tenth of that in endometrial cells. wild type ERβ1 and the splice variant ERβ2 mRNAs were expressed in endometriotic cells at a comparable level of the ERα. 2) PCA suggested the presence of at least two cell types in endometriotic cells. 3) Cluster analysis of gene expression suggested the presence of 2 cell types: endometriotic cells with or without GATA6 expression (3). 4) Estrogen-responsive genes were significantly different among the cells examined. 4) Differential gene GO enrichment analysis suggested the diversity of gene expression profiles depending on the cells. Conclusion In the hope of overcoming the limits of endocrine-targeted therapy in endometriosis, we examined the estrogen-responsive genes in endometriotic cells. The finding suggests the diversity of estrogen-responsive genes in endometriotic lesions. References(1) Fertil Steril (2019) 111: 327–39. (2) Reprod Sci (2016) 23: 871-6. (3) Am J Reprod Immunol (2019) 81: e13078. Presentation: No date and time listed

The 'Alu-ome'shapes the epigenetic environment of regulatory elements controlling cellular defense.

Promoters and enhancers are sites of transcription initiation (TSSs) and carry specific histone modifications, including H3K4me1, H3K4me3, and H3K27ac. Yet, the principles governing the boundaries of such regulatory elements are still poorly characterized. Alu elements are good candidates for a boundary function, being highly abundant in gene-rich regions, while essentially excluded from regulatory elements. Here, we show that the interval ranging from TSS to first upstream Alu, accommodates all H3K4me3 and most H3K27ac marks, while excluding DNA methylation. Remarkably, the average length of these intervals greatly varies in-between tissues, being longer in stem- and shorter in immune-cells. The very shortest TSS-to-first-Alu intervals were observed at promoters active in T-cells, particularly at immune genes, where first-Alus were traversed by RNA polymerase II transcription, while accumulating H3K4me1 signal. Finally, DNA methylation at first-Alus was found to evolve with age, regressing from young to middle-aged, then recovering later in life. Thus, the first-Alus upstream of TSSs appear as dynamic boundaries marking the transition from DNA methylation to active histone modifications at regulatory elements, while also participating in the recording of immune gene transcriptional events by positioning H3K4me1-modified nucleosomes.

Epigenetic Analysis of Different Tissues using Oxford Nanopore Technology

Global changes in the epigenetic landscape are hallmarks of cancer and many other diseases. One component of cancer epigenetics is DNA methylation. DNA methylation is responsible for regular biological processes, but decreased methylation leads to changes in gene expression which leads to an increase in cancerous activity. Methylation analysis allows insights into gene regulation and disease predispositions. Many different technologies are able to analyze DNA methylation through DNA/RNA sequencing. Nanopore Technology is used to analyze, in real time, long nucleotide fragments. The technology works by monitoring changes in electrical current through the membrane within the flow cell. Tissue samples were collected, and DNA was extracted using the Monarch Genomic DNA Purification Kit. Nanopore’s Rapid Sequencing Kit/Protocol was used to carry out the DNA extraction steps before sequencing. Real time DNA sequencing was conducted using Nanopore’s MINION and Flongle Cell. Epigenetic analysis was performed using secondary softwares Megalodon, Guppy basecaller, and EPI2ME. Studying epigenetic environments can furtherer understanding of disease etiology and understanding the function of diagnostic biomarkers.

MiR-27b inhibition contributes to cytotoxicity in patulin-exposed HEK293 cells

Patulin (PAT) is a mycotoxin produced by Penicillium and other fungi that contaminate fruit. PAT targets the kidney and is associated with nephrotoxicity. Micro-RNAs (miRNA) may offer new insights into PAT-induced nephrotoxicity. Cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1), involved in metabolism of dietary toxins is negatively regulated by miR-27b and linked with the nuclear factor kappa B (NF-κB) pathway and peroxisome proliferator activated receptor gamma (PPARɣ) in renal fibrosis. This study investigated the effects of PAT on miR-27b, CYP1B1, PPARɣ and cytotoxicity in human kidney (HEK293) cells.HEK293 cells were exposed to PAT (2.5 μM, 24h). Protein expression of CYP1B1, PPARɣ, NF-κB (p65), pNF-κB (p65) (phospho-Ser563) and cleaved PARP-1 was quantified using western blotting. QPCR evaluated mRNA levels of CYP1B1, IL-6, miR-27b, OGG1, mtDNA, TFAM and UCP2. Mitochondrial membrane potential and phosphatidylserine (PS) externalization was evaluated by flow cytometry while levels of ATP and caspase −9, −8, −3/7 activity was measured using luminometry.PAT significantly decreased miR-27b levels (p = 0.0014) and increased CYP1B1 mRNA (p = 0.0015) and protein (p = 0.0013) levels. PPARɣ protein expression was significantly increased (p = 0.0002) and associated with decreased NF-κB activation (p = 0.0273) and IL-6 mRNA levels (p = 0.0265). Finally, PAT significantly compromised mitochondrial repair mechanisms and increased apoptotic biomarkers.PAT altered miR-27b levels and PPARɣ, with associated changes to NF-κB activation, downstream IL-6 and CYP1B1 expression. These results show that PAT impairs detoxification mechanisms leading to mitochondrial damage and apoptosis. In conclusion, PAT altered the epigenetic environment and impaired detoxification processes, supporting a mechanism for nephrotoxic outcomes.

Mutational synergy during leukemia induction remodels chromatin accessibility, histone modifications and three-dimensional DNA topology to alter gene expression.

Altered transcription is a cardinal feature of acute myeloid leukemia (AML), however, exactly how mutations synergize to remodel the epigenetic landscape and rewire 3-Dimensional (3D) DNA topology is unknown. Here we apply an integrated genomic approach to a murine allelic series that models the two most common mutations in AML, Flt3-ITD and Npm1c. We then deconvolute the contribution of each mutation to alterations of the epigenetic landscape and genome organization, and infer how mutations synergize in the induction of AML. Our studies demonstrate that Flt3-ITD signals to chromatin to alter the epigenetic environment and synergizes with Npm1c mutation to alter gene expression and drive leukemia induction. These analyses also allow the identification of long-range cis-regulatory circuits, including a novel super-enhancer of Hoxa locus, as well as larger and more detailed gene-regulatory networks, driven by transcription factors including PU.1 and IRF8, whose importance we demonstrate through perturbation of network members.

Introgressed DNA within a Zea mays near-isogenic line displays lower levels of 24nt sRNA expression than the homologous region from the recurrent parent

Near-isogenic lines (NILs) are classical genetic tools used to dissect the actions of an allele when placed in a uniform genetic background. Although the goal of NIL creation is to examine the effects of a single allele in isolation, DNA linked to the allele is invariably retained and can confound any allele-specific effects. In addition to genetic variation, highly polymorphic species such as Zea mays will contain introgressed polymorphisms encompassing transposable elements (TEs) and the cis-acting small RNA (sRNA) that represses them. Through transcriptomics, we described the differences in sRNA and TE transcriptional expression between a W22-derived introgression and its homologous B73 region. As anticipated, many differences in sRNA expression were observed. Unexpectedly, however, 24nt sRNA expression over the introgressed region was low overall compared to both the homologous B73 region and the rest of the genome. Across the introgression, low sRNA expression was accompanied by increased TE transcription. Possible explanations for the observed trends in sRNA and TE expression across the introgression region are discussed. These findings support the notion that any introgressed allele is in an epigenetic environment distinct from that found at the allele from the recurrent parent. Additionally, these results suggest that further study of sRNA expression levels during the introgression process is warranted.

The lncRNA APOLO interacts with the transcription factor WRKY42 to trigger root hair cell expansion in response to cold

Plant long noncoding RNAs (lncRNAs) have emerged as important regulators of chromatin dynamics, impacting on transcriptional programs leading to different developmental outputs. The lncRNA AUXIN-REGULATED PROMOTER LOOP (APOLO) directly recognizes multiple independent loci across the Arabidopsis genome and modulates their three-dimensional chromatin conformation, leading to transcriptional shifts. Here, we show that APOLO recognizes the locus encoding the root hair (RH) master regulator ROOT HAIR DEFECTIVE 6 (RHD6) and controls RHD6 transcriptional activity, leading to cold-enhanced RH elongation through the consequent activation of the transcription factor gene RHD6-like RSL4. Furthermore, we demonstrate that APOLO interacts with the transcription factor WRKY42 and modulates its binding to the RHD6 promoter. WRKY42 is required for the activation of RHD6 by low temperatures and WRKY42 deregulation impairs cold-induced RH expansion. Collectively, our results indicate that a novel ribonucleoprotein complex with APOLO and WRKY42 forms a regulatory hub to activate RHD6 by shaping its epigenetic environment and integrate signals governing RH growth and development.

Reconsidering LINE-1's role in cancer: does LINE-1 function as a reporter detecting early cancer-associated epigenetic signatures?

Long interspersed nuclear element-1 (LINE-1 or L1) is the only autonomously active retrotransposon in humans. While L1 has been implicated in several pathologies and the aging process, I present a model which challenges an understanding of L1 as predominantly antagonistic to human health. I hypothesize that L1 serves as a reporter in an early cancer alert system: a tripwire strung throughout the genome poised to trigger p53 and a type I interferon (IFN-1) response when the epigenetic landscape portends cancer. Cell proliferation and a shift to aerobic glycolysis cause dramatic changes in the epigenome which are permissive to L1’s escape from suppression. L1 has several properties which make it particularly apt to fulfill this hypothesized sentinel function. Being present in many copies spread throughout the genome allows it to monitor many regions for epigenetic instability and renders it robust to deactivation by mutation. This proposed cancer alert system would alter the cancer cell fitness landscape discouraging the use of growth-favoring aerobic glycolysis by threatening the activation of tumor-suppressive mechanisms. It also imposes costs on a strategy of non-specific global transcriptional derepression aimed at activating oncogenes. Erroneous activations of this system are predicted to increase the rate of aging, suggesting this represents a case of antagonistic pleiotropy trading prolonged youth for cancer prevention. More research is needed to assess this model. Lay summary: During carcinogenesis the epigenome is remodeled by the Warburg effect and cellular proliferation. These processes globally relax chromatin. This epigenetic environment is permissive to the retrotransposon long interspersed nuclear element-1’s (LINE-1 or L1) escape from suppression. I hypothesize and present evidence for the notion that L1 has been co-opted to serve as a reporter in an early cancer alert system, poised to trigger tumor suppressive mechanisms when the epigenetic landscape portends cancer. This hypothesis describes a potentially major means by which transformation is thwarted early on.