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Results for “Chromatin Immunoprecipitation Sequencing”

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PubMed2026

Chromatin-binding protein HMGN1 promotes HCC tumorigenesis via histone methylation-induced RALB transcriptional suppression.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with metastasis being the primary cause of its high mortality. The chromatin-binding protein, high mobility group nucleosome binding domain 1 (HMGN1), has been implicated in tumour progression, but its specific role and mechanism in HCC metastasis remain unclear. This study investigates the function of HMGN1 and its potential as a therapeutic target. Analysis of patient samples confirms an upregulation of HMGN1 in HCC tissues, correlating with advanced disease and poor prognosis. Functional assays demonstrate that HMGN1 promotes HCC metastasis in vitro and in vivo. Mechanistically, integrated RNA sequencing and chromatin immunoprecipitation sequencing analyses reveal that HMGN1 binds to the promoter of RAS-like proto-oncogene B (RALB) gene, recruiting the repressive histone mark H3K9me2 to epigenetically silence its transcription and drive metastasis. Therapeutically, a nanoparticle delivery system for siRNA against HMGN1 effectively silences its expression and inhibits metastasis in orthotopic liver xenograft tumour models. Our findings establish HMGN1 as a key epigenetic driver of HCC metastasis and highlight siRNA-nanoparticle targeting of HMGN1 as a promising precision therapeutic strategy.

Humans↗

PubMed2026

Detecting Meiotic Crossing-Overs in Maize Using Chromatin Immunoprecipitation-Sequencing (ChIP-seq).

During meiosis, homologous chromosomes engage in reciprocal exchanges of segments in a process known as crossing over (CO). About 85% of CO events in maize are products of the class I pathway. Class I COs are interference-sensitive, meaning that the formation of one CO reduces the likelihood of another CO forming close by. This protocol describes a chromatin immunoprecipitation-sequencing (ChIP-seq)-based method for mapping meiotic COs in maize, using an antibody against MutL Homolog 3 (MLH3), a key component of the class I CO pathway. CO sites are determined by Illumina sequencing of DNA isolated from MLH3-associated chromatin fragments. Traditionally, COs have been identified through genetic mapping, which relies on the segregation of genetic markers in the progeny of hybrid plants. However, conventional genetic mapping provides limited resolution and requires large numbers of progeny individuals. The MLH3 ChIP-seq approach enables direct detection of COs, providing high-resolution and genome-wide coverage, including genome regions with low DNA sequence polymorphism, which are inaccessible to genetic CO mapping. Furthermore, MLH3 ChIP-seq enables screening of thousands of CO events, greatly accelerating the analysis and reducing its cost. This protocol can also be used to examine any chromatin-bound meiotic proteins and adapted to studying chromatin-associated proteins in somatic cells.

Journal Article↗

PubMed2026

Improved spike-in normalization clarifies the relationship between active histone modifications and transcription.

Spike-in normalization enables quantitative analysis of chromatin immunoprecipitation sequencing (ChIP-seq) signal. Here we introduce a robust dual spike-in normalization approach for ChIP-seq (ChIP-wrangler), optimize parameters and verify its accuracy in quantifying changes in ChIP-seq signal and detecting technical artifacts. We use ChIP-wrangler to revisit recent claims that active histone marks depend on transcription. We show that acute depletion of RNA polymerase II (RNAPII) has a modest impact on H3K27ac levels, with only 6% of peaks significantly changing after RNAPII depletion, indicating that histone acetylation maintenance is not entirely dependent on ongoing transcription. Promoters and enhancers are differentially affected, with 82% of decreasing acetylation peaks located at promoter-distal elements with enhancer-related motifs. ChIP-wrangler provides increased rigor and 'guardrails' for successful spike-in normalization and, as applied here, refines the understanding of crosstalk between RNAPII activity and transcription-associated histone marks.

Histones↗

PubMed2025

3D chromatin structures precede genome activation in Drosophila embryogenesis.

3D chromatin structure is critical for the regulation of gene expression during development. Here we used Micro-C assays at 100-bp resolution to map genome organization in Drosophila melanogaster throughout the first half of embryogenesis. These high-resolution contact maps reveal fine-scale features such as loops and boundaries delineating topologically associating domains. Notably, we observe that 3D chromatin structures form prior to zygotic genome activation and persist during successive mitotic cycles. Integrative analysis with 149 public chromatin immunoprecipitation sequencing (ChIP-seq) datasets identifies four classes of chromatin structuring elements, including a distinct group enriched for GAGA-associated factor (GAF) and Zelda binding, associated with developmental-gene regulation. These elements are mitotically retained and exhibit sequence and structure similarity between D. melanogaster and D. virilis. We propose that 3D chromatin organization in the pre-cellular embryo facilitates deployment of developmentally regulated genes during Drosophila embryogenesis.

Animals↗

PubMed2026

GHT-SELEX demonstrates unexpectedly high intrinsic sequence specificity and complex DNA binding of many human transcription factors.

There is ongoing debate regarding the degree to which transcription factors (TFs) independently specify genomic binding: TF binding motifs are typically short and degenerate, yielding many more binding site predictions than observed in cells. Here we present genomic high-throughput SELEX (GHT-SELEX)-a scalable method that surveys intrinsic binding of purified TFs to the fragmented, naked and unmodified genome. GHT-SELEX peaks for 179 diverse human TFs display surprisingly high overlap with chromatin immunoprecipitation sequencing peaks for the same TF. Comparable overlap can be obtained from motifs using appropriate analytical approaches. For C2H2 zinc finger (zf) proteins-the largest class of human TFs-GHT-SELEX shows that modular, alternative engagement of C2H2-zf domains is the norm, enabling several types of distinct target sites, and frequently involving internal duplication and divergence within the C2H2-zf array. Altogether, it is common for TFs to delineate a large fraction of in vivo genomic binding sites independently of other cellular factors.

Humans↗

PubMed2026

The TUBG meshwork is associated with centromere dynamics and micronuclear organization.

This study investigates how γ-tubulin and the centrosome contribute to interphase centromere dynamics and nuclear organization. Although classically associated with mitotic microtubule nucleation, here we show that γ-tubulin associates with chromatin and is enriched within centromere-defined volumes. Using live-cell imaging, immunofluorescence, and chromatin immunoprecipitation sequencing, we detect γ-tubulin-associated signal at satellite-rich, centromere-proximal chromatin. Reduced γ-tubulin levels are associated with increased centromere fluorescence intensity and reduced mobility, linking the γ-tubulin network to centromere organization. Under acute cisplatin-induced stress, centromere mobility increases, whereas centromere clustering is observed in separate fixed-cell analyses. Ser131 phosphorylation is associated with γ-tubulin self-assembly and centromere-related dynamics. Additionally, γ-tubulin accumulates in micronuclei, coinciding with increased replication-associated signal and DNA fluorescence. In primary clear cell renal cell carcinoma cells, stress is associated with higher γ-tubulin fluorescence intensity within centromere-defined volumes. Together, these findings support an association between the γ-tubulin meshwork and centromere organization, chromatin compartmentalization, and responses to genomic stress.

Centromere↗

PubMed2025

ChIP-Rx: Arabidopsis Chromatin Profiling Using Quantitative ChIP-Seq.

Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) is widely used to probe the chromatin landscape of transcription factors, chromatin components, and associated proteins. Conventional ChIP normalization procedures robustly allow estimating differences in local enrichment across genomic regions. Yet, inter-sample comparisons can be biased by technical variability and biological differences. This is notably the case when samples display large differences in the abundance of the target protein or its enrichment at chromatin. For example, epigenome defects are improperly detected or quantified upon large-effect genetic or chemical inhibition of chromatin modifiers. To circumvent these caveats and robustly determine biological variations while minimizing technical variability, ChIP adaptations using an external reference have flourished. Here, we describe a step-by-step protocol employing a reference exogenous chromatin (ChIP-Rx) that allows absolute comparisons of epigenome variations in Arabidopsis samples displaying drastic differences in chromatin mark abundance. In contrast to the originally published ChIP-Rx approach, which assumes that exogenous spike-in references are constant across samples, the method detailed here involves the sequencing of each input sample to account for technical variability in initial reference chromatin contents. We also report a detailed computational workflow with an accompanying Github resource to help in calculating spike-in normalization factors, applying them to normalize epigenome tracks, and performing spike-in normalized inter-sample differential analyses. We propose two ways of computing the spike-in factor: a classically used method based on raw counts and a noise-corrected method using peak detection on the exogenous genome.

Arabidopsis↗

PubMed2025

ATAC-seq for Characterizing Host and Pathogen Genome Accessibility During Virus Infection.

Chromatin regulation provides a mechanism through which cells dynamically and rapidly regulate their gene expression profiles, playing a pivotal role in diverse biological processes and disease states. The Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) is a method that enables genome-wide detection of accessible chromatin regions, providing information on nucleosome positioning and the epigenetic regulation of the chromatin structure. ATAC-seq has been used in various biological contexts, and several reports have demonstrated its application to studying infections with viral or bacterial pathogens. The ability to characterize changes in viral or bacterial genome accessibility during infections provides insights into both pathogen replication and host defense mechanisms. Viral genomes undergo dynamic changes in their structural landscape to facilitate replication and evade host immune responses. Additionally, host cells encode DNA sensors, which are specialized proteins that bind to viral genomes to initiate innate immune responses and sometimes, to suppress viral gene expression. ATAC-seq enables the systematic detection of key structural changes on the viral genome mediated by either viral or host proteins, offering mechanistic insights into virus-host interactions. Here, we describe an ATAC-seq method optimized for studying changes in chromatin accessibility in both host and viral genomes. We have previously applied this method to demonstrate a systematic decrease in the genome accessibility of herpes simplex virus type I (HSV-1) enabled by a host antiviral factor, the interferon-gamma inducible protein 16 (IFI16) during infection of human fibroblasts. This protocol can be adapted to various biological contexts involving the introduction of foreign DNA, making it a valuable tool for a broad range of research endeavors.

Humans↗

PubMed2024

PML::RARA and GATA2 proteins interact via DNA templates to induce aberrant self-renewal in mouse and human hematopoietic cells.

The underlying mechanism(s) by which the PML::RARA fusion protein initiates acute promyelocytic leukemia is not yet clear. We defined the genomic binding sites of PML::RARA in primary mouse and human hematopoietic progenitor cells with V5-tagged PML::RARA, using anti-V5-PML::RARA chromatin immunoprecipitation sequencing and CUT&RUN approaches. Most genomic PML::RARA binding sites were found in regions that were already chromatin-accessible (defined by ATAC-seq) in unmanipulated, wild-type promyelocytes, suggesting that these regions are "open" prior to PML::RARA expression. We found that GATA binding motifs, and the direct binding of the chromatin "pioneering factor" GATA2, were significantly enriched near PML::RARA binding sites. Proximity labeling studies revealed that PML::RARA interacts with ~250 proteins in primary mouse hematopoietic cells; GATA2 and 33 others require PML::RARA binding to DNA for the interaction to occur, suggesting that binding to their cognate DNA target motifs may stabilize their interactions. In the absence of PML::RARA, Gata2 overexpression induces many of the same epigenetic and transcriptional changes as PML::RARA. These findings suggested that PML::RARA may indirectly initiate its transcriptional program by activating Gata2 expression: Indeed, we demonstrated that inactivation of Gata2 prior to PML::RARA expression prevented its ability to induce self-renewal. These data suggested that GATA2 binding creates accessible chromatin regions enriched for both GATA and Retinoic Acid Receptor Element motifs, where GATA2 and PML::RARA can potentially bind and interact with each other. In turn, PML::RARA binding to DNA promotes a feed-forward transcriptional program by positively regulating Gata2 expression. Gata2 may therefore be required for PML::RARA to establish its transcriptional program.

Animals↗

PubMed2026

ATX1-COMPASS-like complex participates in the bud dormancy release of tree peony by regulating H3K4me3 modification.

Bud dormancy release in woody plants is crucial for survival, regrowth, flowering, and fruiting. Tree peony (Paeonia suffruticosa), an important ornamental and economic plant, undergoes bud endodormancy in winter, and sufficient chilling duration and exogenous gibberellins (GAs) can effectively break the dormancy. However, the epigenetic regulation mechanism remains poorly understood. Here, immunoblotting revealed that H3K4me3, but not H3K4me1 or H3K4me2, was associated with chilling- and GA3-induced dormancy release. Chromatin immunoprecipitation sequencing (ChIP-seq) combined with RNA-seq results revealed that H3K4me3 enriched near transcription start sites (TSS). H3K4me3 enrichment genes (HEGs) and differentially expressed genes (DEGs) were commonly enriched in KEGG pathways, such as plant hormone signal transduction and MAPK signaling. The expression patterns of these marker genes, such as EARLY BUD-BREAK 3 (PsEBB3), CYCLIND3.1 (PsCYCD3.1), CYCLIND3.3 (PsCYCD3.3), and β-1,3-glucanase 6 (PsBG6), were correlated with their H3K4me3 enrichment and were validated by chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR). Four COMPASS-like component homologs and one histone methyltransferase were screened; among them, PsWDR5a, PsRBL, PsASH2R, and PsATX1 were upregulated by prolonged chilling and GA3 treatments. Yeast two-hybrid (Y2H), yeast three-hybrid (Y3H), luciferase complementation (LCA), and co-immunoprecipitation (Co-IP) analyses revealed that PsRBL interacts with PsWDR5a and PsASH2R as a bridge. PsATX1 was confirmed as an H3K4me3 methyltransferase and interacted with PsWDR5a and PsRBL to form the PsATX1-COMPASS-like complex using Y2H, LCA, and Co-IP assays. Functional analyses showed that PsWDR5a, PsRBL, PsASH2R, and PsATX1 significantly promoted budburst by elevating genomic H3K4me3 levels. Our findings provide insights into the epigenetic regulation of dormancy transitions in woody perennials.

Histones↗

PubMed2026

Decreased H3K79 acetylation and dysregulation of neurodevelopmental genes in fetal down syndrome.

BACKGROUND: Down syndrome (DS), the most prevalent chromosomal disorder caused by trisomy 21, manifests intellectual disability and cognitive dysfunction. Cumulative studies confirm epigenetic pathways including DNA methylation and non-coding RNAs drive DS pathological progression. Histone post-translational modifications (PTMs) are core epigenetic regulators of fetal brain development. However, genome-wide PTM alterations and their downstream functions in fetal DS brains remain poorly characterized, leaving a key gap in revealing epigenetic mechanisms underlying DS neurodevelopmental defects. To address this, we aimed to establish the first comprehensive landscape of histone PTMs in fetal DS cortex and investigate whether specific PTM changes contribute to aberrant neurodevelopmental gene expression. METHODS: Fetal cortexs from control and DS groups were subjected to global histone modification profiling via high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). We detected mono-, di-, and tri-methylation, acetylation, homocysteinylation and malonylation on all four core histones (H2A, H2B, H3, H4). Chromatin immunoprecipitation sequencing (ChIP-seq) was used to map genomic binding profiles of H3 lysine 79 acetylation (H3K79ac). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to quantify mRNA levels of candidate neurodevelopmental genes. RESULTS: HPLC-MS/MS analysis identified 172 distinct histone PTMs in control fetal cortices and 168 PTMs in DS fetal cortical samples. Quantitative comparison of 22 quantifiable histone PTMs revealed that H3K79ac showed the most prominent reduction in DS samples, with a 34% decrease (P<0.05). Chromatin immunoprecipitation (ChIP)-seq verified specific H3K79ac occupancy at the genomic loci of three vital neurodevelopmental genes: TNFSF13B, NXPH1 and CAMK4. Correspondingly, qRT-PCR revealed aberrant transcription levels of these three genes in DS fetal cortices. CONCLUSIONS: This study establishes the first quantitative landscape of histone PTMs in in DS fetal cortical tissues. We demonstrate that depleted H3K79ac acts as a candidate epigenetic driver of DS neuropathology by disrupting the transcription of critical neurodevelopmental genes. This work reveals a novel epigenetic mechanism and a promising therapeutic target for DS-related neurodevelopmental disorders.

Down syndrome (DS)↗

PubMed2026

Driver genomic lesions in MDM2, CDK4, and JUN co-opt targetable super-enhancer networks to impose liposarcomagenic core regulatory circuitry.

INTRODUCTION: Amplification of chromosome 12q13-15 spanning MDM2 and CDK4 genes serves as a molecular diagnostic hallmark of dedifferentiated liposarcoma (DDLPS), an aggressive soft-tissue sarcoma. Epigenetic activation of master transcription factors (RUNX proteins, FOSL2, and MYC) establishes a self-reinforcing oncogenic transcriptional circuitry in DDLPS. Nevertheless, the collaborative interplay between genomic alterations and epigenetic dysregulation in defining DDLPS cell identity remains elusive. OBJECTIVES: This work aimed to elucidate the primary genetic drivers and mechanistic basis of DDLPS-specific core transcriptional regulatory circuitry. METHODS: We performed integrative chromatin profiling analysis of DDLPS clinical specimens and cell lines to map cis-regulatory landscapes. Cistromes of MDM2, JUN, and E2F1 were delineated through chromatin immunoprecipitation sequencing in two DDLPS models. Essential driver functions and transcriptional regulatory effects of key regulators were assessed via various genetic manipulation approaches. Synergistic interactions between BET-targeting agents and MDM2/p53 or CDK4 inhibitors were quantified by cell viability assays. In vivo xenograft assays evaluated the oncogenic potential of key regulators and the therapeutic efficacy of novel strategies. RESULTS: Co-amplification of MDM2, CDK4, and JUN during sarcomagenesis converges with BET protein-dependent chromatin remodeling to fuel feed-forward transcriptional circuits among master transcription factors. Mechanistically, excessively expressed MDM2 stabilizes the core regulatory circuitry by forming chromatin-bound complexes with JUN/FOSL2 at cis-regulatory elements, especially super-enhancers across DDLPS genome. Concurrently, CDK4 maintains expression of E2F1 which further fosters transcriptional output of master transcription factors in DDLPS cells. Leveraging DDLPS-selective overexpression of MDM2 and its E3 ligase activity, targeted degradation of BET proteins by MDM2-recruiting proteolysis targeting chimera selectively disrupted the core regulatory circuitry, suppressing DDLPS growth and exhibiting strong synergy with CDK4 inhibitor. CONCLUSION: DDLPS-associated genomic lesions collaborate with BET-dependent chromatin regulation to establish disease-sustaining transcriptional circuitry. Our findings also provide a mechanistic rationale for harnessing MDM2's E3 ligase activity to therapeutically degrade oncoproteins in MDM2-amplified malignancies.

Core transcriptional regulatory circuitry↗

PubMed2026

Ovarian H3K27ac remodeling is associated with impaired follicular development in laying hens with fatty liver hemorrhagic syndrome.

Fatty liver hemorrhagic syndrome (FLHS) is a metabolic disease of laying hens that reduces egg production and is accompanied by reproductive impairment, but the ovarian regulatory mechanisms that connect nutritional stress to follicular dysfunction remain unclear. This study examined whether active chromatin remodeling in the ovary is associated with FLHS induced by a high-energy, low-protein (HELP) diet. Hy-Line Brown hens were assigned to a basal diet or HELP diet, and ovarian tissue was collected for histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing and RNA sequencing. The HELP diet reduced laying performance and the numbers of small yellow and hierarchical follicles, indicating compromised follicular development. Genome-wide H3K27ac profiling identified 2,111 regions with lower acetylation and 1,707 regions with higher acetylation in FLHS ovaries. Genes linked to differential H3K27ac regions were enriched in pathways related to oocyte meiosis, cell cycle control, FoxO signaling, gonadotropin-releasing hormone signaling, and steroid hormone biosynthesis. RNA sequencing identified 341 differentially expressed genes, with a predominance of downregulated genes. Integration of chromatin and transcriptome data highlighted folliculogenesis-related genes, including FGF1, FGF9, and MMP10, that showed reduced H3K27ac enrichment together with decreased expression. Super-enhancer analysis further identified 131 regions with reduced H3K27ac signal in FLHS ovaries, including regions located near PCNA and RAP1A, two genes involved in cellular proliferation and survival signaling. Motif enrichment of differential H3K27ac regions implicated Fos, SF-1/NR5A1, and GATA-4 as candidate transcriptional regulators. These findings indicate that HELP diet-induced FLHS is associated with broad attenuation of active ovarian regulatory elements and reduced expression of genes required for follicle growth, tissue remodeling, and steroidogenic function. The study provides an ovarian epigenomic framework for understanding reproductive decline in FLHS-affected laying hens.

Fatty liver hemorrhagic syndrome↗

PubMed2026

Chromatin Remodeling Subunit ARID1A Negatively Regulates the Malignant Progression of Gastrointestinal Stromal Tumors by Targeting the MEMO1 Promoter.

Gastrointestinal stromal tumors (GISTs) are the most common sarcomas of the alimentary tract and are primarily characterized by malignant progression, a major cause of mortality. AT-rich interaction domain 1A (ARID1A), a core component of the chromatin-remodeling SWI/SNF complex, has been found to correlate with GIST tumor grade, although the underlying mechanism remains unclear. Its frequent inactivation across diverse cancer types reveals pleiotropic roles that intersect multiple hallmarks of cancer. In this study, we aimed to investigate the potential relationship between ARID1A and malignant progression in GISTs, as well as the underlying mechanism. Western blotting, real-time polymerase chain reaction, and immunohistochemistry were used to assess ARID1A expression in GIST tissues. Cell Counting Kit-8 (CCK-8) assays were performed to evaluate cell proliferation. Wound-healing and Transwell assays were conducted to assess cell migration and invasion. Flow cytometry was used to analyze apoptosis and cell cycle distribution. Label-free quantitative proteomics and chromatin immunoprecipitation sequencing (ChIP-seq) were employed to identify top candidate downstream targets of ARID1A. ARID1A expression was decreased in high-risk GIST tissues. Furthermore, ARID1A knockdown in GIST cells promoted proliferation and metastasis both in vitro and in vivo, and led to reduced apoptosis and impaired cell cycle arrest. We further demonstrated that ARID1A suppresses GIST proliferation and metastasis by inhibiting MEMO1 expression and inactivating the ERK1/2 signaling pathway. Notably, this regulatory axis was observed in KIT-null GIST cells, indicating that the ARID1A-MEMO1 pathway may function independently of canonical KIT signaling. Thus, ARID1A inhibits malignant progression in GISTs, providing new insights into its role in the prevention and treatment of human GISTs and suggesting its potential as a biomarker of malignant progression in GISTs.

Humans↗

PubMed2026

Histone deacetylases: From acetylation homeostasis to oncogenic and neurodegenerative disorders.

Histone deacetylases (HDACs) are central regulators of acetylation homeostasis, governing chromatin architecture, transcriptional dynamics, and diverse cellular processes through reversible lysine deacetylation. Dysregulation of HDAC activity disrupts epigenetic balance and is strongly implicated in oncogenic transformation and the progression of neurodegenerative disorders. This chapter provides a comprehensive overview of HDAC biology with a particular emphasis on experimental and analytical methodologies used to investigate their function. We describe the structural and functional diversity of HDAC classes and their roles in multiprotein complexes that regulate gene expression and cellular signaling. A major focus is placed on screening-compatible and mechanistic assays, including fluorometric, colorimetric, radiometric, fluorescence polarization, TR-FRET, AlphaScreen/AlphaLISA, and differential scanning fluorimetry approaches for quantitative measurement of enzymatic activity and inhibitor profiling. In addition, advanced methodologies such as mass spectrometry-based acetylome analysis, chromatin immunoprecipitation sequencing (ChIP-seq), recombinant enzyme assays, and cell-based reporter systems are discussed in the context of functional genomics and drug discovery. The integration of high-throughput screening, structural biology, and multi-omics strategies is highlighted as essential for dissecting HDAC-mediated regulatory networks. Collectively, this chapter serves as a methodological framework for studying HDAC function and developing targeted epigenetic therapies in cancer and neurodegenerative diseases.

Histone Deacetylases↗

PubMed2026

Super enhancer-driven transcriptional reprogramming promotes abiraterone resistance via neuroendocrine transition and ferroptosis evasion in castration-resistant prostate cancer.

Abiraterone resistance represents a major clinical challenge in the management of castration-resistant prostate cancer (CRPC), yet the epigenetic mechanisms that sustain this resistance remain poorly understood. In particular, how super enhancers (SEs) reprogram transcriptional networks to promote this therapy resistance has not been fully elucidated. Here, by integrating chromatin immunoprecipitation sequencing and transcriptome profiling, we identified aberrantly activated oncogenic SEs that drive the transcriptional upregulation of the transcription factors ELF3 and JUNB in abiraterone-resistance CRPC cells. Importantly, SE-driven activation of the ELF3/JUNB axis promotes abiraterone resistance by inducing WNT11-mediated neuroendocrine transition. In parallel, this transdifferentiated state is closely associated with ferroptosis resistance, as evidenced by the upregulation of key ferroptosis-protective genes, including FTH1 and GPX4. In contrast, disruption of the ELF3/JUNB-WNT11 axis markedly restored abiraterone sensitivity and triggered ferroptotic cell death in CRPC cells both in vitro and in vivo. Collectively, our findings highlight targeting SE-driven transcriptional programs as a promising strategy for overcoming abiraterone resistance in CRPC.

Male↗

PubMed2026

Regulation of the histone H3K36 methyltransferase Set2 by the histone chaperone Spt6.

Histone H3 lysine 36 methylation is a conserved histone modification that is critical for maintaining eukaryotic transcriptional fidelity and genomic stability. In Saccharomyces cerevisiae, this modification is catalyzed by Set2, an ortholog of the mammalian H3K36 methyltransferase SETD2. Previous genetic, biochemical, and structural studies showed that Set2 activity is repressed by a Set2 autoinhibitory domain (AID) and that activation requires the direct binding of the histone chaperone Spt6. To study the role of Spt6 and Set2 autoinhibition in vivo, we have isolated and analyzed multiple classes of Spt6 and Set2 mutants. Our results suggest an autoinhibited form of Set2 in which the catalytic domain (CD) is bound by the AID. In strong agreement with our genetic results, biophysical experiments demonstrate that the CD and AID physically interact, and that the autoinhibition mutants disrupt this interaction. Finally, RNA sequencing and chromatin immunoprecipitation and sequencing studies show the importance of the Set2-Spt6 interaction for transcription and H3K36 methylation genome-wide. Taken together, our results support a model in which Set2 exists in an inactive, autoinhibited state in vivo through direct CD-AID interactions, with binding by Spt6 required to release the autoinhibition.

Saccharomyces cerevisiae Proteins↗

PubMed2026

The H3K27me3 reader GmLHP1 impairs Phytophthora sojae resistance by repressing ethylene precursor accumulation in soybean.

Phytophthora root rot, caused by Phytophthora sojae, is a devastating soilborne disease of soybean (Glycine max). However, the epigenetic regulation of soybean responses to P. sojae remains incompletely understood. Here, using genetic, molecular and biochemical approaches, we characterized the functions of LIKE HETEROCHROMATIN PROTEIN 1 (GmLHP1) and its downstream regulatory network. We demonstrated that GmLHP1, as a reader of H3K27me3, negatively regulates soybean resistance to P. sojae. GmLHP1 binds to H3K27me3 peptides in vitro and colocalizes with H3K27me3 marks genome-wide in vivo. The integrated chromatin immunoprecipitation sequencing and RNA sequencing analysis identified the ethylene biosynthesis pathway gene 1-AMINO-CYCLOPROPANE-1-CARBOXYLATE SYNTHASE 18 (GmACS18) as being enriched for H3K27me3 and bound by GmLHP1, leading to its transcriptional downregulation. Notably, GmLHP1 associates with the GmACS18 promoter by directly binding to AATTAA motifs and recognizing H3K27me3 marks. Moreover, GmACS18 enhances defense against P. sojae by accumulating the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC). Further analysis unveiled that recognition of H3K27me3 by GmLHP1 is essential for regulating soybean resistance to P. sojae through repressing GmACS18 transcription and decreasing ACC accumulation. Our findings reveal a novel epigenetic regulatory mechanism in which the H3K27me3 reader GmLHP1 blocks soybean resistance to P. sojae by repressing ethylene precursor ACC accumulation.

ACC accumulation↗