RESUMEN
SETD2 is the only enzyme responsible for transcription-coupled histone H3 lysine 36 trimethylation (H3K36me3). Mutations in SETD2 cause human diseases including cancer and developmental defects. In mice, Setd2 is essential for embryonic vascular remodeling. Given that many epigenetic modifiers have recently been found to possess noncatalytic functions, it is unknown whether the major function(s) of Setd2 is dependent on its catalytic activity or not. Here, we established a site-specific knockin mouse model harboring a cancer patient-derived catalytically dead Setd2 (Setd2-CD). We found that the essentiality of Setd2 in mouse development is dependent on its methyltransferase activity, as the Setd2CD/CD and Setd2-/- mice showed similar embryonic lethal phenotypes and largely comparable gene expression patterns. However, compared with Setd2-/-, the Setd2CD/CD mice showed less severe defects in allantois development, and single-cell RNA-seq analysis revealed differentially regulated allantois-specific 5' Hoxa cluster genes in these two models. Collectively, this study clarifies the importance of Setd2 catalytic activity in mouse development and provides a new model for comparative study of previously unrecognized Setd2 functions.
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A significant variation in chromatin accessibility is an epigenetic feature of leukemia. The cause of this variation in leukemia, however, remains elusive. Here, we identify SMARCA5, a core ATPase of the imitation switch (ISWI) chromatin remodeling complex, as being responsible for aberrant chromatin accessibility in leukemia cells. We find that SMARCA5 is required to maintain aberrant chromatin accessibility for leukemogenesis and then promotes transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1. Higher levels of AKR1B1 are associated with a poor prognosis in leukemia patients and promote leukemogenesis by reprogramming fructose metabolism. Moreover, pharmacological inhibition of AKR1B1 has been shown to have significant therapeutic effects in leukemia mice and leukemia patient cells. Thus, our findings link the aberrant chromatin state mediated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming and shed light on the essential role of AKR1B1 in leukemogenesis, which may provide therapeutic strategies for leukemia.
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Fructosa , Humanos , Animales , Ratones , Fructosa/metabolismo , Cromatina/metabolismo , Aldehído Reductasa/metabolismo , Aldehído Reductasa/genética , Leucemia/metabolismo , Leucemia/patología , Leucemia/genética , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Ensamble y Desensamble de Cromatina , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinogénesis/genética , Línea Celular Tumoral , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Adenosina TrifosfatasasRESUMEN
Transposable elements (TEs) comprise ~85% of the common wheat genome, which are highly diverse among subgenomes, possibly contribute to polyploid plasticity, but the causality is only assumed. Here, by integrating data from gene expression cap analysis and epigenome profiling via hidden Markov model in common wheat, we detect a large proportion of enhancer-like elements (ELEs) derived from TEs producing nascent noncoding transcripts, namely ELE-RNAs, which are well indicative of the regulatory activity of ELEs. Quantifying ELE-RNA transcriptome across typical developmental stages reveals that TE-initiated ELE-RNAs are mainly from RLG_famc7.3 specifically expanded in subgenome A. Acquisition of spike-specific transcription factor binding likely confers spike-specific expression of RLG_famc7.3-initiated ELE-RNAs. Knockdown of RLG_famc7.3-initiated ELE-RNAs resulted in global downregulation of spike-specific genes and abnormal spike development. These findings link TE expansion to regulatory specificity and polyploid developmental plasticity, highlighting the functional impact of TE-driven regulatory innovation on polyploid evolution.
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Elementos Transponibles de ADN , Triticum , Elementos Transponibles de ADN/genética , Triticum/genética , Regulación de la Expresión Génica , Poliploidía , Transcriptoma , ARNRESUMEN
Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 (ROBO1) mutations in patients with MDS, while the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here, we report that ROBO1 deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, Robo1 deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates that Cdc42, a member of the Rho-guanosine triphosphatase family, acts as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the self-renewal and erythropoiesis of HSPCs in Robo1-deficient mice. Collectively, our result implicates the essential role of ROBO1 in maintaining HSPC homeostasis and erythropoiesis via CDC42.
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Eritropoyesis , Síndromes Mielodisplásicos , Animales , Humanos , Ratones , Eritropoyesis/genética , Síndromes Mielodisplásicos/genética , Proteínas del Tejido Nervioso/genética , Pronóstico , Receptores Inmunológicos/genética , Proteínas RoundaboutRESUMEN
Polyploidization is a major driver of genome diversification and environmental adaptation. However, the merger of different genomes may result in genomic conflicts, raising a major question regarding how genetic diversity is interpreted and regulated to enable environmental plasticity. By analyzing the genome-wide binding of 191 trans-factors in allopolyploid wheat, we identified like heterochromatin protein 1 (LHP1) as a master regulator of subgenome-diversified genes. Transcriptomic and epigenomic analyses of LHP1 mutants reveal its role in buffering the expression of subgenome-diversified defense genes by controlling H3K27me3 homeostasis. Stripe rust infection releases latent subgenomic variations by eliminating H3K27me3-related repression. The simultaneous inactivation of LHP1 homoeologs by CRISPR-Cas9 confers robust stripe rust resistance in wheat seedlings. The conditional repression of subgenome-diversified defenses ensures developmental plasticity to external changes, while also promoting neutral-to-non-neutral selection transitions and adaptive evolution. These findings establish an LHP1-mediated buffering system at the intersection of genotypes, environments, and phenotypes in polyploid wheat. Manipulating the epigenetic buffering capacity offers a tool to harness cryptic subgenomic variations for crop improvement.
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Epigenómica , Triticum , Triticum/genética , Triticum/metabolismo , Histonas/metabolismo , Epigénesis Genética , Genoma de Planta/genéticaRESUMEN
The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which the BMM maintains LSCs may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSCs, previously identified by us, controls cytokine production in the BMM, but the role of ID1 in acute myeloid leukemia (AML) BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of patients with AML, especially in BM mesenchymal stem cells, and that the high expression of ID1 in the AML BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of cocultured AML cells. Loss of Id1 in the BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells cocultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction via truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1-deficient BM supernatant fluid to regulate AML progression in mice. Our study highlights the critical role of ID1 in the AML BMM and aids the development of therapeutic strategies for AML.
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Proteína 7 Similar a la Angiopoyetina , Proteína 1 Inhibidora de la Diferenciación , Leucemia Mieloide Aguda , Animales , Ratones , Proteína 7 Similar a la Angiopoyetina/genética , Proteína 7 Similar a la Angiopoyetina/metabolismo , Médula Ósea/metabolismo , Modelos Animales de Enfermedad , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Microambiente Tumoral , Humanos , Proteína 1 Inhibidora de la Diferenciación/metabolismoRESUMEN
Host-guest doping systems with phthalimides (BI) and N-methylphthalimide (NMeBI) as the host and 1,8-naphthalimide (NI) and 4-bromo-1,8-naphthalimide (4BrNI) as the guest have been developed. The 0.2% NI/BI (molar ratio) with a strong C=O···H-N hydrogen bond exhibited a phosphorescence quantum efficiency (29.2%) higher than that of NI/NMeBI with a weak C=O···H-C hydrogen bond (10.1%). A similar trend was observed in the 4BrNI guest system. A remarkable phosphorescent efficiency of 42.1% was achieved in a 0.5% 4BrNI/BI composite, which represents the highest value in NI-based phosphors. This research indicates stronger hydrogen bonding may have a greater contribution in boosting the phosphorescence efficiency.
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In recent studies, the tolerable safety profile and positive bone marrow (BM) response suggest a beneficial use of anti-PD-1 agents in the treatment of Myelodysplastic Syndromes (MDS), but the underlying mechanism is still unknown. MDS is mainly characterized by ineffective hematopoiesis, which may contribute to inflammatory signaling or immune dysfunction. Our previous studies focused on inflammatory signaling, and the results showed that S100a9 expression was higher in low-risk MDS and lower in high-risk MDS. In this study, we combine the inflammatory signaling and immune dysfunction. SKM-1 cells and K562 cells co-cultured with S100a9 acquire apoptotic features. Moreover, we confirm the inhibitory effect of S100a9 on PD-1/PD-L1. Importantly, PD-1/PD-L1 blockade and S100a9 can both activate the PI3K/AKT/mTOR signaling pathway. The cytotoxicity is higher in lower-risk MDS-lymphocytes than in high-risk MDS-lymphocytes, and S100a9 partially rescues the exhausted cytotoxicity in lymphocytes. Our study demonstrates that S100a9 may inhibit MDS-associated tumor escape via PD-1/PD-L1 blockade through PI3K/AKT/mTOR signaling pathway activation. Our findings indicate the possible mechanisms by which anti-PD-1 agents may contribute to the treatment of MDS. These insights may provide mutation-specific treatment as a supplementary therapy for MDS patients with high-risk mutations, such as TP53, N-RAS or other complex mutations.
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Síndromes Mielodisplásicos , Proteínas Proto-Oncogénicas c-akt , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Escape del Tumor , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Serina-Treonina Quinasas TORRESUMEN
The patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have poor prognosis, and a novel and effective therapeutic strategy for these patients is urgently needed. Although ubiquitin-specific protease 1 (USP1) plays a key role in cancer, the carcinogenic effect of USP1 in B-cell lymphoma remains elusive. Here we found that USP1 is highly expressed in DLBCL patients, and high expression of USP1 predicts poor prognosis. Knocking down USP1 or a specific inhibitor of USP1, pimozide, induced cell growth inhibition, cell cycle arrest and autophagy in DLBCL cells. Targeting USP1 by shRNA or pimozide significantly reduced tumor burden of a mouse model established with engraftment of rituximab/chemotherapy resistant DLBCL cells. Pimozide significantly retarded the growth of lymphoma in a DLBCL patient-derived xenograft (PDX) model. USP1 directly interacted with MAX, a MYC binding protein, and maintained the stability of MAX through deubiquitination, which promoted the transcription of MYC target genes. Moreover, pimozide showed a synergetic effect with etoposide, a chemotherapy drug, in cell and mouse models of rituximab/chemotherapy resistant DLBCL. Our study highlights the critical role of USP1 in the rituximab/chemotherapy resistance of DLBCL through deubiquitylating MAX, and provides a novel therapeutic strategy for rituximab/chemotherapy resistant DLBCL.
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Linfoma de Células B Grandes Difuso , Linfoma no Hodgkin , Animales , Ratones , Humanos , Rituximab/uso terapéutico , Pimozida/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Linfoma no Hodgkin/tratamiento farmacológico , Proteasas Ubiquitina-Específicas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
The success of common wheat as a global staple crop was largely attributed to its genomic diversity and redundancy due to the merge of different genomes, giving rise to the major question how subgenome-divergent and -convergent transcription is mediated and harmonized in a single cell. Here, we create a catalog of genome-wide transcription factor-binding sites (TFBSs) to assemble a common wheat regulatory network on an unprecedented scale. A significant proportion of subgenome-divergent TFBSs are derived from differential expansions of particular transposable elements (TEs) in diploid progenitors, which contribute to subgenome-divergent transcription. Whereas subgenome-convergent transcription is associated with balanced TF binding at loci derived from TE expansions before diploid divergence. These TFBSs have retained in parallel during evolution of each diploid, despite extensive unbalanced turnover of the flanking TEs. Thus, the differential evolutionary selection of paleo- and neo-TEs contribute to subgenome-convergent and -divergent regulation in common wheat, highlighting the influence of TE repertory plasticity on transcriptional plasticity in polyploid.
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Elementos Transponibles de ADN , Triticum , Elementos Transponibles de ADN/genética , Triticum/genética , Genoma de Planta/genética , Poliploidía , Diploidia , Evolución MolecularRESUMEN
Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML.
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Leucemia Mieloide Aguda , Humanos , Carcinogénesis , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Histona Desacetilasas , Leucemia Mieloide Aguda/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Exorbitant sequencing cost is one of the main obstacles limiting the widespread application of Global Run-On sequencing (GRO-seq) to detect transcriptional activity. Here, we describe a more efficient and affordable protocol for GRO-seq that incorporates an rRNA removal step after nuclear RNA isolation and before nascent RNA immunoprecipitation. We have successfully applied this protocol to profile enhancer transcription in allohexaploid bread wheat and increased the proportion of valid data by 20 times. For complete details on the use and execution of this protocol, please refer to Xie et al. (2022).
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Pan , Triticum , ARN/genética , ARN Nuclear , Análisis de Secuencia de ARN/métodos , Triticum/genéticaRESUMEN
The development of covalent organic framework nanosheet (COF NS) is becoming a vitally important research field by reason of its high permeability, ordered structure, high utilization of functional site, favourable dispersability and large aspect ratio, resulting in their widespread applications in separation, catalysis, sensing and optical device. In this work, a Tp-Bpy COF NS was prepared via an interfacial synthesis of 2,4,6-triformylphloroglucinol (Tp) and 5,5'-diamino-2,2'-bipyridine (Bpy), which has film morphology, high surface area, large pore, excellent stability and various functional site. It was utilized as a functional material to immobilize aptamers for constructing a sensitive electrochemical aptasensor. Compared with bulk Tp-Bpy COF, Tp-Bpy COF NS can significantly enhance the biosensing performance toward ultra-trace tobramycin. This work is benefit for the exploration of COF NSs and their electrochemical aptasensors in biosensing applications.
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Aptámeros de Nucleótidos , Técnicas Biosensibles , Estructuras Metalorgánicas , Aptámeros de Nucleótidos/química , Técnicas Biosensibles/métodos , Técnicas Electroquímicas/métodos , Límite de Detección , Estructuras Metalorgánicas/químicaRESUMEN
Triticeae species, including wheat, barley, and rye, are critical for global food security. Mapping agronomically important genes is crucial for elucidating molecular mechanisms and improving crops. However, Triticeae includes many wild relatives with desirable agronomic traits, and frequent introgressions occurred during Triticeae evolution and domestication. Thus, Triticeae genomes are generally large and complex, making the localization of genes or functional elements that control agronomic traits challenging. Here, we developed Triti-Map, which contains a suite of user-friendly computational packages specifically designed and optimized to overcome the obstacles of gene mapping in Triticeae, as well as a web interface integrating multi-omics data from Triticeae for the efficient mining of genes or functional elements that control particular traits. The Triti-Map pipeline accepts both DNA and RNA bulk-segregated sequencing data as well as traditional QTL data as inputs for locating genes and elucidating their functions. We illustrate the usage of Triti-Map with a combination of bulk-segregated ChIP-seq data to detect a wheat disease-resistance gene with its promoter sequence that is absent from the reference genome and clarify its evolutionary process. We hope that Triti-Map will facilitate gene isolation and accelerate Triticeae breeding.
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Evolución Molecular , Genoma de Planta , Fitomejoramiento , Poaceae/genética , Triticum/genéticaRESUMEN
The precise spatiotemporal gene expression is orchestrated by enhancers that lack general sequence features and thus are difficult to be computationally identified. By nascent RNA sequencing combined with epigenome profiling, we detect active transcription of enhancers from the complex bread wheat genome. We find that genes associated with transcriptional enhancers are expressed at significantly higher levels, and enhancer RNA is more precise and robust in predicting enhancer activity compared to chromatin features. We demonstrate that sub-genome-biased enhancer transcription could drive sub-genome-biased gene expression. This study highlights enhancer transcription as a hallmark in regulating gene expression in wheat.
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Pan , Triticum , Cromatina/genética , Elementos de Facilitación Genéticos , Transcriptoma , Triticum/genéticaRESUMEN
More than 80% of the wheat genome consists of transposable elements (TEs), which act as major drivers of wheat genome evolution. However, their contributions to the regulatory evolution of wheat adaptations remain largely unclear. Here, we created genome-binding maps for 53 transcription factors (TFs) underlying environmental responses by leveraging DAP-seq in Triticum urartu, together with epigenomic profiles. Most TF binding sites (TFBSs) located distally from genes are embedded in TEs, whose functional relevance is supported by purifying selection and active epigenomic features. About 24% of the non-TE TFBSs share significantly high sequence similarity with TE-embedded TFBSs. These non-TE TFBSs have almost no homologous sequences in non-Triticeae species and are potentially derived from Triticeae-specific TEs. The expansion of TE-derived TFBS linked to wheat-specific gene responses, suggesting TEs are an important driving force for regulatory innovations. Altogether, TEs have been significantly and continuously shaping regulatory networks related to wheat genome evolution and adaptation.
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BACKGROUND: Polyploidy has played a prominent role in the evolution of plants and many other eukaryotic lineages. However, how polyploid genomes adapt to the abrupt presence of two or more sets of chromosomes via genome regulation remains poorly understood. Here, we analyzed genome-wide histone modification and gene expression profiles in relation to domestication and ploidy transition in the A and B subgenomes of polyploid wheat. RESULTS: We found that epigenetic modification patterns by two typical euchromatin histone markers, H3K4me3 and H3K27me3, for the great majority of homoeologous triad genes in A and B subgenomes were highly conserved between wild and domesticated tetraploid wheats and remained stable in the process of ploidy transitions from hexaploid to extracted tetraploid and then back to resynthesized hexaploid. However, a subset of genes was differentially modified during tetraploid and hexaploid wheat domestication and in response to ploidy transitions, and these genes were enriched for particular gene ontology (GO) terms. The extracted tetraploid wheat manifested higher overall histone modification levels than its hexaploid donor, and which were reversible and restored to normal levels in the resynthesized hexaploid. Further, while H3K4me3 marks were distally distributed along each chromosome and significantly correlated with subgenome expression as expected, H3K27me3 marks showed only a weak distal bias and did not show a significant correlation with gene expression. CONCLUSIONS: Our results reveal overall high stability of histone modification patterns in the A and B subgenomes of polyploid wheat during domestication and in the process of ploidy transitions. However, modification levels of a subset of functionally relevant genes in the A and B genomes were trans-regulated by the D genome in hexaploid wheat.
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Domesticación , Genoma de Planta , Código de Histonas , Poliploidía , TriticumRESUMEN
Wheat (Triticum aestivum) has a large allohexaploid genome. Subgenome-divergent regulation contributed to genome plasticity and the domestication of polyploid wheat. However, the specificity encoded in the wheat genome determining subgenome-divergent spatio-temporal regulation has been largely unexplored. The considerable size and complexity of the genome are major obstacles to dissecting the regulatory specificity. Here, we compared the epigenomes and transcriptomes from a large set of samples under diverse developmental and environmental conditions. Thousands of distal epigenetic regulatory elements (distal-epiREs) were specifically linked to their target promoters with coordinated epigenomic changes. We revealed that subgenome-divergent activity of homologous regulatory elements is affected by specific epigenetic signatures. Subgenome-divergent epiRE regulation of tissue specificity is associated with dynamic modulation of H3K27me3 mediated by Polycomb complex and demethylases. Furthermore, quantitative epigenomic approaches detected key stress responsive cis- and trans-acting factors validated by DNA Affinity Purification and sequencing, and demonstrated the coordinated interplay between epiRE sequence contexts, epigenetic factors, and transcription factors in regulating subgenome divergent transcriptional responses to external changes. Together, this study provides a wealth of resources for elucidating the epiRE regulomics and subgenome-divergent regulation in hexaploid wheat, and gives new clues for interpreting genetic and epigenetic interplay in regulating the benefits of polyploid wheat.
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Epigénesis Genética , Secuencias Reguladoras de Ácidos Nucleicos , Estrés Fisiológico/genética , Triticum/genética , Regulación de la Expresión Génica de las Plantas , Genoma de Planta , Histonas/genética , Histonas/metabolismo , Lisina/genética , Lisina/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Triticum/fisiologíaRESUMEN
Nanostructured all-inorganic metal halide perovskites have attracted considerable attention due to their outstanding photonic and optoelectronic properties. Particularly, they can exhibit room-temperature exciton-polaritons (EPs) capable of confining electromagnetic fields down to the subwavelength scale, enabling efficient light harvesting and guiding. However, a real-space nanoimaging study of the EPs in perovskite crystals is still absent. Additionally, few studies focused on the ambient-pressure and reliable fabrication of large-area CsPbBr3 microsheets. Here, CsPbBr3 orthorhombic microsheet single crystals were successfully synthesized under ambient pressure. Their EPs were examined using a real-space nanoimaging technique, which reveal EP waveguide modes spanning the visible to near-infrared spectral region. The EPs exhibit a sufficient long propagation length of over 16 µm and a very low propagation loss of less than 0.072 dB·µm-1. These results demonstrate the potential applications of CsPbBr3 microsheets as subwavelength waveguides in integrated optics.