Ferroptosis is implicated in various tumors, including glioblastoma. Artesunate (ART), an anti-malarial drug, exerted antitumor properties in several cancer types. However, the role of ferroptosis in ...the inhibiting effect of artesunate on glioblastoma remains unclear. The purpose of this study was to investigate the effects of ART on the ferroptosis of glioblastoma and to elucidate the underlying mechanisms. We found that ART inhibited the proliferation of glioblastoma cells in vitro and glioblastoma tumorigenesis in vivo. Characteristic changes of ferroptosis were observed in ART group, including GSH depletion, lipid peroxidation and iron overload. Meanwhile, the protein level of GPX4 were lower in ART group than that in control group. Ferrostatin-1, a ferroptosis inhibitor, could rescue the cell death induced by ART in U251 cells. Further examination of the mechanism revealed that the effect of ART on ferroptosis was partially governed by regulating iron homeostasis and p38 and ERK signaling pathway. These findings support that ART triggers ferroptosis in glioblastoma and might be a potential therapeutic agent for glioblastoma treatment.
Circadian clocks regulate growth and development in plants and animals, but the role of circadian regulation in crop production is poorly understood. Rice (
) grain yield is largely determined by ...tillering, which is mediated by physiological and genetic factors. Here we report a regulatory loop that involves the circadian clock, sugar, and strigolactone (SL) pathway to regulate rice tiller-bud and panicle development. Rice
(
) positively regulates expression of
(
, also known as
),
(
), and
(
, also known as
) to repress tiller-bud outgrowth. Downregulating and overexpressing
increases and reduces tiller numbers, respectively, whereas manipulating
(
) expression results in the opposite effects.
also regulates
expression to mediate panicle and grain development. Genetic analyses using double mutants and overexpression in the mutants show that
,
, and
act downstream of
Sugars repress
expression in roots and tiller buds to promote tiller-bud outgrowth. The circadian clock integrates sugar responses and the SL pathway to regulate tiller and panicle development, providing insights into improving plant architecture and yield in rice and other cereal crops.
Polyploidy is a pervasive evolutionary feature of all flowering plants and some animals, leading to genetic and epigenetic changes that affect gene expression and morphology. DNA methylation changes ...can produce meiotically stable epialleles, which are transmissible through selection and breeding. However, the relationship between DNA methylation and polyploid plant domestication remains elusive.
We report comprehensive epigenomic and functional analyses, including ~12 million differentially methylated cytosines in domesticated allotetraploid cottons and their tetraploid and diploid relatives. Methylated genes evolve faster than unmethylated genes; DNA methylation changes between homoeologous loci are associated with homoeolog-expression bias in the allotetraploids. Significantly, methylation changes induced in the interspecific hybrids are largely maintained in the allotetraploids. Among 519 differentially methylated genes identified between wild and cultivated cottons, some contribute to domestication traits, including flowering time and seed dormancy. CONSTANS (CO) and CO-LIKE (COL) genes regulate photoperiodicity in Arabidopsis. COL2 is an epiallele in allotetraploid cottons. COL2A is hypermethylated and silenced, while COL2D is repressed in wild cottons but highly expressed due to methylation loss in all domesticated cottons tested. Inhibiting DNA methylation activates COL2 expression, and repressing COL2 in cultivated cotton delays flowering.
We uncover epigenomic signatures of domestication traits during cotton evolution. Demethylation of COL2 increases its expression, inducing photoperiodic flowering, which could have contributed to the suitability of cotton for cultivation worldwide. These resources should facilitate epigenetic engineering, breeding, and improvement of polyploid crops.
Polyploidy provides new genetic material that facilitates evolutionary novelty, species adaptation, and crop domestication. Polyploidy often leads to an increase in cell or organism size, which may ...affect transcript abundance or transcriptome size, but the relationship between polyploidy and transcriptome changes remains poorly understood. Plant cells often undergo endoreduplication, confounding the polyploid effect.
To mitigate these effects, we select female gametic cells that are developmentally stable and void of endoreduplication. Using single-cell RNA sequencing (scRNA-seq) in Arabidopsis thaliana tetraploid lines and isogenic diploids, we show that transcriptome abundance doubles in the egg cell and increases approximately 1.6-fold in the central cell, consistent with cell size changes. In the central cell of tetraploid plants, DEMETER (DME) is upregulated, which can activate PRC2 family members FIS2 and MEA, and may suppress the expression of other genes. Upregulation of cell size regulators in tetraploids, including TOR and OSR2, may increase the size of reproductive cells. In diploids, the order of transcriptome abundance is central cell, synergid cell, and egg cell, consistent with their cell size variation. Remarkably, we uncover new sets of female gametophytic cell-specific transcripts with predicted biological roles; the most abundant transcripts encode families of cysteine-rich peptides, implying roles in cell-cell recognition during double fertilization.
Transcriptome in single cells doubles in tetraploid plants compared to diploid, while the degree of change and relationship to the cell size depends on cell types. These scRNA-seq resources are free of cross-contamination and are uniquely valuable for advancing plant hybridization, reproductive biology, and polyploid genomics.
Purpose: Temozolomide is used in first-line treatment for glioblastoma. However, chemoresistance to temozolomide is commonin glioma patients. In addition, mechanisms for the anti-tumor effects of ...temozolomide are largely unknown. Ferroptosis is a formof programmed cell death triggered by disturbed redox homeostasis, overloaded iron, and increased lipid peroxidation. The presentstudy was performed to elucidate the involvement of ferroptosis in the anti-tumor mechanisms of temozolomide.
Materials and Methods: We utilized the CCK8 assay to evaluate cytotoxicity. Levels of lactate dehydrogenase (LDH), malondialdehyde(MDA), iron, and glutathione (GSH) were measured. Flow cytometry and fluorescence microscope were used to detectthe production of reactive oxygen species (ROS). Western blotting, RT-PCR and siRNA transfection were used to investigate molecularmechanisms.
Results: Temozolomide increased the levels of LDH, MDA, and iron and reduced GSH levels in TG905 cells. Furthermore, wefound that ROS levels and DMT1 expression were elevated in TG905 cells treated with temozolomide and were accompanied bya decrease in the expression of glutathione peroxidase 4, indicating an iron-dependent cell death, ferroptosis. Our results alsoshowed that temozolomide-induced ferroptosis is associated with regulation of the Nrf2/HO-1 pathway. Conversely, DMT1 knockdownby siRNA evidently blocked temozolomide-induced ferroptosis in TG905 cells.
Conclusion: Taken together, our findings indicate that temozolomide may suppress cell growth partly by inducing ferroptosis bytargeting DMT1 expression in glioblastoma cells. KCI Citation Count: 0
The genetic distance between hybridizing parents affects heterosis; however, the mechanisms for this remain unclear. Here we report that this genetic distance correlates with natural variation and ...epigenetic regulation of circadian clock-mediated stress responses. In intraspecific hybrids of Arabidopsis thaliana, genome-wide expression of many biotic and abiotic stress-responsive genes is diurnally repressed and this correlates with biomass heterosis and biomass quantitative trait loci. Expression differences of selected stress-responsive genes among diverse ecotypes are predictive of heterosis in their hybrids. Stress-responsive genes are repressed in the hybrids under normal conditions but are induced to mid-parent or higher levels under stress at certain times of the day, potentially balancing the tradeoff between stress responses and growth. Consistent with this hypothesis, repression of two candidate stress-responsive genes increases growth vigour. Our findings may therefore provide new criteria for effectively selecting parents to produce high- or low-yield hybrids.
During evolution successful allopolyploids must overcome 'genome shock' between hybridizing species but the underlying process remains elusive. Here, we report concerted genomic and epigenomic ...changes in resynthesized and natural Arabidopsis suecica (TTAA) allotetraploids derived from Arabidopsis thaliana (TT) and Arabidopsis arenosa (AA). A. suecica shows conserved gene synteny and content with more gene family gain and loss in the A and T subgenomes than respective progenitors, although A. arenosa-derived subgenome has more structural variation and transposon distributions than A. thaliana-derived subgenome. These balanced genomic variations are accompanied by pervasive convergent and concerted changes in DNA methylation and gene expression among allotetraploids. The A subgenome is hypomethylated rapidly from F
to resynthesized allotetraploids and convergently to the T-subgenome level in natural A. suecica, despite many other methylated loci being inherited from F
to all allotetraploids. These changes in DNA methylation, including small RNAs, in allotetraploids may affect gene expression and phenotypic variation, including flowering, silencing of self-incompatibility and upregulation of meiosis- and mitosis-related genes. In conclusion, concerted genomic and epigenomic changes may improve stability and adaptation during polyploid evolution.
Upland cotton is a model for polyploid crop domestication and transgenic improvement. Here we sequenced the allotetraploid Gossypium hirsutum L. acc. TM-1 genome by integrating whole-genome shotgun ...reads, bacterial artificial chromosome (BAC)-end sequences and genotype-by-sequencing genetic maps. We assembled and annotated 32,032 A-subgenome genes and 34,402 D-subgenome genes. Structural rearrangements, gene loss, disrupted genes and sequence divergence were more common in the A subgenome than in the D subgenome, suggesting asymmetric evolution. However, no genome-wide expression dominance was found between the subgenomes. Genomic signatures of selection and domestication are associated with positively selected genes (PSGs) for fiber improvement in the A subgenome and for stress tolerance in the D subgenome. This draft genome sequence provides a resource for engineering superior cotton lines.
DNA methylation is essential for plant and animal development. In plants, methylation occurs at CG, CHG, and CHH (H = A, C or T) sites via distinct pathways. Cotton is an allotetraploid consisting of ...two progenitor genomes. Each cotton fiber is a rapidly-elongating cell derived from the ovule epidermis, but the molecular basis for this developmental transition is unknown. Here we analyzed methylome, transcriptome, and small RNAome and revealed distinct changes in CHH methylation during ovule and fiber development. In ovules, CHH hypermethylation in promoters correlated positively with siRNAs, inducing RNA-dependent DNA methylation (RdDM), and up-regulation of ovule-preferred genes. In fibers, the ovule-derived cells generated additional heterochromatic CHH hypermethylation independent of RdDM, which repressed transposable elements (TEs) and nearby genes including fiber-related genes. Furthermore, CHG and CHH methylation in genic regions contributed to homoeolog expression bias in ovules and fibers. Inhibiting DNA methylation using 5-aza-2'-deoxycytidine in cultured ovules has reduced fiber cell number and length, suggesting a potential role for DNA methylation in fiber development. Thus, RdDM-dependent methylation in promoters and RdDM-independent methylation in TEs and nearby genes could act as a double-lock feedback mechanism to mediate gene and TE expression, potentiating the transition from epidermal to fiber cells during ovule and seed development.
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