ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2025
·
IF 11.3
Wenmiao He,Xiu Chen,Shijie Zhou,Zuqiang Fu,Jin Xu,Qian Liu,Francisco Javier Cubero,Zhong Li,Yong Zhou,Dayong Wang,Guibin Jiang,Aihua Gu
Despite the widespread prevalence of BPS in human populations, its potential impacts on offspring and the underlying mechanisms remain poorly understood. In this study, we found that parental exposure to BPS at environmental doses induced lipid accumulation in Caenorhabditis elegans from one-generational parent (P0) to two-generational offspring (F2), even in the absence of BPS exposure in offspring. Mechanistically, BPS-induced transgenerational lipid accumulation was due to the activation of lipogenic genes (fat-5 and fat-7, encoding delta-9 desaturases) and the associated transcriptional regulators (sbp-1 and mdt-15). Knockdown of methyltransferase wdr-5.1 reversed BPS-induced transgenerational inheritance via inhibiting histone H3K4 trimethylation (H3K4me3). Interestingly, germline-specific wdr-5.1/H3K4me3, rather than intestinal, was identified as being responsible for transgenerational inheritance. Our study provides the first evidence elucidating the mechanisms through which environmentally relevant BPS exposure induces lipid accumulation and transmits this effect across generations.
研究领域:
环境毒理学
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表观遗传学
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发育生物学
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DOI
PubMed
高影响因子
Theranostics
·
2021
·
IF 11.556
Yumeng Miao,Yun Zheng,Yanzhi Geng,Ling Yang,Na Cao,Yue Dai,Zhifeng Wei
Background: Peroxisome proliferator-activated receptor gamma (PPARγ) has the ability to counter Th17 responses, but the full mechanisms remain elusive. Herein, we aimed to elucidate this process in view of cellular metabolism, especially glutaminolysis. Methods: MTT, CCK-8, Annexin V-FITC/PI staining or trypan blue exclusion assays were used to analyze cytotoxicity. Flow cytometry and Q-PCR assays were applied to determine Th17 responses. The detection of metabolite levels using commercial kits and rate-limiting enzyme expression using western blotting assays was performed to illustrate the metabolic activity. ChIP assays were used to examine H3K4me3 modifications. Mouse models of dextran sulfate sodium (DSS)-induced colitis and house dust mite (HDM)/lipopolysaccharide (LPS)-induced asthma were established to confirm the mechanisms studied in vitro . Results: The PPARγ agonists rosiglitazone and pioglitazone blocked glutaminolysis but not glycolysis under Th17-skewing conditions, as indicated by the detection of intracellular lactate and α-KG and the fluorescence ratios of BCECF-AM. The PPARγ agonists prevented the utilization of glutamine and thus directly limited Th17 responses even when Foxp3 was deficient. The mechanisms were ascribed to restricted conversion of glutamine to glutamate by reducing the expression of the rate-limiting enzyme GLS1, which was confirmed by GLS1 overexpression. Replenishment of α-KG and 2-HG but not succinate weakened the effects of PPARγ agonists, and α-KG-promoted Th17 responses were dampened by siIDH1/2. Inhibition of KDM5 but not KDM4/6 restrained the inhibitory effect of PPARγ agonists on IL-17A expression, and the H3K4me3 level in the promoter and CNS2 region of the il-17 gene locus down-regulated by PPARγ agonists was rescued by 2-HG and GLS1 overexpression. However, the limitation of PPARγ agonists on the mRNA expression of RORγt was unable to be stopped by 2-HG but was attributed to GSH/ROS signals subsequent to GLS1. The exact role of PPARγ was proved by GW9662 or PPARγ knockout, and the mechanisms for PPARγ-inhibited Th17 responses were further confirmed by GLS1 overexpression in vivo . Conclusion: PPARγ agonists repressed Th17 responses by counteracting GLS1-mediated glutaminolysis/2-HG/H3K4me3 and GSH/ROS signals, which is beneficial for Th17 cell-related immune dysregulation.
研究领域:
免疫学
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细胞代谢
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药理学
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DOI
PubMed
高影响因子
NUCLEIC ACIDS RESEARCH
·
2020
·Vol. 48
·期 19
·10768-10784
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IF 11.502
Sun Ge,Wang Chunyu,Wang Shengli,Sun Hongmiao,Zeng Kai,Zou Renlong,Lin Lin,Liu Wei,Sun Ning,Song Huijuan,Liu Wensu,Zhou Tingting,Jin Feng,Shan Zhongyan,Zhao Yue
Estrogen receptor alpha (ERα) signaling pathway is essential for ERα-positive breast cancer progression and endocrine therapy resistance. Bromodomain PHD Finger Transcription Factor (BPTF) associated protein of 18kDa (BAP18) has been recognized as a crucial H3K4me3 reader. However, the whole genomic occupation of BAP18 and its biological function in breast cancer is still elusive. Here, we found that higher expression of BAP18 in ERα-positive breast cancer is positively correlated with poor prognosis. ChIP-seq analysis further demonstrated that the half estrogen response elements (EREs) and the CCCTC binding factor (CTCF) binding sites are the significant enrichment sites found in estrogen-induced BAP18 binding sites. Also, we provide the evidence to demonstrate that BAP18 as a novel co-activator of ERα is required for the recruitment of COMPASS-like core subunits to the cis-regulatory element of ERα target genes in breast cancer cells. BAP18 is recruited to the promoter regions of estrogen-induced genes, accompanied with the enrichment of the lysine 4-trimethylated histone H3 tail (H3K4me3) in the presence of E2. Furthermore, BAP18 promotes cell growth and associates the sensitivity of antiestrogen in ERα-positive breast cancer. Our data suggest that BAP18 facilitates the association between ERα and COMPASS-like core subunits, which might be an essential epigenetic therapeutic target for breast cancer.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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癌症治疗
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
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IF 5.6
Shan Yu,Jinghui Yang,Rui Zhang,Yu Zhang,Xinyi Fei
Cerebral ischemia-reperfusion injury (CIRI) usually has a high mortality and disability rate, and inflammatory stimulation is an important risk factor for CIRI. ISL LIM Homeobox 1 (ISL1) is involved in the regulation of inflammatory response, and its role in CIRI progression has not been reported. Here, we established an animal model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) and found that ISL1 was up-regulated in the peri-infarct cortex of tMCAO/R mice (log 2 FC = 4.7, adj. p < 0.01) and improved neurological dysfunction and reduced infarct size. At the same time, we found that ISL1 suppressed the expression of proinflammatory markers in the peri-infarct cortex. Consistently, in an oxygen-glucose deprivation/reoxygenation (OGD/R)-induced microglial HMC3 cell model, ISL1 overexpression significantly curtailed the inflammatory response, as evidenced by reduced iNOS and CD16/32 expression. Mechanistically, dual-luciferase and ChIP assays confirmed that ISL1 promotes the transcriptional activation of Stanniocalcin 1 (STC1) by enhancing H3K4me3 enrichment at its promoter region. Furthermore, GST pull-down analyses suggested that this transcriptional regulation is likely mediated through the physical interaction between ISL1 and WDR5, which may recruit the MLL complex to facilitate H3K4me3 deposition. Collectively, our findings indicate that the ISL1-WDR5-H3K4me3 axis contributes to the upregulation of STC1, thereby attenuating neuroinflammation and CIRI-induced brain injury.
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DOI
PubMed
高影响因子
DEVELOPMENT
·
2025
·Vol. 152
·期 6
·
IF 3.6
Lin Zhen,Rong Bowen,Wu Meixia,Yan Junyi,Hong Tong,Hou Linjun,Tang Xinzhe,Liu Qiang,Peng Xiaozhong,Chen Yao,Lan Fei,Tong Ming-Han
ASH2L is a core component of KMT2 complexes, crucial for H3K4 trimethylation. However, its role in spermatogenesis remains elusive. Here, we demonstrate an essential role of Ash2l for meiotic prophase but dispensable for mitosis in differentiated spermatogonia. Using a germ cell-specific Ash2l knockout mouse model, we reveal that Ash2l deficiency leads to meiotic arrest and sterility in both sexes. Ash2l -deficient spermatocytes exhibit failures in chromosomal synapsis associated with persistent DMC1 foci and γH2AX, resulting in meiocyte loss due to apoptosis. Conversely, Ash2l -deficient differentiated spermatogonia show normal development. Mechanistically, Ash2l deficiency results in a global loss of H3K4me3 in promoter regions and significantly decreases expression of thousands of genes. Among these are genes involved in epigenetic silencing pathways, such as H3K9 di-methylation, DNA methylation and piRNA pathways, that are crucial for transposon repression during meiotic prophase I progression. Supporting this, we observe that Ash2l mutant spermatocytes display ectopic expression of LINE1-ORF1P. Our findings therefore reveal the previously unappreciated role of ASH2L-dependent H3K4me3 modification in spermatogenesis and provide clues to the molecular mechanisms in epigenetic disorders underlying male infertility.
研究领域:
分子生物学
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生殖生物学
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遗传学
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DOI
PubMed
高影响因子
Pigment Cell & Melanoma Research
·
2025
·Vol. 38
·期 4
·e70034
·
IF 2.6
Man Cai,Liangyu Wang,Miao Sun,Meixi Liu,Yingchun Liu
Protein arginine methyltransferase 6 (PRMT6), a member of the PRMT family capable of self-arginine methylation, is down-regulated in melanoma, but the specific mechanism is still unclear. Our work demonstrated that PRMT6 overexpression significantly inhibited the ability of melanoma cells to proliferate, tumorigenicity, migration, and invasion, whereas PRMT6 knockdown rescued these malignant behaviors of melanoma cells. Mechanistically, we identified aldehyde dehydrogenase 1A1 (ALDH1A1) as a critical downstream target of PRMT6. PRMT6 knockdown up-regulated ALDH1A1 expression, exacerbating melanoma aggressiveness in vitro. Further investigations revealed that PRMT6 modulates ALDH1A1 expression by catalyzing asymmetric dimethylation of histone H3 at arginine 2 (H3R2me2a) and antagonizing the enrichment of histone H3 lysine 4 trimethylation (H3K4me3) at the ALDH1A1 promoter. In addition, dual-luciferase experiments showed that the transcription factor KLF4 may bind to the −1800 ~ +45 sequence of PRMT6, thereby negatively regulating PRMT6 expression in melanoma. Our findings underscore the tumor-suppressive role of PRMT6 in melanoma pathogenesis, highlighting its potential as a novel therapeutic target, particularly for metastatic melanoma.
研究领域:
癌症生物学
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分子生物学
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表观遗传学
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生物化学
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细胞生物学
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DOI
PubMed
高影响因子
Cell Reports
·
2023
·
IF 8.8
Xue Wen,Yang Xiao,Haitao Xiao,Xueqin Tan,Beiyi Wu,Zehua Li,Ru Wang,Xuewen Xu,Tao Li
Summary Bisphenol S (BPS) exposure has been implied epidemiologically to increase obesity risk, but the underlying mechanism is unclear. Here, we propose that BPS exposure at an environmentally relevant dose aggravates diet-induced obesity in female mice by inducing brown adipose tissue (BAT) whitening. We explored the underlying mechanism by which KDM5A-associated demethylation of the trimethylation of lysine 4 on histone H3 (H3K4me3) in thermogenic genes is overactivated in BAT upon BPS exposure, leading to the reduced expression of thermogenic genes. Further studies have suggested that BPS activates KDM5A transcription in BAT by binding to glucocorticoid receptor (GR) in an estrogen-dependent manner. Estrogen-estrogen receptors facilitate the accessibility of the KDM5A gene promoter to BPS-activated GR by recruiting the activator protein 1 (AP-1) complex. These results indicate that BAT is another important target of BPS and that targeting KDM5A-related signals may serve as an approach to counteract the BPS-induced susceptivity to obesity.
研究领域:
内分泌学
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分子生物学
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肥胖研究
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表观遗传学
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DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
·
2022
·Vol. 30
·期 5
·13739-13754
·
IF 5.19
Wu Hao,Bao Yuling,Yan Tongtong,Huang Hui,Jiang Ping,Zhang Zhan,Li Lei,Wu Qian
Epidemiological studies have shown that PAHs may exert adverse effects on childhood asthma. However, the underlying molecular mechanism remains to be fully elucidated. This study aimed to investigate this process in view of metabolic pathways, especially one-carbon metabolism and tryptophan metabolism. Fifty asthmatic children and 50 control subjects were recruited for this study. Serum IgE and IL-17A levels were detected by ELISA. Serum PAH concentrations were measured by GC-MS. One-carbon-related metabolites and tryptophan metabolites were determined by UPLC-Orbitrap-MS. DNA methylation was analyzed by bisulfite sequencing PCR. ChIP assays were used to examine H3K4me3 enrichment on IL-17A gene. Multivariable linear regression was performed to evaluate the association between PAHs and childhood asthma mediated by intermediators. HE staining in lung tissue, IgE and IL-17A in BALF, metabolic profiles in urine, and Ahr , Il-17a , and Cyp1a1 gene expression were determined in PAH-exposed mice. Serum Fla level was associated with childhood asthma (OR = 1.380, 95% CI: 1.063–1.792), and had a great effect on one-carbon metabolites, especially SAH, SAM, and Ser, which exerted significant mediation effects on the relationship between the Fla concentration and asthma. Moreover, we did find significant mediation effects between serum Fla and asthma by LINE-1 DNA methylation and H3K4me3 levels in the IL-17A promoter region. The differential Trp metabolites, such as Trp, tryptamine, IA, IAA, indole, IAld, and IAAld, indicated that asthmatic children had increased indole-AhR pathway. Mediation analysis failed to show a mediator effect of Trp metabolites in the association between PAHs and childhood asthma. An animal study confirmed that PAH exposure increased methylation levels, and altered Trp metabolite-AhR-IL-17A axis, which may be influenced by gender. PAHs disturbed one-carbon metabolism to influence the methyl group refilling DNA methylation and histone methylation, and disturbed tryptophan metabolism to regulate Th17-cell differentiation, which may elevate serum IL-17A concentration in asthmatic children.
研究领域:
环境卫生
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免疫学
·
分子生物学
·
儿科
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2019
·
IF 7.65
Zhuo Li,Zhenyang Yu,Changzheng Cui,Fangting Ai,Daqiang Yin
Increasing concerns are earned on the multigenerational hazards of antibiotics due to the connection between their mother-children transfer via cord blood and breast milk and obesity in the children. Currently, Caenorhabditis elegans was exposed to sulfamethoxazole (SMX) over 11 generations (F0–F10). Indicators of obesogenic effects and gene expressions were measured in each generation and also in T11 to T13 that were the offspring of F10. Biochemical analysis results showed that SMX stimulated fatty acids in most generations including T13. The stimulation was resulted from the balance between enzymes for fatty acid synthesis (e.g., fatty acid synthetase) and those for its consumption (e.g., fatty acid transport protein). Gene expression analysis demonstrated that the obesogenic effects of SMX involved peroxisome proliferator activated receptors (PPARs, e.g., nhr-49 ) and insulin/insulin-like signaling (IIS) pathways (e.g., ins-1 , daf-2 and daf-16 ). Further epigenetic analysis demonstrated that SMX caused 3-fold more H3K4me3 binding genes than the control in F10 and T13. In F10, the most significantly activated genes were in metabolic and biosynthetic processes of various lipids, nervous system and development. The different gene expressions in T13 from those in F10 involved development, growth, reproduction and responses to chemicals in addition to metabolic processes.
研究领域:
药理学
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毒理学
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表观遗传学
·
分子生物学
·
发育生物学
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DOI
PubMed
高影响因子
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