JOURNAL OF CLINICAL LABORATORY ANALYSIS
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2022
·Vol. 36
·期 11
·e24698
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IF 3.124
Chunfa Chen,Liang Liu
Background Osteosarcoma (OS) is a highly recurrent malignancy occurring among adolescents. The goal of this research was to scrutinize the role and action mechanism of KLF3-AS1 in OS. Methods Western blotting and quantitative reverse transcription real-time PCR were conducted to ascertain the mRNA expressions of miR-338-3p, KLF3-AS1, and MEF2C in OS cell lines and tissue samples. Colony formation and CCK-8 experiments were done to evaluate the proliferative capacity of the cells. Western blotting was also executed to measure the relative expressions of the proteins Bcl-2 and Bax. RNA immunoprecipitation and dual luciferase reporter experiments were carried out to validate the target relationships among MEF2C, KLF3-AS1, and miR-338-3p. Mouse xenograft models were created to assess the influences of KLF3-AS1 on the growth of tumors in vivo. Results Elevated levels of KLF3-AS1 and MEF2C and reduced amounts of miR-338-3p were identified in OS. KLF3-AS1 targeted miR-338-3p, and miR-338-3p further targeted MEF2C. Silencing KLF3-AS1 induced apoptosis and attenuated proliferation in vitro and repressed the tumor growth in vivo. Inhibiting miR-338-3p inverted the cancer-suppressing effects of KLF3-AS1 silencing. Meanwhile, loss of MEF2C partially eliminated the effects brought about by miR-338-3p downregulation, namely the stimulation of cell growth and suppression of apoptosis. Conclusions Silencing of KLF3-AS1 could repress the growth of cells and induce apoptosis by regulating miR-338-3p/MEF2C in OS. This suggests that the regulatory axis KLF3-AS1/miR-338-3p/MEF2C is a prospective target for OS treatment.
研究领域:
肿瘤学
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分子生物学
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遗传学
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产品关联
DOI
PubMed
高影响因子
Communications Biology
·
2020
·Vol. 3
·期 1
·1-15
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IF 4.165
Ren Hongyan,Xiao Wei,Qin Xingliang,Cai Gangzhi,Chen Hao,Hua Zaidong,Cheng Cheng,Li Xinglei,Hua Wenjun,Xiao Hongwei,Zhang Liping,Dai Jiali,Zheng Xinmin,Zhu Zhe,Qian Chong,Yao Jie,Bi Yanzhen
Myostatin (MSTN), associated with the “double muscling” phenotype, affects muscle growth and fat deposition in animals, whereas how MSTN affects adipogenesis remains to be discovered. Here we show that MSTN can act through the MEF2C/miR222/SCD5 cascade to regulate fatty acid metabolism. We generated MSTN-knockout (KO) cloned Meishan pigs, which exhibits typical double muscling trait. We then sequenced transcriptome of subcutaneous fat tissues of wild-type (WT) and MSTN-KO pigs, and intersected the differentially expressed mRNAs and miRNAs to predict that stearoyl-CoA desaturase 5 (SCD5) is targeted by miR222. Transcription factor binding prediction showed that myogenic transcription factor 2C (MEF2C) potentially binds to the miR222 promoter. We hypothesized that MSTN-KO upregulates MEF2C and consequently increases the miR222 expression, which in turn targets SCD5 to suppress its translation. Biochemical, molecular and cellular experiments verified the existence of the cascade. This novel molecular pathway sheds light on new targets for genetic improvements in pigs.
研究领域:
动物遗传学
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分子生物学
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动物科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Wei Zhu,Pei Zhao,Tingting Liu,Feng Gao,Qi Li,Xin Cai,Man Zhang,Alex Aliper,Feng Ren,Alex Zhavoronkov,Xiao Ding
The dual inhibition of SIK2/3 has been considered as a potential treatment approach for MEF2C-high acute myeloid leukemia (AML). Although diverse scaffolds of pan-SIK or SIK2/3 inhibitors have been reported, few of them showed sufficient in vitro or in vivo antitumor activity. Based on the proposed binding mode of the hit molecule (7), chemical space in the solvent/P-loop region was explored via fragment growing/replacement, supported by the generative chemistry platform. Further SAR exploration and ADME optimization led to the discovery of 7s, which exhibited excellent potency and strong selectivity in MEF2C high-expression cell lines over MEF2C-low cell lines. Moreover, oral administration of 7s was found to demonstrate significant tumor growth inhibition in a MV4-11 AML mice CDX model without any body weight loss. This work highlights the potential of targeting MEF2C-dependent AML by selective oral SIK2/3 inhibitors, which was supported by the generative models.
研究领域:
药理学
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肿瘤学
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药物化学
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血液学
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产品关联
DOI
PubMed
高影响因子
iScience
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2024
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IF 4.6
Xiaoyin Rong,Ruixiao Li,Tianye Gong,Haonan Li,Xiaolei Zhao,Guoqing Cao,Meng Li,Bugao Li,Yang Yang,Xiaohong Guo
Circular RNA is a special category of non-coding RNA that has emerged as epigenetic regulator of adipose tissue development. However, the mechanism governing intramuscular adipogenesis of circRNA remains largely uncharted. In this study, circMEF2C(2, 3), looped by MEF2C exons 2 and 3, was identified from the pig MEF2C gene. Expression of circMEF2C(2, 3) is upregulated in early stage of intramuscular adipogenesis and muscular tissue of lean pigs (DLY pig). Subsequently, overexpression or knockdown of circMEF2C(2, 3) reflected that it participates in promoting proliferation and inhibiting adipogenic differentiation in porcine intramuscular preadipocytes and murine C3H10T1/2 cells. Mechanically, circMEF2C(2, 3) competitively combined with miR-383 and miR-671-3p to the 3′-UTR of MEF2C , which maintains MEF2C expression in regulating proliferation and adipogenesis. In summary, circMEF2C(2, 3) is a key regulator in the proliferation and adipogenic differentiation of intramuscular adipogenesis, suggesting its potential as a multi-target strategy for adipose development and associated diseases.
研究领域:
分子生物学
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发育生物学
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动物遗传育种
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脂肪代谢
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
Genes & Diseases
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2026
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IF 14.6
Mi Zhang,Hui Gan,Qing Xu,Yaying He,Yuhao Duan,Chenyang Li,Le Qin,Yutong Hu,Lanyu Zhang,Jing Zhao,Xuan Zhai
Ferroptosis plays a critical role in secondary brain injury following intracerebral hemorrhage (ICH). However, the regulatory mechanisms governing ferroptosis after ICH remain unexplored. By transcriptome sequencing of brain tissues from ICH patients and mouse models, we identified myocyte enhancer factor 2C (MEF2C) as a key ferroptosis-related gene. MEF2C was downregulated in human and mouse ICH brains and mainly localized to neurons. Neuron-specific MEF2C overexpression suppressed ferroptosis and improved neurological outcomes after ICH in mice. We further overexpressed and knocked out MEF2C in the mouse neuronal cell line HT22 and conducted in vitro experiments using hemoglobin (Hb) and ferroptosis inducers (RSL3 and erastin). Our findings indicated that MEF2C inhibited reactive oxygen species (ROS) accumulation, lipid peroxidation, and Fe 2+ overload, thereby inhibiting ferroptosis. Subsequent transcriptomic analysis identified fibroblast growth factor 21 (FGF21), a protein previously reported to regulate ferroptosis, as a downstream gene of MEF2C. Dual-luciferase and chromatin immunoprecipitation assays confirmed that MEF2C directly activates Fgf21 transcription. Finally, the in vitro model of ICH demonstrated that FGF21 modulates oxidant stress and Fe 2+ accumulation and that FGF21 knockdown abrogated MEF2C-reduced oxidative stress and Fe 2+ accumulation, indicating that FGF21 is required for MEF2C-mediated anti-ferroptosis. Taken together, MEF2C protects against ICH-induced ferroptosis by transcriptionally regulating FGF21. Our work provides new insights and potential therapeutic targets for the treatment of ICH.
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DOI
高影响因子
EMBO REPORTS
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2020
·Vol. 21
·期 11
·e50283
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IF 7.497
Mingliang Bai,Dan Ye,Xudong Guo,Jiajie Xi,Nana Liu,Yukang Wu,Wenwen Jia,Guiying Wang,Wen Chen,Guoping Li,Zeyidan Jiapaer,Jiuhong Kang
A microdeletion within human chromosome 5q14.3 has been associated with the occurrence of neurodevelopmental disorders, such as autism and intellectual disability, and MEF2C haploinsufficiency was identified as main cause. Here, we report that a brain-enriched long non-coding RNA, NDIME, is located near the MEF2C locus and is required for normal neural differentiation of mouse embryonic stem cells (mESCs). NDIME interacts with EZH2, the major component of polycomb repressive complex 2 (PRC2), and blocks EZH2-mediated trimethylation of histone H3 lysine 27 (H3K27me3) at the Mef2c promoter, promoting MEF2C transcription. Moreover, the expression levels of both NDIME and MEF2C were strongly downregulated in the hippocampus of a mouse model of autism, and the adeno-associated virus (AAV)-mediated expression of NDIME in the hippocampus of these mice significantly increased MEF2C expression and ameliorated autism-like behaviors. The results of this study reveal an epigenetic mechanism by which NDIME regulates MEF2C transcription and neural differentiation and suggest potential effects and therapeutic approaches of the NDIME/MEF2C axis in autism.
研究领域:
神经科学
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干细胞生物学
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遗传学
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表观遗传学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Nature Communications
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2026
·Vol. 17
·期 1
·4225
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IF 18.1
Wang Yu-Meng,Jia Yanyan,Wu Yu,Zhao Qiaohang,Guo Yumeng,Zhang Li,Jin Min,Zheng Yufang
Elevated prenatal androgen levels have been associated with an increased incidence of several neurodevelopmental conditions in offspring. However, the underlying mechanisms remain poorly understood. Here we showed that elevated prenatal androgens, modeled via aromatase inhibition in mice, disrupt cortical development and behavior in male offspring by activating androgen receptors (AR). AR interacts with MeCP2 to upregulate the transcription factor MEF2C, bypassing standard androgen response elements. Knocking down Mecp2 or Mef2c , or blocking AR, reversed these effects. Mecp2 duplication alone also upregulated MEF2C, driving similar neurogenesis and behavioral changes that were reversed by AR blockade. This reveals a MeCP2-mediated, non-canonical pathway by which androgens may contribute to male-biased neurodevelopmental conditions.
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DOI
高影响因子
Communications Biology
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2025
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IF 5.1
Wang Shanshan,Wu Zankai,Song Wenqin,Zhang Hui,Bu Xueshan,Gao Wenwei,Wu Kefan,Xia Zhongyuan,Zhao Bo,Wang Wei
Activation of the cGAS-STING pathway has been proposed as a potential pathogenic mechanism underlying postoperative cognitive dysfuncton (POCD). Analysis of public transcriptomic data from the hippocampus of male mice suggests upregulation of Rbm47 in an experimental POCD model. In vitro, knockdown (KD) of Rbm47 in BV2 cells reduces levels of cGAS, STING, TNF-α, IL-6, and IFN-β under isoflurane and lipopolysaccharide (Iso + LPS) conditions. HT22 cells exposed to culture medium from Rbm47 -KD BV2 cells treated with Iso + LPS show increased levels of MEF2C, GPX4, GSH, and SOD, and reduced levels of MDA and iron. Microglial Rbm47 overexpression amplifies cGAS-STING signaling and aggravates neuronal ferroptosis, which is reversed by the cGAS inhibitor RU.521. Rbm47 KD combined with RU.521 treatment synergistically ameliorates POCD in male mice. Mechanistically, the RRM2 domain of RBM47 interacts with the 3’UTR of cGAS mRNA, enhancing its stability. RUNX1 directly binds to the Rbm47 promoter and facilitates its transcription. RUNX1 overexpression activates the RBM47-cGAS-STING axis and exacerbates neuronal ferroptosis. Conversely, RUNX1 ablation ameliorates POCD, dampens the cGAS-STING signaling, and inhibits ferroptosis, which is abolished by RBM47 depletion. Our findings suggest that repression of RUNX1/RBM47 may represent a promising therapeutic strategy for POCD.
研究领域:
神经科学
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分子生物学
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免疫学
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细胞生物学
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麻醉与围术期医学
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DOI
PubMed
高影响因子
DEVELOPMENT
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2024
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IF 3.7
Yu Meng,Thorner Konrad,Parameswaran Sreeja,Wei Wei,Yu Chuyue,Lin Xinhua,Kopan Raphael,Hass Matthew R.
The conserved Runt-related (RUNX) transcription factor family are master regulators of developmental and regenerative processes. Runx1 and Runx2 are expressed in satellite cells (SC) and in skeletal myotubes. Conditional deletion of Runx1 in adult SC negatively impacted self-renewal and impaired skeletal muscle maintenance even though Runx2 expression persisted. Runx1 deletion in C2C12 cells that retain Runx2 expression identified unique molecular functions of Runx1 that cannot be compensated by Runx2. The reduced myoblast fusion in vitro caused by Runx1 loss was due in part to ectopic expression of Mef2c, a target repressed by Runx1 . Structure-function analysis demonstrated that the Ets-interacting MID/EID region of Runx1, absent from Runx2, is critical to Runx1 myoblast function and for Etv4 binding. Analysis of ChIP-seq datasets from Runx1 (T-cells, muscle) versus Runx2 (preosteoblasts) dependent tissues identified a composite Ets:Runx motif enriched in Runx1 -dependent tissues. The Ets:Runx composite motif was enriched in peaks open exclusively in ATAC-seq datasets from WT cells compared to ATAC peaks unique to Runx1KO cells. Thus, engagement of a set of targets by the RUNX1/ETS complex define the non-redundant functions of Runx1 .
研究领域:
分子生物学
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细胞生物学
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转录因子
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肌肉再生
✓ 已验证
DOI
高影响因子
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