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Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation
Xie, Zhongyu,Zhang, Di,Chung, Dongjun,Tang, Zhanyun,Huang, He,Dai, Lunzhi,Qi, Shankang,Li, Jingya,Colak, Gozde,Chen, Yue,Xia, Chunmei,Peng, Chao,Ruan, Haibin,Kirkey, Matt,Wang, Danli,Jensen, Lindy M. Elsevier 2016 Molecular cell Vol.62 No.2
<P><B>Summary</B></P> <P>Here we report the identification and verification of a β-hydroxybutyrate-derived protein modification, lysine β-hydroxybutyrylation (Kbhb), as a new type of histone mark. Histone Kbhb marks are dramatically induced in response to elevated β-hydroxybutyrate levels in cultured cells and in livers from mice subjected to prolonged fasting or streptozotocin-induced diabetic ketoacidosis. In total, we identified 44 histone Kbhb sites, a figure comparable to the known number of histone acetylation sites. By ChIP-seq and RNA-seq analysis, we demonstrate that histone Kbhb is a mark enriched in active gene promoters and that the increased H3K9bhb levels that occur during starvation are associated with genes upregulated in starvation-responsive metabolic pathways. Histone β-hydroxybutyrylation thus represents a new epigenetic regulatory mark that couples metabolism to gene expression, offering a new avenue to study chromatin regulation and diverse functions of β-hydroxybutyrate in the context of important human pathophysiological states, including diabetes, epilepsy, and neoplasia.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Lysine β-hydroxybutyrylation (Kbhb) is a new type of histone mark </LI> <LI> 44 non-redundant histone Kbhb sites are identified in human and mouse cells </LI> <LI> Histone Kbhb increases under starvation and STZ-induced ketoacidosis </LI> <LI> Starvation-induced H3K9bhb is associated with active gene expression </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>
Xie Zhongyu,Yu Wenhui,Ye Guiwen,Li Jinteng,Zheng Guan,Liu Wenjie,Lin Jiajie,Su Zepeng,Che Yunshu,Ye Feng,Zhang Zhaoqiang,Wang Peng,Wu Yanfeng,Shen Huiyong 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-
Mesenchymal stem cells (MSCs) are a common kind of multipotent cell in vivo, but their heterogeneity limits their further applications. To identify MSC subpopulations and clarify their relationships, we performed cell mapping of bone-marrow-derived MSCs through single-cell RNA (scRNA) sequencing. In our study, three main subpopulations, namely, the stemness subpopulation, functional subpopulation, and proliferative subpopulation, were identified using marker genes and further bioinformatic analyses. Developmental trajectory analysis showed that the stemness subpopulation was the root and then became either the functional subpopulation or the proliferative subpopulation. The functional subpopulation showed stronger immunoregulatory and osteogenic differentiation abilities but lower proliferation and adipogenic differentiation. MSCs at different passages or isolated from different donors exhibited distinct cell mapping profiles, which accounted for their corresponding different functions. This study provides new insight into the biological features and clinical use of MSCs at the single-cell level, which may contribute to expanding their application in the clinic.
Jinteng Li,Peng Wang,Zhongyu Xie,Rui Yang,Yuxi Li,Xiaohua Wu,Hongjun Su,Wen Deng,Shan Wang,Zhenhua Liu,Shuizhong Cen,Yi Ouyang,Yanfeng Wu,Huiyong Shen 생화학분자생물학회 2017 Experimental and molecular medicine Vol.49 No.-
Ankylosing spondylitis (AS) is a type of autoimmune disease that predominantly affects the spine and sacroiliac joints. However, the pathogenesis of AS remains unclear. Some evidence indicates that infection with bacteria, especially Gram-negative bacteria, may have an important role in the onset and progression of AS. Recently, many studies have demonstrated that mesenchymal stem cells (MSCs) dysfunction may contribute to the pathogenesis of many rheumatic diseases. We previously demonstrated that MSCs from AS patients exhibited markedly enhanced osteogenic differentiation capacity in vitro under non-inflammatory conditions. However, the properties of MSCs from AS patients in an inflammatory environment have never been explored. Lipopolysaccharide (LPS), a proinflammatory substance derived from the outer membrane of Gram-negative bacteria, can alter the status and function of MSCs. However, whether MSCs from AS patients exhibit abnormal responses to LPS stimulation has not been reported. Autophagy is a lysosome-mediated catabolic process that participates in many physiological and pathological processes. The link between autophagy and AS remains largely unknown. The level of autophagy in ASMSCs after LPS stimulation remains to be addressed. In this study, we demonstrated that although the basal level of autophagy did not differ between MSCs from healthy donors (HDMSCs) and ASMSCs, LPS-induced autophagy was weaker in ASMSCs than in HDMSCs. Specifically, increased TRAF4 expression in ASMSCs impaired LPS-induced autophagy, potentially by inhibiting the phosphorylation of Beclin-1. These data may provide further insight into ASMSC dysfunction and the precise mechanism underlying the pathogenesis of AS.
Zihao Chen,Lei He,Lijun Huang,Zhongyu Liu,Jianwen Dong,Bin Liu,Ruiqiang Chen,Liangming Zhang,Peigen Xie,Limin Rong 대한척추신경외과학회 2022 Neurospine Vol.19 No.1
Objective: A post hoc subgroup analysis of prospectively collected data from a randomized controlled trial was conducted to identify risk factors related to poor outcomes in patients who underwent minimally invasive discectomy. Methods: Patients were divided into satisfied and dissatisfied subgroups based on Oswestry Disability Index (ODI), visual analogue scale (VAS) back pain score (VAS-back) and leg pain score (VAS-leg) at short-term and midterm follow-up according to the patient acceptable symptom state threshold. Demographic characteristics, radiographic parameters, and clinical outcomes between the satisfied and dissatisfied subgroups were compared using univariate and multivariate analysis. Results: A total of 222 patients (92.1%) completed 2-year follow-up, and the postoperative ODI, VAS-back, and VAS-leg were significantly improved after surgery as compared to preoperatively. Multivariate analysis indicated older age (p = 0.026), lateral recess stenosis (p = 0.046), and lower baseline ODI (p = 0.027) were related to poor short-term functional improvement. Higher baseline VAS-back (p = 0.048) was associated with poor short-term relief of back pain, while absence of decreased sensation (p = 0.019) and far-lateral disc herniation (p = 0.004) were associated with poorer short-term relief of leg pain. Lumbar facet joint osteoarthritis was identified as a risk factor for poor functional improvement (p = 0.003) and relief of back pain (p = 0.031). Disc protrusion (p = 0.036) predicted poorer relief of back pain at midterm follow-up. Conclusion: In this study, several factors were identified to be predictive of poor surgical outcomes following minimally invasive discectomy. (ClinicalTrials.gov number: NCT01997086).
Ye Guiwen,Li Jinteng,Yu Wenhui,Xie Zhongyu,Zheng Guan,Liu Wenjie,Wang Shan,Cao Qian,Lin Jiajie,Su Zepeng,Li Dateng,Che Yunshu,Fan Shuai,Wang Peng,Wu Yanfeng,Shen Huiyong 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-
Improving health and delaying aging is the focus of medical research. Previous studies have shown that mesenchymal stem cell (MSC) senescence is closely related to organic aging and the development of aging-related diseases such as osteoarthritis (OA). m6A is a common RNA modification that plays an important role in regulating cell biological functions, and ALKBH5 is one of the key m6A demethylases. However, the role of m6A and ALKBH5 in MSC senescence is still unclear. Here, we found that the m6A level was enhanced and ALKBH5 expression was decreased in aging MSCs induced by multiple replications, H2O2 stimulation or UV irradiation. Downregulation of ALKBH5 expression facilitated MSC senescence by enhancing the stability of CYP1B1 mRNA and inducing mitochondrial dysfunction. In addition, IGF2BP1 was identified as the m6A reader restraining the degradation of m6A-modified CYP1B1 mRNA. Furthermore, Alkbh5 knockout in MSCs aggravated spontaneous OA in mice, and overexpression of Alkbh5 improved the efficacy of MSCs in OA. Overall, this study revealed a novel mechanism of m6A in MSC senescence and identified promising targets to protect against aging and OA.