Evaluation of time-dependent phenotypes of myocardial ischemia-reperfusion in mice.

BACKGROUND: A mouse model of myocardial ischemia-reperfusion (I/R) is widely used to study myocardial ischemia-reperfusion injury (I/RI). However, few studies focus on the direct comparison of the extent of pathological events resulting from variant durations of ischemia and reperfusion process. METHODS: A mouse model of I/RI was established by ligation and perfusion of the left anterior descending coronary artery (LAD), and the dynamic changes were recorded by electrocardiogram at different stages of I/R. Subsequently, reperfusion duration was used as a variable to directly compare the phenotypes of different myocardial injury degrees induced by 3 h, 6 h and 24 h reperfusion from myocardial infarct size, myocardial apoptosis, myocardial enzyme, and inflammatory cytokine levels. RESULTS: All mice subjected to myocardial I/R surgery showed obvious myocardial infarction, extensive myocardial apoptosis, dynamic changes in serum myocardial enzyme and inflammatory cytokines, at least for the first 24 h of reperfusion. The infarct size and apoptosis rates gradually increased with the extension of reperfusion time. The peaks of serum myocardial enzyme and inflammatory cytokines occurred at 6 h and 3 h of reperfusion, respectively. We also established I/R mice models with 30 and 60 mins of ischemia. After 21 days of remodeling, longer periods of ischemia increased the degree of fibrosis and reduced cardiac function. CONCLUSIONS: In summary, we conclude that reperfusion durations of 3 h, 6 h, and 24 h induces different injury phenotypes in ischemia-reperfusion mouse model. At the same time, the ischemia duration before reperfusion also affects the degree of cardiac remodeling.

Loss of Histone Methyltransferase KMT2D Attenuates Angiogenesis in the Ischemic Heart by Inhibiting the Transcriptional Activation of VEGF-A.

Angiogenesis occurred after myocardial infarction (MI) protects heart failure (HF). The aim of our study was to explore function of histone methyltransferase KMT2D (MLL4, mixed-lineage leukemia 4) in angiogenesis post-MI. Western blotting showed that KMT2D protein expression was elevated in MI mouse myocardial. Cardiomyocyte-specific Kmt2d-knockout (Kmt2d-cKO) mice were generated, and echocardiography and immunofluorescence staining detected significantly attenuated cardiac function and insufficient angiogenesis following MI in Kmt2d-cKO mice. Cross-talk assay suggested that Kmt2d-KO H9c2-derived conditioned medium attenuates EA.hy926 EC function. ELISA further identified that VEGF-A released from Kmt2d-KO H9c2 was significantly reduced. CUT&Tag and RT-qPCR revealed that KMT2D deficiency reduced Vegf-a mRNA expression and enrichment of H3K4me1 on the Vegf-a promoter. Moreover, KMT2D silencing in ECs also suppressed endothelial function. Our study indicates that KMT2D depletion in both cardiomyocytes and ECs attenuates angiogenesis and that loss of KMT2D exacerbates heart failure after MI in mice.

Human Adipose-Derived Mesenchymal Stem Cell-Based Microspheres Ameliorate Atherosclerosis Progression In Vitro.

Atherosclerosis (AS) is a chronic inflammatory disease associated with lipid deposition, which could be converted into acute clinical events by thrombosis or plaque rupture. Adipose-derived mesenchymal stem cell (ADSC)-encapsulated repair units could be an effective cure for the treatment of AS patients. In this study, we encapsulate human adipose-derived mesenchymal stem cells (hADSCs) in collagen microspheres to fabricate stem cell repair units. Besides, we show that encapsulation in collagen microspheres and cultured in vitro for 14 days maintain the viability and stemness of hADSCs. Moreover, we generate AS progression model and niche in vitro by combining hyperlipemia serum of AS patients with AS cell models. We further systematically demonstrate that hADSC-based microspheres could ameliorate AS progression by inhibiting oxidative stress injury, cell apoptosis, endothelial dysfunction, inflammation, and lipid accumulation. In addition, we perform transcriptomic analysis and functional studies to demonstrate how hADSCs (three dimensional cultured in microspheres) respond to AS niche compared with healthy microenvironment. These findings reveal a role for ADSC-based microspheres in the treatment of AS and provide new ideas for stem cell therapy in cardiovascular disease. The results may have implications for improving the efficiency of hADSC therapies by illuminating the mechanisms of hADSCs exposed in special pathological niche.

Comparative Study of Different Acupoints for Treating Acute Myocardial Ischemia in Mice.

Acupuncture point specificity has been recognized as a key scientific issue in traditional Chinese medicine (TCM), but there is limited clinical trial or animal study to verify the characteristics of PC6, BL15, and ST36 in the protection from myocardial injury. We aimed to compare the effects among these three acupoints on the acute myocardial infarction mice model and to explore possible mechanisms for the first time. We found that PC6 is the most appropriate acupoint to deliver efficacy and safety to treat acute MI in mice. BL15 stimulation improved the systolic function, but increased the risk of arrhythmia. ST36 only slightly attenuated systolic function and had no effect on arrhythmia during MI. RNA profiles of skin tissue in local acupoints demonstrated that the most altered DEGs and related pathways may partly support its best effects of PC6 treatment on MI injury, and support the observed phenomenon of the acupoint specificity.

Cryptotanshinone inhibits ovarian tumor growth and metastasis by degrading c-Myc and attenuating the FAK signaling pathway.

Cryptotanshinone (CT), a natural compound derived from Salvia miltiorrhiza Bunge that is also known as the traditional Chinese medicine Danshen, exhibits antitumor activity in various cancers. However, it remains unclear whether CT has a potential therapeutic benefit against ovarian cancers. The aim of this study was to test the efficacy of CT in ovarian cancer cells in vitro and using a xenograft model in NSG mice orthotopically implanted with HEY A8 human ovarian cancer cells and to explore the molecular mechanism(s) underlying CT's antitumor effects. We found that CT inhibited the proliferation, migration, and invasion of OVCAR3 and HEY A8 cells, while sensitizing the cell responses to the chemotherapy drugs paclitaxel and cisplatin. CT also suppressed ovarian tumor growth and metastasis in immunocompromised mice orthotopically inoculated with HEY A8 cells. Mechanistically, CT degraded the protein encoded by the oncogene c-Myc by promoting its ubiquitination and disrupting the interaction with its partner protein Max. CT also attenuated signaling via the nuclear focal adhesion kinase (FAK) pathway and degraded FAK protein in both cell lines. Knockdown of c-Myc using lentiviral CRISPR/Cas9 nickase resulted in reduction of FAK expression, which phenocopies the effects of CT and the c-Myc/Max inhibitor 10058-F4. Taken together, our studies demonstrate that CT inhibits primary ovarian tumor growth and metastasis by degrading c-Myc and FAK and attenuating the FAK signaling pathway.

Histone methyltransferase KMT2D contributes to the protection of myocardial ischemic injury.

Histone H3 lysine 4 (H3K4) methyltransferase 2D (KMT2D) plays an important role in cell development in early life. However, the function of KMT2D in adult cells such as cardiomyocytes or neurons has not been reported. In this study, cardiomyocyte-specific KMT2D knockout (KMT2D-cKO) and control (KMT2D-Ctl) mice were exposed to sham or myocardial ischemia (MI) surgery. Depletion of KMT2D aggravated the ischemic area, led to the increased mortality (26.5% in KMT2D-cKO vs 12.5% in KMT2D-Ctl) of the mice, and weakened the left ventricular systolic function. RNA-seq analysis in cardiac tissues identified genes whose expression was changed by MI and KMT2D deletion. Combined with the genome-wide association study (GWAS) analysis, cardiac disease-associated genes Rasd1, Thsd7a, Ednra, and Tns1 were identified. The expression of the Rasd1 was significantly decreased by MI or the loss of KMT2D in vivo. Meanwhile, ChIP assays demonstrated that either MI or loss of KMT2D attenuated monomethylated H3K4 (H3K4me1) enrichment on the enhancer of Rasd1. By generating a KMT2D knockout (H9C2-KO) H9C2 monoclone, we verified that the expression of Rasd1 was controlled by KMT2D, and the expression of Rasd1 was decreased by serum starvation but not low-(O2) treatment in H9C2 cells. KMT2D has a protective effect on ischemic myocardium by regulating cardiac disease-associated genes including Rasd1. KMT2D is required for the H3K4me1 deposition on the enhancer of Rasd1. Our data for the first time suggest that KMT2D-mediated Rasd1 expression may play an important protective effect on adult cells during nutritional deficiency caused by ischemic injury.

[Histone methylation and diabetic cardiomyopathy].

Histone methylation is one of the key post-translational modifications that plays a critical role in various heart diseases, including diabetic cardiomyopathy. A great deal of evidence has shown that histone methylation is closely related to hyperglycemia, insulin resistance, lipid and advanced glycation end products deposition, inflammatory and oxidative stress, endoplasmic reticulum stress and cell apoptosis, and these pathological factors play an important role in the pathogenesis of diabetic cardiomyopathy. In order to provide a novel theoretical basis and potential targets for the treatment of diabetic cardiomyopathy from the perspective of epigenetics, this review discussed and elucidated the association between histone methylation and the pathogenesis of diabetic cardiomyopathy in details.

Acupuncture at Neiguan suppresses PVCs occurring post-myocardial infarction by alleviating inflammation and fibrosis.

BACKGROUND: Acupuncture at Neiguan (PC6) has long been used for treating cardiovascular diseases, but its antiarrhythmic effect and the underlying mechanisms have not yet been well investigated, especially regarding premature ventricular complexes (PVCs) that occur post-myocardial infarction (MI). The purpose of this study was to study the antiarrhythmic effect of manual acupuncture applied to PC6 for a relatively long period (28 days) and to elucidate the mechanism in mice. METHODS: An MI mouse model was generated by ligating the left anterior descending coronary artery in male C57/BL6 mice (n = 31). Manual acupuncture at PC6 was applied seven times weekly for 4 weeks. The state of myocardial injury was characterized by electrocardiography (ECG) and echocardiography. Inflammation was detected by ELISA and immunohistochemical stanning. Fibrosis was evaluated by Masson's trichrome staining. RNA sequencing was used to explore the differentially expressed genes (DEGs) among the different groups after treatment. RESULTS: Acupuncture at PC6 lowered the incidence of spontaneous PVCs after MI injury (1/9, 11%) compared to that in mice without acupuncture treatment (6/9, 67%) and improved the ejection fraction from 31.77% in the MI mice to 44.18% in the MI + PC6 mice. Fibrosis was reduced after PC6 treatment. RNA-seq showed many DEGs involved in the immune system and inflammatory response pathway. Further studies confirmed that inflammation at the circulation level and cardiac tissue was inhibited in MI + PC6 mice, accompanied by suppressed sympathetic activation. CONCLUSIONS: In conclusion, 28-day treatment of acupuncture at PC6 reduced spontaneous PVCs and improved systolic function, possibly by suppressing inflammatory response-mediated fibrosis and sympathetic hyperactivity.

Electroacupuncture altered expression of microRNAs in Stat5 knockout obese mice.

BACKGROUND: Increasing evidence shows that miRNAs contribute to the establishment and development of obesity by affecting many biological and pathological processes, such as adipocyte differentiation, hepatic lipid metabolism, insulin resistance, and neurological regulation of obesity. As a clinical intervention approach, acupuncture has been shown to be effective in the treatment of obesity and other metabolic diseases. Our previous whole genome study in central nervous system (CNS)-specific Stat5 knockout (NKO) obese mice found that electroacupuncture (EA) could reduce body weight and promote white browning. OBJECTIVE: To clarify the effect of EA on miRNAs and understand how it regulates gene expression. METHODS: Twelve-week-old male Stat5NKO mice with body weight 20% greater than that of Stat5fl/fl (control) mice were divided into a Stat5NKO (model) group and EA-treated Stat5NKO + EA group. A cohort of Stat5fl/fl mice of the same age were included as the control group. EA was administered under isoflurane anesthesia at unilateral ST36 and ST44 daily (left and right sides were treated every other day), 6 times per week for a total of 4 weeks. The miRNA profile was generated and miRNA regulatory networks were analyzed in the Stat5 nestin-cre mice before and after EA treatment. Autophagy-related proteins in adipocytes were detected after over-expression of miR27a. RESULTS: EA altered abnormal miRNA expression, including miRNA27a expression, and reduced the autophagy-related proteins ATG5 and ATG12. CONCLUSION: We found that EA could regulate miRNA27a-mediated autophagy-related proteins and promote white fat browning, which may contribute to weight loss. To our knowledge, this is the first report of miRNAs potentially driving the effect of EA on white fat browning through the autophagy process.

Adipose-derived stem cells in ovarian cancer progression, metastasis, and chemoresistance.

Ovarian cancer is the deadliest gynecological malignancy due to its symptomless early stage, metastasis, and high recurrence rate. The tumor microenvironment contributes to the ovarian cancer progression, metastasis, and chemoresistance. Adipose-derived stem cell in the tumor microenvironment of ovarian cancer, as a key player, interacts with ovarian cancer cells to form the cancer-associated fibroblasts and cancer-associated adipocytes, and secretes soluble factors to activate tumor cell signaling, which can promote ovarian cancer metastasis and chemoresistance. We summarize in this review the recent progress in the studies of interactions between adipose-derived stem cell and ovarian cancer, thus, to provide some insight for ovarian cancer therapy through targeting adipose-derived stem cell.

STAT3 but Not STAT5 Contributes to the Protective Effect of Electroacupuncture Against Myocardial Ischemia/Reperfusion Injury in Mice.

Electroacupuncture (EA) can help reduce infarct size and injury resulting from myocardial ischemia/reperfusion (I/R); however, the underlying molecular mechanism remains unknown. We previously reported that STAT5 plays a critical role in the cardioprotective effect of remote ischemic preconditioning (RIPC). Here, we assessed the effects of electroacupuncture pretreatment (EAP) on myocardial I/R injury in the presence and/or absence of Stat5 in mice and investigated whether EAP exerts its cardioprotective effects in a STAT5-dependent manner. Adult Stat5 fl/fl and Stat5-cKO mice were exposed to EAP at Neiguan (PC6) for 7 days before the induction of I/R injury by left anterior descending (LAD) coronary artery ligation. The myocardial infarct size (IS), area at risk, and apoptotic rate of cardiomyocytes were detected. RT-qPCR and western blotting were used to measure gene and protein expression, respectively, in homogenized heart tissues. RNA-seq was used to identify candidate genes and pathways. Our results showed that EAP decreased IS and the rate of cardiomyocyte apoptosis. We further found that STAT5 was activated by EAP in Stat5 fl/fl mice but not in Stat5-cKO mice, whereas the opposite was observed for STAT3. Following EAP, the levels of the antiapoptotic proteins Bcl-xL, Bcl-2, and p-AKT were increased in the presence of Stat5, while that of interleukin 10 (IL-10) was increased in both Stat5 fl/fl and Stat5-cKO. The gene expression profile in heart tissues was different between Stat5 fl/fl and the Stat5-cKO mice with EAP. Importantly, the top 30 DEGs under EAP in the Stat5-cKO mice were enriched in the IL-6/STAT3 signaling pathway. Our results revealed for the first time that the protective effect of EAP following myocardial I/R injury was attributable to, but not dependent on, STAT5. Additionally, we found that EAP could activate STAT3 signaling in the absence of the Stat5 gene, and could also activate antiapoptotic, survival, and anti-inflammatory signaling pathways.

Adipose-Derived Stem Cells Facilitate Ovarian Tumor Growth and Metastasis by Promoting Epithelial to Mesenchymal Transition Through Activating the TGF-ß Pathway.

Adipose-derived stem cells (ADSC) are multipotent mesenchymal stem cells derived from adipose tissues and are capable of differentiating into multiple cell types in the tumor microenvironment (TME). The roles of ADSC in ovarian cancer (OC) metastasis are still not well defined. To understand whether ADSC contributes to ovarian tumor metastasis, we examined epithelial to mesenchymal transition (EMT) markers in OC cells following the treatment of the ADSC-conditioned medium (ADSC-CM). ADSC-CM promotes EMT in OC cells. Functionally, ADSC-CM promotes OC cell proliferation, survival, migration, and invasion. We further demonstrated that ADSC-CM induced EMT via TGF-ß growth factor secretion from ADSC and the ensuing activation of the TGF-ß pathway. ADSC-CM-induced EMT in OC cells was reversible by the TGF-ß inhibitor SB431542 treatment. Using an orthotopic OC mouse model, we also provide the experimental evidence that ADSC contributes to ovarian tumor growth and metastasis by promoting EMT through activating the TGF-ß pathway. Taken together, our data indicate that targeting ADSC using the TGF-ß inhibitor has the therapeutic potential in blocking the EMT and OC metastasis.

Epigenetic Mechanisms of Angiogenesis in the Ischemic Heart Diseases with Acupuncture Treatment.

Objective: Epigenetics, including DNA methylation, histone modification, and posttranscriptional regulation of microRNAs, is the study of heritable changes in gene expression that do not include DNA-sequence alterations. Epigenetics has become a new strategy for basic and clinical research on acupuncture in the last decade. The aim of this research update was to summarize the epigenetic mechanisms of angiogenesis induced by acupuncture treatment in ischemic heart diseases. Materials and Methods: The current authors' group has been working to illustrate the mechanism of acupuncture from an epigenetics perspective, which has shed new lights on the mechanisms and applications of acupuncture in cardiovascular diseases. This article summarizes the group's new findings in animal models as well as in patients with chronic stable angina. Progress since 2011 in other teams' research in this field is also discussed in this article. Conclusions: Acupuncture could regulate histone modifications and could rescue patients who sustain ischemic injuries. This treatment could possibly work through promoting angiogenesis.

Epigenetic Landscape Changes Due to Acupuncture Treatment: From Clinical to Basic Research.

Acupuncture has been widely used for treating diseases since the ancient days in China, but the mechanism by which acupuncture exerts such powerful roles is unclear. Epigenetics, including DNA methylation, histone modification, and post-transcriptional regulation of miRNAs, is the study of heritable changes in gene expression that do not include DNA sequence alterations. Epigenetics has become a new strategy for the basic and clinical research of acupuncture in the last decade. Some investigators have been trying to illustrate the mechanism of acupuncture from an epigenetics perspective, which has shed new lights on the mechanisms and applications of acupuncture. Moreover, the introduction of epigenetics into the regulatory mechanism in acupuncture treatment has provided more objective and scientific support for acupuncture theories and brought new opportunities for the improvement of acupuncture studies. In this paper, we reviewed the literatures that has demonstrated that acupuncture could directly or indirectly affect epigenetics, in order to highlight the progress of acupuncture studies correlated to epigenetic regulations. We do have to disclose that the current evidence in this review is not enough to cover all the complex interactions between multiple epigenetic modifications and their regulations. However, the up-to-date results can help us to better understand acupuncture's clinical applications and laboratory research.

Comparative study of gene expression profiles rooted in acute myocardial infarction and ischemic/reperfusion rat models.

Mining data in depth of genome-wide sequencing data generated from pathological target tissues under disease conditions is necessary for seeking novel functional genes, and developing more biological study directions for the field. Based on our previous published RNA-seq data generated from acute myocardial ischemia and ischemia-reperfusion in rat heart, we re-analysed these two data sets using bioinformatics tools. All these raw fastq files were extracted from Illumina BCL using the Illumina CASAVA program. Four groups were obtained: UD (genes up-regulated in MI but down-regulated in I/R injury), DU (genes down-regulated in MI but up-regulated in I/R injury), UU (genes both up-regulated in MI and I/R injury), and DD (genes both down-regulated in MI and I/R injury) groups. The results showed that 304 common genes in the UD group, 236 common genes in the DU group, 318 common genes in the UU group, and 159 common genes in the DD group detected by comparing data sets of the MI and the I/R injury. We then listed the top 30 DEGs for each group, and carried out GO and KEGG analyses for enrichment and pathway studies for those top expressed genes. Further analysis of INTERPRO Protein Domains and Features enriched by DEGs showed that 20% of the Domains enriched were related to c-type lectin, and 17% of these domains are related to neurotransmitter-gated ion-channel. 15% of PFAM Protein Domains were about Neurotransmitter-gated ion-channel. There were only 8 SMART Protein Domains DEGs enriched and 37.5% of which were concerned about leucine-rich. Collagen involvement in Reactome Pathways accounted for 22.7%. We found that only a few DEGs in these two disease conditions have been reported in the literatures, suggesting that there are many new genes would be considered in the future studies. These analyses would provide some information for seeking more novel targets of these two clinic diseases, acute myocardial ischemia and myocardial ischemia/reperfusion.

[Research and thinking of acupuncture on promoting white adipose tissue browning].

Acupuncture has become an effective approach in clinic for treating obesity, but its mechanism has not been clarified yet. A large number of researches have been conducted on the obesity mechanism in the aspects of neurophysiological regulation, feeding center regulation and peripheral digestion and absorption regulation at home and abroad. But, regarding the main storage site of excess energy, i．e. the remodeling and functional regulation of white adipose tissue (WAT), is still a new field in research. In the paper, focusing on the new filed of weight loss, in view of the promotion of WAT browning through the re-gulation of UCP1 and PPARγ signal pathway with acupuncture, the potential peripheral mechanism of acupuncture was explored on weight loss.

Electroacupuncture Alleviates Cerebral Ischemia/Reperfusion Injury in Rats by Histone H4 Lysine 16 Acetylation-Mediated Autophagy.

Background: Electroacupuncture (EA) treatment in ischemic stroke has been highlighted recently; however, the specific mechanism is still elusive. Autophagy is considered a new target for cerebral ischemia/reperfusion (I/R), but whether it plays a role of protecting or causing rapid cell apoptosis remains unclear. Studies have reported that the reduction in lysine 16 of histone H4 acetylation coheres with autophagy induction. The primary purpose of the study was to explore whether EA could alleviate I/R via autophagy-mediated histone H4 lysine 16 acetylation in the middle cerebral artery occlusion (MCAO) rat model. Methods: One hundred and twenty male Sprague-Dawley rats were divided into five groups: control group, MCAO group, MCAO+EA group, MCAO+EA+hMOF siRNA group, and MCAO+EA+Sirt1 inhibitor group. EA was applied to "Baihui" (Du20) and "Renzhong" (Du26) at 5 min after modeling and 16 h after the first EA intervention. The structure and molecular markers of the rat brain were evaluated. Results: EA significantly alleviated I/R injury by upregulating the expressions of Sirt1, Beclin1, and LC3-II and downregulating the expressions of hMOF and H4K16ac. In contrast, the Sirt1 inhibitor lowered the increase in Sirt1, Beclin1, and LC3-II and enhanced the level of hMOF and H4K16ac expressions associated with EA treatment. Besides, ChIP assay revealed that the binding of H4K16ac in the Beclin1 promoter region of the autophagy target gene was significantly raised in the MCAO+EA group and MCAO+EA+hMOF siRNA group. Conclusions: EA treatment inhibited the H4K16ac process, facilitated autophagy, and alleviated I/R injury. These findings suggested that regulating histone H4 lysine 16 acetylation-mediated autophagy may be a key mechanism of EA at Du20 and Du26 to treat I/R.

[Possibility of acupuncture treatment of ischemic stroke via regulating intestinal flora-immune response].

At present, intestinal flora has attracted more and more attention from scholars in China and foreign countries, and its association with ischemic stroke (IS) has gradually become a new research hotspot in the field of stroke. Studies also showed that intestinal flora may be a risk factor which directly or indirectly affects the occurrence and development of IS through bacterial metabolites and immune activities. In the present paper, we review the positive effect of acupuncture and moxibustion in alleviating the symptoms of limb locomotor, speech, swallowing dysfunction, cognition, etc. to improve the IS patients' daily life ability and in strengthening the cellular immune function of the body. In addition, acupuncture and moxibustion have a positive effect in regulating intestinal flora and immune inflammation. Hence, in the present paper, we discuss their relationship and the possibility of application of acupuncture and moxibustion therapies to the treatment of IS according to the theory of "intestinal flora-immune response". It is thus reasonable to speculate that acupuncture and moxibustion can be used to promote the recovery of brain tissue injury and neurological function after stroke via correcting intestinal flora disturbance and reducing immune inflammatory response. In-depth exploration of the role of "intestinal flora-immune response" in the treatment of IS and the specific regulatory function of acupuncture and moxibustion will provide new ideas and research approaches to reveal their mechanisms in the treatment of stroke from a new perspective.

[Research progress of histone 3 methyltransferase MLL4].

Mixed linked leukemia 4 (MLL4) is a specific methyltransferase of histone 3 position lysine 4 (H3K4). It is also one of the important members of COMPASS/Set1-like protein complex. Both MLL4 protein itself and its mediated H3K4 methylation modification can cause changes in chromatin structure and function, thus regulating gene transcription and expression. With the studies of MLL4 protein in recent years, the roles of MLL4 gene, MLL4 protein and protein complex in the development of tissues and organs, tumor diseases and other physiological and pathophysiological processes have been gradually revealed. In this paper, the research progress of MLL4 gene, MLL4 protein characteristics, biological function and its effect on disease were reviewed, in order to further understand the effect of histone methyltransferase on gene expression regulation, as well as its non-enzyme dependent function. This paper may provide new ideas for the prevention, diagnosis and treatment of related diseases.