更新于：2024-09-19

BHLHE40

更新于：2024-09-19

基本信息

别名

basic helix-loop-helix family member e40、BHLHB2、BHLHE40

+ [10]

简介

Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes (PubMed:12397359, PubMed:18411297). Acts as the negative limb of a novel autoregulatory feedback loop (DEC loop) which differs from the one formed by the PER and CRY transcriptional repressors (PER/CRY loop) (PubMed:14672706). Both these loops are interlocked as it represses the expression of PER1/2 and in turn is repressed by PER1/2 and CRY1/2 (PubMed:15193144). Represses the activity of the circadian transcriptional activator: CLOCK-BMAL1|BMAL2 heterodimer by competing for the binding to E-box elements (5'-CACGTG-3') found within the promoters of its target genes (PubMed:15560782). Negatively regulates its own expression and the expression of DBP and BHLHE41/DEC2 (PubMed:14672706). Acts as a corepressor of RXR and the RXR-LXR heterodimers and represses the ligand-induced RXRA and NR1H3/LXRA transactivation activity (PubMed:19786558). May be involved in the regulation of chondrocyte differentiation via the cAMP pathway (PubMed:19786558). Represses the transcription of NR0B2 and attentuates the transactivation of NR0B2 by the CLOCK-BMAL1 complex (PubMed:28797635). Drives the circadian rhythm of blood pressure through transcriptional repression of ATP1B1 in the cardiovascular system (PubMed:30012868).

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100 项与 BHLHE40 相关的临床结果

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100 项与 BHLHE40 相关的转化医学

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0 项与 BHLHE40 相关的专利（医药）

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323

项与 BHLHE40 相关的文献（医药）

2024-10-01·Poultry Science

Effect of myristic acid supplementation on triglyceride synthesis and related genes in the pectoral muscles of broiler chickens

Article

作者: Zhao, Guiping ; Wang, Yanke ; Liu, Xiaojing ; Guo, Yuming ; Wang, Yidong ; Wen, Jie ; Cui, Huanxian

Fatty acids (FAs) can serve as energy for poultry, maintain normal cell structure and function, and support a healthy immune system. Although the addition of polyunsaturated fatty acids (PUFAs) to the diet has been extensively studied and reported, the mechanism of action of saturated fatty acids (SFAs) remains to be elucidated. We investigated the effect of 0.04% dietary myristic acid (MA) on slaughter performance, lipid components, tissue FAs, and the transcriptome profile in chickens. The results showed that dietary MA had no effect on slaughter performance (body weight, carcass weight, eviscerated weight, and pectoral muscle weight) (P > 0.05). Dietary MA enrichment increased MA (P < 0.001) and triglycerides (TGs) (P < 0.01) levels in the pectoral muscle. The levels of palmitic acid, linoleic acid (LA), arachidonic acid (AA), SFAs, monounsaturated fatty acids (MUFAs), and PUFAs were significantly higher (P < 0.01) in the MA supplementation group compared to the control group. However, there were no significant differences in the ratios of PUFA/SFA and n6/omega-3 (n3) between the two groups. The MA content was positively correlated with the contents of palmitic acid, LA, linolenic acid (ALA), n3, n6, SFAs, and unsaturated fatty acids (UFA). DHCR24, which is known to be involved in steroid metabolism and cholesterol biosynthesis pathways, was found to be a significantly lower in the MA supplementation group compared to the control group (P < 0.05, log2(fold change) = -0.85). Five overlapping co-expressed genes were identified at the intersection between the differential expressed genes and Weighted Gene Co‑expression Network Analysis-derived hub genes associated with MA phenotype, namely BHLHE40, MSL1, PLAGL1, SRSF4, and ENSGALG00000026875. For the TG phenotype, a total of 28 genes were identified, including CHKA, KLF5, TGIF1, etc. Both sets included the gene PLAGL1, which has a negative correlation with the levels of MA and TG. This study provides valuable information to further understand the regulation of gene expression patterns by dietary supplementation with MA and examines at the molecular level the phenotypic changes induced by supplementation with MA.

2024-09-01·Matrix Biology

IGF-II regulates lysyl oxidase propeptide and mediates its effects in part via basic helix-loop-helix E40

Article

作者: Bradshaw, Amy D ; Mouawad, Joe E ; Adewale, Adegboyega Timothy ; Sharma, Shailza ; Feghali-Bostwick, Carol ; Nguyen, Xinh-Xinh

Pulmonary fibrosis (PF) is a clinically severe and commonly fatal complication of Systemic Sclerosis (SSc). Our group has previously reported profibrotic roles for Insulin-like Growth Factor II (IGF-II) and Lysyl Oxidase (LOX) in SSc-PF. We sought to identify downstream regulatory mediators of IGF-II. In the present work, we show that SSc lung tissues have higher baseline levels of the total (N-glycosylated/unglycosylated) LOX-Propeptide (LOX-PP) than control lung tissues. LOX-PP-mediated changes were consistent with the extracellular matrix (ECM) deregulation implicated in SSc-PF progression. Furthermore, Tolloid-like 1 (TLL1) and Bone Morphogenetic Protein 1 (BMP1), enzymes that can cleave ProLOX to release LOX-PP, were increased in SSc lung fibrosis and the bleomycin (BLM)-induced murine lung fibrosis model, respectively. In addition, IGF-II regulated the levels of ProLOX, active LOX, LOX-PP, BMP1, and isoforms of TLL1. The Class E Basic Helix-Loop-Helix protein 40 (BHLHE40) transcription factor localized to the nucleus in response to IGF-II. BHLHE40 silencing downregulated TLL1 isoforms and LOX-PP, and restored features of ECM deregulation triggered by IGF-II. Our findings indicate that IGF-II, BHLHE40, and LOX-PP may serve as targets of therapeutic intervention to halt SSc-PF progression.

2024-07-02·Cancer Research

Single-Cell and Spatial Transcriptome Profiling Identifies the Transcription Factor BHLHE40 as a Driver of EMT in Metastatic Colorectal Cancer

Article

作者: Wang, Xiaowei ; Nie, Hongxu ; Sun, Yueming ; Zhang, Yue ; Zhang, Dongsheng ; Sun, Qingyang ; Huang, Yuanjian ; Yang, Sheng

AbstractColorectal cancer is one of the most common malignant tumors in humans, with liver metastasis being the primary cause of mortality. The epithelial–mesenchymal transition (EMT) process endows cancer cells with enhanced metastatic potential. To elucidate the cellular mechanisms driving EMT in colorectal cancer, we analyzed single-cell RNA sequencing data from 11 nonmetastatic primary tumors (TnM) and 11 metastatic primary tumors (TM) from colorectal cancer patients. Compared with the TnM group, the TM samples showed elevated numbers of malignant epithelial cell and cancer-associated fibroblast (CAF) subsets that displayed enrichments of EMT, angiogenesis, and TGFβ signaling pathways. One specific TM-enriched subgroup of malignant epithelial cells underwent EMT to transdifferentiate into CXCL1+ CAFs that subsequently differentiated into SFRP2+ CAFs, which was validated by spatial transcriptomic and pseudotime trajectory analyses. Furthermore, cell–cell communication analysis identified BHLHE40 as a probable key transcription factor driving EMT that was associated with poor prognosis. Finally, in vitro and in vivo experiments functionally substantiated that BHLHE40 promoted the proliferation, invasion, migration, EMT, and liver metastasis of colorectal cancer cells. In summary, this study identified BHLHE40 as a key transcription factor regulating EMT that promotes liver metastasis in colorectal cancer.Significance: Integrated analysis of single-cell RNA sequencing and spatial transcriptomics in metastatic colorectal cancer provides insights into the mechanisms underlying EMT and cancer-associated fibroblast differentiation, which could help improve patient diagnosis and treatment.

项与 BHLHE40 相关的新闻（医药）

2024-03-26

·生物谷

Nat Commun：新研究揭示小胶质细胞在维护大脑健康中起着关键作用

研究人员使用先进的模型进一步验证了转录因子 BHLHE40 和 BHLHE41在控制免疫细胞反应中发挥的关键作用，为治疗干预提供了潜在靶点。点。” 在一项新的研究中，来自美国西奈山伊坎医学院的研究人员利用新型遗传和基因组工具，揭示了称为巨噬细胞的免疫细胞在大脑等脂质丰富组织中的作用，从而加深了人们对阿尔茨海默病和其他疾病的了解。这一发现标志着人们在理解免疫细胞调控及其对疾病进展的影响方面又向前迈进了一步。相关研究结果于2024年3月6日发表在Nature Communications期刊上，论文标题为“BHLHE40/41 regulate microglia and peripheral macrophage responses associated with Alzheimer’s disease and other disorders of lipid-rich tissues”。这些作者最初研究的是控制大脑巨噬细胞（也称小胶质细胞）的基因，当它们在大脑中时，尤其是在对大脑等脂肪组织的损伤做出反应时。疾病相关的小胶质细胞/巨噬细胞被认为具有保护作用，因为它们参与清除组织损伤产生的富含脂质的废物。因此，他们希望找到促进这些细胞“清除垃圾”活动的因子。他们发现了两个有影响力的基因---BHLHE40和BHLHE41，并利用先进的基因编辑技术（CRISPR-Cas9）使它们在实验室培养的细胞中失活。他们然后将这些细胞转化为小胶质细胞。结果发现，缺乏BHLHE40和BHLHE41的小胶质细胞与阿尔茨海默病中观察到的疾病相关小胶质细胞相似，它们清除富含胆固醇废物的能力提高了。对体外培养的人类外周巨噬细胞和缺乏这些基因的小鼠的小胶质细胞进行的实验证实了这一点。论文共同通讯作者、西奈山伊坎医学院遗传学与基因组科学教授Alison M. Goate博士说，“通过对来自多个器官的单细胞数据集的分析，我们发现了对组织健康至关重要的免疫细胞功能的关键调控因子。我们使用先进的模型进一步验证了转录因子 BHLHE40 和 BHLHE41（通过与特定 DNA 序列结合来调节基因表达的蛋白）在控制免疫细胞反应中发挥的关键作用，为治疗干预提供了潜在靶点。” 接下来，这些作者将研究缺乏BHLHE40和BHLHE41的小胶质细胞能否帮助清除有害的淀粉样蛋白。在一项实验中，他们将在培养皿中培养诸如神经元和星形胶质细胞之类的携带有害阿尔茨海默病突变的脑细胞，并测试缺乏BHLHE40和BHLHE41的小胶质细胞是否会影响β-淀粉样蛋白水平、神经变性和细胞因子反应（神经炎症）。图片来自Nature Communications, 2024, doi:10.1038/s41467-024-46315-7 在另一项实验中，他们将把含有或不含有BHLHE40和BHLHE41的小胶质细胞注射到阿尔茨海默病小鼠模型中，观察它们如何影响阿尔茨海默病样斑块的形成。 Goate 博士说，“我们想看看这些小胶质细胞，尤其是不含这两个基因的小胶质细胞，如何在培养皿和小鼠模型中影响阿尔茨海默病相关表型。我们预测，在小鼠体内，没有BHLHE40和BHLHE41 的小胶质细胞将比 BHLHE40和BHLHE41水平正常的对照小胶质细胞更有效地清除β-淀粉样蛋白斑块。此外，我们还在探索这些大脑免疫细胞中缺乏这些基因会如何影响大脑中的其他类型细胞，如神经元和星形胶质细胞。”（生物谷 Bioon.com）参考资料： Anna Podleśny-Drabiniok et al. BHLHE40/41 regulate microglia and peripheral macrophage responses associated with Alzheimer's disease and other disorders of lipid-rich tissues. Nature Communications, 2024, doi:10.1038/s41467-024-46315-7. Immune cells identified as key players in brain healthhttps://medicalxpress.com/news/2024-03-immune-cells-key-players-brain.html

临床1期

2024-03-21

·Science Daily

Immune cells identified as key players in brain health

Using novel genetic and genomic tools, researchers have shed light on the role of immune cells called macrophages in lipid-rich tissues like the brain, advancing our understanding of Alzheimer's and other diseases. The study represents a step forward in understanding immune cell regulation and its impact on disease progression. Using novel genetic and genomic tools, researchers at the Icahn School of Medicine at Mount Sinai have shed light on the role of immune cells called macrophages in lipid-rich tissues like the brain, advancing our understanding of Alzheimer's and other diseases. The study, published in the March 6 online issue of Nature Communications, represents a step forward in understanding immune cell regulation and its impact on disease progression. The researchers initially studied genes controlling macrophages, also referred to as microglia when they are in the brain, particularly in response to damage of fatty tissues like the brain. Disease-associated microglia/macrophages are thought to be protective, as they participate in removing lipid-rich waste derived from tissue damage. Therefore, researchers wanted to find factors that promote the "garbage removal" activity of these cells. They identified two influential genes, BHLHE40 and BHLHE41, and used advanced gene editing technology (CRISPR-Cas9) to deactivate them in lab-grown cells. These cells were then transformed into microglia. The resulting microglia lacking BHLHE40 and BHLHE41 resembled disease-associated microglia observed in Alzheimer's disease, showing improved ability to clear cholesterol-rich waste. Confirmation came from experiments on cultured human peripheral macrophages and microglia from mice lacking these genes. "Through our analysis of single-cell datasets from multiple organs, we've uncovered pivotal regulators of immune cell function essential for tissue health," says senior study author Alison M. Goate, DPhil, the Jean C. and James W. Crystal Professor and Chair of Genetics and Genomic Sciences at Icahn Mount Sinai. "Our use of advanced models has further validated the critical role played by transcription factors BHLHE40 and BHLHE41, proteins that regulate gene expression by binding to specific DNA sequences, in controlling immune cell responses, presenting potential targets for therapeutic intervention." Next, the researchers will investigate whether microglia without BHLHE40 and BHLHE41 can help clear away harmful amyloid proteins. In one experiment, the investigators will grow brain cells such as neurons and astrocytes that have harmful Alzheimer's mutations in a dish and test whether immune cells without BHLHE40 and 41 influence beta-amyloid levels, neurodegeneration, and cytokine response (neuroinflammation). In another, they will inject the immune cells with and without BHLHE40 and 41 into a mouse model of Alzheimer's to see how they affect the development of Alzheimer's-like plaques. "We want to see how these cells, particularly those without the two genes, impact Alzheimer's-related phenotypes in both dish and mouse models. We predict that in mice, microglia without BHLHE40 and 41 will clear away beta-amyloid plaques more effectively than control microglia that have normal levels of BHLHE40 and 41. Also, we're exploring how lack of these genes in the brain immune cells affect other types of cells in the brain such as neurons and astrocytes," says Dr. Goate. The paper is titled "BHLHE40/41 regulate microglia and peripheral macrophage responses associated with Alzheimer's disease and other disorders of lipid-rich tissues." The remaining authors of the paper, all with Icahn Mount Sinai except where indicated, are: Anna Podlesny-Drabiniok, PhD; Gloriia Novikova, PhD; Yiyuan Liu, PhD; Josefine Dunst, PhD (Anocca in Sweden); Rose Temizer, PhD candidate (National Institute of Mental Health); Samuele Marro, PhD; Taras Kreslavskiy, PhD (Karolinska Institute); and Edoardo Marcora, PhD. The study was made possible by funding from various sources, including NIH grants (RF1AG054011, U01AG058635, R56AG081417, U01AG066757, NHLBI R01HL153712, S10OD026880 and S10OD030463) and support from The JPB Foundation and BrightFocus Foundation (A2021014F), the New York State Department of Health stem cell biology fellowship (NYSTEM- C32561GG), America Heart Association (20SFRN35210252), and Graduate Women in Science Fellowship.

基因疗法AHA会议

2023-12-10

·今日头条

【Adv. Sci.】新致癌因子！上海交通大学医学院发现抑制“癌王”胰腺癌铁死亡的新机制

本文为转化医学网原创，转载请注明出处作者：Rainbow 导读：胰腺癌是最致命的人类恶性肿瘤之一。 12月8日，上海交通大学医学院附属瑞金医院程东峰、蒋玲曦、沈柏用在期刊《ADVANCED SCIENCE》上在线发表题为“BHLHE40 Inhibits Ferroptosis in Pancreatic Cancer Cells via Upregulating SREBF1”的研究论文，研究人员报道了在肿瘤中显著上调的染色质开放性诱导下BHLHE40的表达。通过体外和体内功能实验，鉴定了BHLHE40的致癌作用。由于具有大的无序区域（IDRs），BHLHE40不仅作为传统转录因子调控SREBF1的转录，还通过形成液-液相分离的方式连接SREBF1的增强子和启动子区域。BHLHE40如何上调SREBP的详细机制为PI3K-AKT-mTORC-SREBP信号轴提供了新的见解。此外，首次鉴定了BHLHE40-SREBF1-SCD1-铁死亡轴在胰腺癌进展中的作用，这可能为针对脂肪酸合成和不饱和化的胰腺癌新治疗策略的开发提供了新的线索。 https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202306298 研究背景 01 癌症是由体细胞中发生的遗传异常引起的，导致转录网络失调。"转录上瘾"指的是癌细胞表现出对在肿瘤发展过程中获得的某些致癌调节因子的高度依赖性，并且这些因子对于肿瘤的进展至关重要。胰腺癌是最致命的癌症之一，5年生存率为9% 。通过高通量测序已经确定了一些关键的体细胞突变和转录程序的主控因子。尽管已经对某些分子亚型进行了表征，但由于胰腺癌的强烈异质性，仍需要探索肿瘤特异性转录因子和表观基因组异常。 BHLHE40是已知的免疫应答介质，参与感染、自身免疫和炎症。研究人员之前报道了BHLHE40在胰腺癌肿瘤相关中性粒细胞中与缺氧相关的应激和葡萄糖代谢有关。然而，在胰腺癌肿瘤细胞中，BHLHE40的作用和分子机制尚未被确定。SREBF1是脂肪酸代谢的主要调节因子，在癌症中通常过度表达。异常的脂质代谢是胰腺癌细胞与正常导管细胞相比最显著的代谢改变之一，因此揭示BHLHE40-SREBF1在胰腺癌进展中的作用非常重要。癌细胞具有独特的代谢方式，ROS的积累以及RAS家族成员（如HRAS和KRAS）中的特定突变使得癌细胞固有地易受铁死亡作用的影响，从而表现出可被治疗靶向的脆弱性。传统的癌症治疗，包括化疗、放疗和免疫疗法，都可以触发铁死亡。因此，特别是与传统疗法联合使用时，铁死亡诱导剂在癌症治疗中具有重要的潜力。研究发现 02 在研究中，研究人员对患有胰腺癌的器官样本进行了整合转录组和表观遗传多组学分析，发现BHLHE40在胰腺癌中上调。此外，BHLHE40的上调与mTOR通路活性和启动子区域染色质可及性有关。作为一种转录因子，BHLHE40不仅促进了SREBF1的转录，还通过形成相分离凝胶，促进了SREBF1启动子-增强子区域的连接。SREBF1通过调节下游靶点（FASN、ACLY和SCD1）并抑制ROS诱导的铁死亡，重新编程了胰腺癌的脂肪酸代谢。因此，SREBF1抑制剂fatostatin通过诱导铁死亡显著降低了高表达BHLHE40的胰腺癌肿瘤的生长。 BHLHE40沉默可减少胰腺癌肿瘤发生和转移 03 为探究BHLHE40在胰腺癌中的功能作用，研究人员沉默了两个表达高的细胞系（PANC-1和BxPC-3）中的BHLHE40，并在MIA PaCa-2细胞中进行了过表达。利用免疫印迹法评估了BHLHE40的沉默和过表达。BHLHE40的沉默减少了细胞增殖和迁移。皮下异种移植实验证明，BHLHE40沉默细胞引起的肿瘤明显小于对照组。免疫组化染色显示Ki-67的丰度在BHLHE40沉默组中减少。此外，PET/CT荧光信号显示BHLHE40沉默部分抑制了胰腺癌细胞在肝脏中的转移能力。BHLHE40过表达增强了胰腺癌细胞的体内和体外致瘤能力。BHLHE40在两个建立的胰腺癌器官oid（PTO1和PTO2）中的沉默减少了细胞增殖。因此，这些数据表明BHLHE40具有强大的致癌功能。研究结果 04 综上所述，研究人员报道了在肿瘤中显著上调的染色质开放性诱导下BHLHE40的表达。通过体外和体内功能实验，鉴定了BHLHE40的致癌作用。由于具有大的无序区域（IDRs），BHLHE40不仅作为传统转录因子调控SREBF1的转录，还通过形成液-液相分离的方式连接SREBF1的增强子和启动子区域。BHLHE40如何上调SREBP的详细机制为PI3K-AKT-mTORC-SREBP信号轴提供了新的见解。此外，首次鉴定了BHLHE40-SREBF1-SCD1-铁死亡轴在胰腺癌进展中的作用，这可能为针对脂肪酸合成和不饱和化的胰腺癌新治疗策略的开发提供了新的线索。参考资料： https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202306298 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 北京｜12月19日-20日 ▶第四届单细胞测序技术应用研讨会暨单细胞&空间组学研讨会（日程稍后公布）点击对应文字查看详情

免疫疗法临床结果