更新于：2024-09-19

BHLHE41

更新于：2024-09-19

基本信息

别名

basic helix-loop-helix family member e41、BHLHB3、BHLHE41

+ [8]

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:11278948, PubMed:14672706, PubMed:15193144, PubMed:15560782, PubMed:18411297, PubMed:19786558, PubMed:25083013). 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). Both these loops are interlocked as it represses the expression of PER1 and in turn is repressed by PER1/2 and CRY1/2. Represses the activity of the circadian transcriptional activator: CLOCK-BMAL1 heterodimer by competing for the binding to E-box elements (5'-CACGTG-3') found within the promoters of its target genes (PubMed:25083013). Negatively regulates its own expression and the expression of DBP and BHLHE41/DEC2. Acts as a corepressor of RXR and the RXR-LXR heterodimers and represses the ligand-induced RXRA/B/G, NR1H3/LXRA, NR1H4 and VDR transactivation activity. Inhibits HNF1A-mediated transactivation of CYP1A2, CYP2E1 AND CYP3A11 (By similarity).

关联

100 项与 BHLHE41 相关的临床结果

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100 项与 BHLHE41 相关的转化医学

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0 项与 BHLHE41 相关的专利（医药）

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970

项与 BHLHE41 相关的文献（医药）

2024-12-01·Cellular and Molecular Life Sciences

Novel role of NCoR1 in impairing spatial memory through the mediation of a novel interacting protein DEC2

Article

作者: Lee, Eminy H Y ; Hsu, Wei-Lun ; Liu, Yen-Chen ; Ma, Yun-Li ; Cheng, Kuang-Min

AbstractLong-term memory formation requires de novo RNA and protein synthesis. Using differential display PCR, we found that the NCoR1 cDNA fragment is differentially expressed between fast learners and slow learners, with fast learners showing a lower expression level than slow learners in the water maze learning task. Fast learners also show lower NCoR1 mRNA and protein expression levels. In addition, spatial training decreases both NCoR1 mRNA and protein expression, whereas NCoR1 conditional knockout (cKO) mice show enhanced spatial memory. In studying the molecular mechanism, we found that spatial training decreases the association between NCoR1 and DEC2. Both NCoR1 and DEC2 suppress the expression of BDNF, integrin α3 and SGK1 through C/EBPα binding to their DNA promoters, but overexpression of DEC2 in NCoR1 cKO mice rescues the decreased expression of these proteins compared with NCoR1 loxP mice overexpressing DEC2. Further, spatial training decreases DEC2 expression. Spatial training also enhances C/EBPα binding to Bdnf, Itga3 and Sgk1 promoters, an effect also observed in fast learners, and both NCoR1 and DEC2 control C/EBPα activity. Whereas knockdown of BDNF, integrin α3 or SGK1 expression impairs spatial learning and memory, it does not affect Y-maze performance, suggesting that BDNF, integrin α3 and SGK1 are involved in long-term memory formation, but not short-term memory formation. Moreover, NCoR1 expression is regulated by the JNK/c-Jun signaling pathway. Collectively, our findings identify DEC2 as a novel interacting protein of NCoR1 and elucidate the novel roles and mechanisms of NCoR1 and DEC2 in negative regulation of spatial memory formation.

2024-10-01·Journal of Immunotherapy

Prognostic Value and Immune Signatures of Anoikis-related Genes in Breast Cancer

Article

作者: Lin, Nan ; Xie, Xianhe ; Zheng, Shiyao ; Luo, Yang ; Wu, Qing

From databases of the Cancer Genome Atlas (TCGA) and GSE42568, transcriptome data of breast cancer patients was obtained. Then, anoikis-related genes (ANRGs) were identified and constructed a risk score system. As a threshold value, the median risk score was used to stratify patients into low-risk and high-risk groups. Kaplan-Meier analysis was then conducted to evaluate the prognostic ability of the risk score system, which was validated using GSE7390. Furthermore, we identified potential enrichment of function and tumor immune infiltration in the model. Finally, the biological functions of a risk gene (EPB41L4B) in breast cancer were investigated through in vitro experiments. We constructed a risk score system via 9 prognosis ANRGs (CXCL2, EPB41L4B, SLC7A5, SFRP1, SDC1, BHLHE41, SPINT1, KRT15, and CD24). The Kaplan-Meier analysis showed that both TCGA-BRCA (training set) and GSE7390 (testing set) patients with high-risk status had significantly worse survival outcomes. In addition, the calibration plots were in good agreement with the prognosis prediction. Breast cancer patients with immunosuppressive microenvironment could be screened using risk groups since risk scores were correlated negatively with ESTIMATE score, tumor-infiltration lymphocytes, immune checkpoints, and chemotactic factors. Furthermore, cellular viability and cell migration of cancerous breast cells were inhibited and apoptosis was promoted by down-regulation of EPB41L4B gene expression. Based on ANRGs, a 9-gene prognostic model could be developed to predict breast cancer prognosis; moreover, patients of the high-risk group were in an immunosuppressed tumor microenvironment.

2024-06-01·Journal of Cellular and Molecular Medicine

High expression of DEC2 distinguishes chondroblastic osteosarcoma and promotes tumour growth by activating the VEGFC/VEGFR2 signalling pathway

Article

作者: Xu, Jun ; Zhang, Changqing ; Yang, Quanjun ; Zheng, Xu ; Zhou, Shumin ; Tuerxun, Maimaitiaili ; Yuan, Ting

AbstractOsteosarcoma (OS) is the most common primary malignant bone tumour in children and young adults. Account for 80% of all OS cases, conventional OS are characterized by the presence of osteoblastic, chondroblastic and fibroblastic cell types. Despite this heterogeneity, therapeutic treatment and prognosis of OS are essentially the same for all OS subtypes. Here, we report that DEC2, a transcriptional repressor, is expressed at higher levels in chondroblastic OS compared with osteoblastic OS. This difference suggests that DEC2 is disproportionately involved in the progression of chondroblastic OS, and thus, DEC2 may represent a possible molecular target for treating this type of OS. In the human chondroblastic‐like OS cell line MNNG/HOS, we found that overexpression of DEC2 affects the proliferation of the cells by activating the VEGFC/VEGFR2 signalling pathway. Enhanced expression of DEC2 increased VEGFR2 expression, as well as increased the phosphorylation levels at sites Y951 and Y1175 of VEGFR2. On the one hand, activation of VEGFR2Y1175 enhanced cell proliferation through VEGFR2Y1175‐PLCγ1‐PKC‐SPHK‐MEK‐ERK signalling. On the other hand, activation of VEGFR2Y951 decreased mitochondria‐dependent apoptosis rate through VEGFR2Y951‐VARP‐PI3K‐AKT signalling. Activation of these two signalling pathways resulted in enhanced progression of chondroblastic OS. In conclusion, DEC2 plays a pivotal role in cell proliferation and apoptosis‐resistance in chondroblastic OS via the VEGFC/VEGFR2 signalling pathway. These findings lay the groundwork for developing focused treatments that target specific types of OS.

项与 BHLHE41 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