作者: Hoffman, A. ; Shin, Hyunjin ; Vazquez, Berta N. ; Thackray, Joshua K. ; Londono, Douglas ; Perekatt, Ansu O. ; Musolf, Anthony ; Desai, Kinjal ; Gandhi, Vishal ; Verzi, Michael P. ; Kim, Yona ; Serrano, Lourdes ; Gao, Nan ; Cowper-Sal·lari, Richard ; Kumar, Namit ; Yu, Shiyan ; Chahar, Sanjay ; Kumar, Nikhil ; Lupien, Mathieu

ABSTRACTTranscriptional regulatory mechanisms likely contribute to the etiology of inflammatory bowel disease (IBD), as genetic variants associated with the disease are disproportionately found at regulatory elements. However, the transcription factors regulating colonic inflammation are unclear. To identify these transcription factors, we mapped epigenomic changes in the colonic epithelium upon inflammation. Epigenetic marks at transcriptional regulatory elements responded dynamically to inflammation and indicated a shift in epithelial transcriptional factor networks. Active enhancer chromatin structure at regulatory regions bound by the transcription factor hepatocyte nuclear factor 4α (HNF4A) was reduced during colitis. In agreement, upon an inflammatory stimulus, HNF4A was downregulated and showed a reduced ability to bind chromatin. Genetic variants that confer a predisposition to IBD map to HNF4A binding sites in the human colon cell line CaCo2, suggesting impaired HNF4A binding could underlie genetic susceptibility to IBD. Despite reduced HNF4A binding during inflammation, a temporal knockout model revealed HNF4A still actively protects against inflammatory phenotypes and promotes immune regulatory gene expression in the inflamed colonic epithelium. These findings highlight the potential for HNF4A agonists as IBD therapeutics.

Patho-transcriptomic analysis of invasive mucinous adenocarcinoma of the lung (IMA): comparison with lung adenocarcinoma with signet ring cell features (SRCC)

Article

作者: Tsuchiya, Tomoshi ; Snyder, Eric L ; Guo, Minzhe ; Fukazawa, Takuya ; Okada, Morihito ; Baldauf, Iris-Fink ; Ito, Masaoki ; Yamatsuji, Tomoki ; Watanabe, Hideo ; Maeda, Yutaka ; Mino-Kenudson, Mari ; Stuart, William D

AbstractBackgroundInvasive mucinous adenocarcinoma (IMA) comprises ∼5% of lung adenocarcinoma. There is no effective therapy for IMA when surgical resection is not possible. IMA is sometimes confused with adenocarcinoma with signet ring cell features (SRCC) pathologically since both adenocarcinomas feature tumor cells with abundant intracellular mucin. The molecular mechanisms by which such mucin-producing lung adenocarcinomas develop remain unknown.MethodsUsing a Visium spatial transcriptomics approach, we analyzed IMA and compared it with SRCC patho-transcriptomically. Combining spatial transcriptomics data within vitrostudies using RNA-seq and ChIP-seq, we assessed downstream targets of transcription factors HNF4A and SPDEF that are highly expressed in IMA and/or SRCC.ResultsSpatial transcriptomics analysis indicated that there are 6 distinct cell clusters in IMA and SRCC. Notably, two clusters (C1 and C3) of mucinous tumor cells exist in both adenocarcinomas albeit at a different ratio. Importantly, a portion of genes (e.g.,NKX2-1,GKN1,HNF4AandFOXA3) are distinctly expressed while some mucous-related genes (e.g.,SPDEFandFOXA2) are expressed in both adenocarcinomas. We determined that HNF4A inducesMUC3A/BandTM4SF4and that BI 6015, an HNF4A antagonist, suppressed the growth of IMA cells. Using mutant SPDEF that is associated with COVID-19, we also determined that an intact DNA-binding domain of SPDEF is required for SPDEF-mediated induction of mucin genes (MUC5AC,MUC5BandAGR2). Additionally, we found that XMU-MP-1, a SPDEF inhibitor, suppressed the growth of IMA cells.ConclusionThese results revealed that IMA and SRCC contain heterogenous tumor cell types, some of which are targetable.

PLOS ONE3区 · 综合性期刊

Sodium bicarbonate cotransporter NBCe2 gene variants increase sodium and bicarbonate transport in human renal proximal tubule cells

3区 · 综合性期刊

ArticleOA

作者: Tran, Hanh T ; Felder, Robin A ; Gildea, John J ; Carlson, Julia M ; Xu, Peng ; Kemp, Brandon A ; Jose, Pedro A ; McGrath, Helen E ; Langouët-Astrié, Christophe J ; Carey, Robert M ; Bigler Wang, Dora

RATIONALESalt sensitivity of blood pressure affects >30% of the hypertensive and >15% of the normotensive population. Variants of the electrogenic sodium bicarbonate cotransporter NBCe2 gene, SLC4A5, are associated with increased blood pressure in several ethnic groups. SLC4A5 variants are also highly associated with salt sensitivity, independent of hypertension. However, little is known about how NBCe2 contributes to salt sensitivity, although NBCe2 regulates renal tubular sodium bicarbonate transport. We hypothesized that SLC4A5 rs10177833 and rs7571842 increase NBCe2 expression and human renal proximal tubule cell (hRPTC) sodium transport and may be a cause of salt sensitivity of blood pressure.OBJECTIVETo characterize the hRPTC ion transport of wild-type (WT) and homozygous variants (HV) of SLC4A5.METHODS AND RESULTSThe expressions of NBCe2 mRNA and protein were not different between hRPTCs carrying WT or HV SLC4A5 before or after dopaminergic or angiotensin (II and III) stimulation. However, luminal to basolateral sodium transport, NHE3 protein, and Cl-/HCO3- exchanger activity in hRPTCs were higher in HV than WT SLC4A5. Increasing intracellular sodium enhanced the apical location of NBCe2 in HV hRPTCs (4.24±0.35% to 11.06±1.72% (P<0.05, N = 3, 2-way ANOVA, Holm-Sidak test)) as determined by Total Internal Reflection Fluorescence Microscopy (TIRFM). In hRPTCs isolated from kidney tissue, increasing intracellular sodium enhanced bicarbonate-dependent pH recovery rate and increased NBCe2 mRNA and protein expressions to a greater extent in HV than WT SLC4A5 (+38.00±6.23% vs HV normal salt (P<0.01, N = 4, 2-way ANOVA, Holm-Sidak test)). In hRPTCs isolated from freshly voided urine, bicarbonate-dependent pH recovery was also faster in those from salt-sensitive and carriers of HV SLC4A5 than from salt-resistant and carriers of WT SLC4A5. The faster NBCe2-specific bicarbonate-dependent pH recovery rate in HV SCL4A5 was normalized by SLC4A5- but not SLC4A4-shRNA. The binding of purified hepatocyte nuclear factor type 4A (HNF4A) to DNA was increased in hRPTCs carrying HV SLC4A5 rs7571842 but not rs10177833. The faster NBCe2-specific bicarbonate-dependent pH recovery rate in HV SCL4A5 was abolished by HNF4A antagonists.CONCLUSIONNBCe2 activity is stimulated by an increase in intracellular sodium and is hyper-responsive in hRPTCs carrying HV SLC4A5 rs7571842 through an aberrant HNF4A-mediated mechanism.

项与 HNF4A Project (Omega Therapeutics) 相关的新闻（医药）

2024-04-02

·佰傲谷BioValley

诺和诺德合作伙伴裁员35%

近日，诺和诺德的合作伙伴，临床阶段的生物技术公司Omega Therapeutics 宣布，为了延长公司现金流，集中资源推进其核心管线项目，将裁员35%。截止2023年底，该公司拥有93名员工。Omega是一家表观遗传疗法领域的一家创新药企，其产品管线涉及免疫炎症、肝癌、非小细胞肺癌和肥胖等。其中肥胖项目今年1月与诺和诺德达成合作研发协议，Omega表示裁员并不影响其最近与诺和诺德签署的合作研发协议。表观遗传疗法表观遗传学是20世纪80年代逐渐兴起的一门学科，其核心是组蛋白和核酸的各种共价修饰，这些修饰协同调节染色质结构和基因表达。目前常说的表观遗传修饰主要是包括DNA甲基化、组蛋白乙酰化、组蛋白甲基化。由于表观遗传决定了哪些基因在何种水平表示，因此科学界一直在尝试通过调控表观遗传组来对抗癌症等疾病。OmegaTherapeutics就是一家开发可编程的表观遗传疗法的公司。公司创立于2017年，致力于使用DNA序列靶向、mRNA编码疗法来调控基因的表达。公司正在通过专有平台Omega开发多条管线，旨在针对不同的EpiZips开发对应的OEC，调控不同基因的表达，从而达到治疗、保健等医学目的。公司于2021年7月在美国纳斯达克上市。Omega称，其首创了将mRNA疗法用作一类新的可编程表观遗传药物的首个系统方法。管线Omega模块化和可编程的mRNA药物——Omega Epigenomic Controllers靶向绝缘基因组域（IGDs）内特定的表观基因组位点EpiZips，能够特异性地持久上调或下调单个或多个基因，通过精准基因组调控治疗和治愈疾病。自然界将基因及其调控元件组织在被称为绝缘基因组域（IGDs）的独特和进化保守的3D机构中，以控制基因的表达。Omega利用其专有算法和学习工具，挖掘自有和公共数据库，将大约15000个人类IGDs及其元素归类为基因组“邮政编码”，命名为EpiZips。同时，Omega分析了EpiZips在原始状态和疾病状态之间的差异，为公司将IGDs作为药物靶点来治疗和潜在治愈疾病提供了依据。Omega今目前进展最快的项目是被FDA批准进入1/2期临床的OTX-2002，通过LNP递送的OTX-2002旨在通过表观遗传调节在转录前下调c-Myc（MYC）表达，同时可能克服MYC的自调节，目标适应症是肝细胞癌。OTX-2002治疗肝细胞癌（HCC）患者的1/2期MYCHELANGELO临床试验显示，所有患者均表现出对MYC mRNA表达的受控调节和下调，HCC患者目标人群的中期疾病控制率（DCR）为80%，试验中非HCC实体瘤患者的DCR为40%。除此之外，还有多款临床前项目，包括用于改善继发于COVID-19/SAR-CoV的ARDS患者的预后情况的CXCL 1-8、用于肝脏再生的HNF4A以及用于肥胖的未公开项目。2024年1月，Omega宣布和诺和诺德就减肥新疗法达成研究合作协议，与Omega的合作协议，将使诺和诺德公司利用Omega公司的专有平台技术开发一种旨在增强代谢活性的表观基因组控制器。根据协议条款，诺和诺德将报销所有研发费用，并有权选择一个靶点推进临床开发。Omega和Flagship's Pioneering Medicines有资格获得高达5.32亿美元的预付款、开发和商业里程碑付款，以及许可产品年度净销售额的分级特许权使用费，这些费用将在双方之间平均分配。财务状况根据Omega公布的2023年第四季度及全年财务业绩，截止2023年12月31日，公司拥有总计7340万美元的现金、现金等价物和有价证券。2023年第四季度公司净亏损2020万美元，2022年同期为3080万美元。截止2023年12月31日，年度净亏损为9740万美元，2022年同期为净亏损1.027亿美元。与2022年相比，2023年的净亏损减少主要是由于研发费用的减少。2023年第四季度公司研发费用为1550万美元，2022年同期为2600万美元。2023年的全年研发费用为7720万美元，2022年为8120万美元。与2022年相比，2023年的研发费用减少了400万美元，主要是由于外部研究和制造成本、咨询和专业费用以及实验室费用的降低，部分被人事相关费用的增加所抵消，包括支持业务增长的股票薪酬，以及设施和其他成本。为了将公司的现金跑道延长到2025年，Omega决定裁员35%，集中资源推进几项核心管线项目。保证公司能够实现MYCHELANGELO I临床试验的单药剂量递增和剂量扩展阶段的关键临床数据读数。优先临床前项目包括用于非小细胞肺癌（NSCLC）的OTX-2101项目、用于肝脏再生的HNF4A项目，以及与诺和诺德合作开发用于肥胖的表观基因组控制器。平台生物学、表观基因组控制以及LNP递送至肺和其他组织的表征方面的核心工作将继续进行。参考来源：1.https://endpts.com/omega-cuts-35-of-workforce-rhythm-cervomed-surrozen-raise-new-funding/本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处···

信使RNA寡核苷酸

2022-08-09

·生物谷

J. Exp. Med: 上皮性HNF4a通过直接调节免疫信号分子来塑造上皮内淋巴细胞室

核受体是一种配体依赖的转录因子，调节包括新陈代谢、发育和免疫在内的广泛的生理过程。核受体是一种配体依赖的转录因子，调节包括新陈代谢、发育和免疫在内的广泛的生理过程。在小鼠核受体超家族的49个成员中(人为48个)，肝细胞核因子4α(HNF4a，NR2A1)在肝、肾、胰腺和肠道中特异表达。通过全基因组关联研究发现HNF4a基因座的多态与溃疡性结肠炎相关。此外，HNF4a在人类和小鼠之间高度保守。使用条件性基因敲除，上皮性HNF4a已被证明是预防老年动物急性化学诱导的结肠炎和自发性结肠炎所不可或缺的。图片来源: https://doi.org/10.1084/jem.20212563 近日，来自马萨诸塞大学的研究者们在J. Exp. Med杂志上发表了题为“Epithelial HNF4A shapes the intraepithelial lymphocyte compartment via direct regulation of immune signaling molecules”的文章，该研究发现强调了HNF4a作为控制IEC-IEL串扰的保守转录因子的重要性，并表明HNF4a通过调节IEL间隔来维持肠道内环境的稳定。肝细胞核因子4α(HNF4a)是一种高度保守的核受体，与溃疡性结肠炎有关。在小鼠中，HNF4a对于维持肠道内环境的稳定是不可或缺的，但其潜在的机制尚不清楚。在这里，研究者证明了HNF4a在肠上皮细胞(IECS)中的表达是上皮内淋巴细胞(IEL)室正常发育和组成所必需的。HNF4a直接调节免疫信号分子的表达，包括控制IEC-IEL串扰的类丁咯菲林(Btn1)1、Btn16、H2-T3和Clec2e。 HNF4a选择性地促进TcRγδ+或TcRαβ+CD8αα+的自然IEL的扩张，以形成IEL隔室的组成。在小肠中，HNF4a与其类似的HNF4G合作，驱动免疫信号分子的表达。此外，HNF4a-BTNL调节轴在人类IECs中是保守的。 HNF4a和HNF4G共同调节免疫信号分子图片来源: https://doi.org/10.1084/jem.20212563 在本研究中，研究者确定了一组包括Btnls在内的上皮免疫串扰分子作为IECS中HNF4a依赖的新靶点。通过对这些分子的直接调节，上皮性HNF4a调控IEL的发育和组成，以促进肠道内环境的稳定。此外，与IBD和结直肠癌相关的多个基因，包括Tmid1、Mep1a和SLC26a，都受到HNF4a的直接调控。这些靶点表明，HNF4a可能作为已知和新的IBD候选基因的上游转录因子。（生物谷 Bioon.com）参考文献 Xuqiu Lei et al. Epithelial HNF4A shapes the intraepithelial lymphocyte compartment via direct regulation of immune signaling molecules. J Exp Med. 2022 Aug 1;219(8):e20212563. doi: 10.1084/jem.20212563.