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. ; Serrano, Lourdes ; Kim, Yona ; 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 ; Fukazawa, Takuya ; Guo, Minzhe ; Okada, Morihito ; Baldauf, Iris-Fink ; Ito, Masaoki ; Yamatsuji, Tomoki ; Maeda, Yutaka ; Watanabe, Hideo ; 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）

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.