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Abstract：
Long noncoding RNA (lncRNA)-mediated posttranscriptional and epigenetic landscapes of gene regulation are associated with numerous human diseases. However, the regulatory mechanisms governing human β-cell function and survival remain unknown. Owing to technical and ethical constraints, studying the direct role of lncRNAs in β-cell function and survival in humans in vivo is difficult. Therefore, we utilized humanized mice with human islets to investigate lncRNA expression using whole transcriptome shotgun sequencing. Our study aimed to characterize lncRNAs that may be crucial for human islet cell function and survival.
Human β-cell death was induced in humanized mice engrafted with functional human islets. Using these humanized mice harboring human islets with induced β-cell death, we investigated lncRNA expression through whole transcriptome shotgun sequencing. Additionally, we systematically identified, characterized, and explored the regulatory functions of lncRNAs that are potentially important for human pancreatic islet cell function and survival.
Human islet cell death was induced in humanized mice engrafted with functional human islets. RNA sequencing analysis of isolated human islets, islet grafts from humanized mice with and without induced cell death, revealed aberrant expression of a distinct set of lncRNAs that are associated with the deregulated mRNAs important for cellular processes and molecular pathways related to β-cell function and survival. A total of 10 lncRNA isoforms (SCYL1-1:22, POLG2-1:1, CTRB1-1:1, SRPK1-1:1, GTF3C5-1:1, PPY-1:1, CTRB1-1:5, CPA5-1:1, BCAR1-2:1, and CTRB1-1:4) were identified as highly enriched and specific to human islets. These lncRNAs were deregulated in human islets from donors with different BMIs and with type 2 diabetes (T2D), as well as in cultured human islets with glucose stimulation and induced cell death induced by cytokines. Aberrant expression of these lncRNAs was detected in the exosomes from the medium used to culture islets with cytokines.
Islet-enriched and specific human lncRNAs are deregulated in human islet grafts and cultured human islets with induced cell death. These lncRNAs may be crucial for human β-cell function and survival and could have an impact on identifying biomarkers for β-cell loss and discovering novel therapeutic targets to enhance β-cell function and survival.
Human β-cell death was induced in humanized mice engrafted with functional human islets. Using these humanized mice harboring human islets with induced β-cell death, we investigated lncRNA expression through whole transcriptome shotgun sequencing. Additionally, we systematically identified, characterized, and explored the regulatory functions of lncRNAs that are potentially important for human pancreatic islet cell function and survival.
Human islet cell death was induced in humanized mice engrafted with functional human islets. RNA sequencing analysis of isolated human islets, islet grafts from humanized mice with and without induced cell death, revealed aberrant expression of a distinct set of lncRNAs that are associated with the deregulated mRNAs important for cellular processes and molecular pathways related to β-cell function and survival. A total of 10 lncRNA isoforms (SCYL1-1:22, POLG2-1:1, CTRB1-1:1, SRPK1-1:1, GTF3C5-1:1, PPY-1:1, CTRB1-1:5, CPA5-1:1, BCAR1-2:1, and CTRB1-1:4) were identified as highly enriched and specific to human islets. These lncRNAs were deregulated in human islets from donors with different BMIs and with type 2 diabetes (T2D), as well as in cultured human islets with glucose stimulation and induced cell death induced by cytokines. Aberrant expression of these lncRNAs was detected in the exosomes from the medium used to culture islets with cytokines.
Islet-enriched and specific human lncRNAs are deregulated in human islet grafts and cultured human islets with induced cell death. These lncRNAs may be crucial for human β-cell function and survival and could have an impact on identifying biomarkers for β-cell loss and discovering novel therapeutic targets to enhance β-cell function and survival.
摘要：
■长链非编码RNA（lncRNA）介导的基因调控的转录后和表观遗传景观与许多人类疾病有关。然而,控制人类β细胞功能和存活的调节机制仍然未知。由于技术和道德方面的限制,研究lncRNAs在人体内β细胞功能和存活中的直接作用是困难的。因此,我们利用人类胰岛的人源化小鼠，使用全转录组鸟枪测序研究lncRNA表达。我们的研究旨在表征可能对人类胰岛细胞功能和存活至关重要的lncRNAs。
■在移植有功能性人胰岛的人源化小鼠中诱导人β细胞死亡。使用这些带有诱导β细胞死亡的人类胰岛的人源化小鼠，我们通过全转录组鸟枪测序研究了lncRNA的表达。此外,我们系统地确定，characterized,并探索了对人类胰岛细胞功能和存活潜在重要的lncRNAs的调控功能。
■在移植有功能性人胰岛的人源化小鼠中诱导人胰岛细胞死亡。分离的人胰岛的RNA测序分析，来自有和没有诱导细胞死亡的人源化小鼠的胰岛移植物，揭示了一组不同的lncRNAs的异常表达，这些lncRNAs与对β细胞功能和存活相关的细胞过程和分子通路重要的去调节的mRNAs相关。总共10种lncRNA同工型（SCYL1-1：22，POLG2-1：1，CTRB1-1：1，SRPK1-1：1，GTF3C5-1：1，PPY-1：1，CTRB1-1：5，CPA5-1：1，BCAR1-2：1和CTRB1-1：4）被鉴定为高度富集的，对人类胰岛这些lncRNAs在来自不同BMI和2型糖尿病（T2D）供体的人类胰岛中失调，以及在具有葡萄糖刺激和细胞因子诱导的诱导细胞死亡的培养的人胰岛中。在来自用于用细胞因子培养胰岛的培养基的外来体中检测到这些lncRNA的异常表达。
■富含胰岛和特异性的人lncRNAs在人胰岛移植物和培养的人胰岛中失调，诱导细胞死亡。这些lncRNAs可能对于人β细胞功能和存活至关重要，并且可能对鉴定β细胞丢失的生物标志物和发现新的治疗靶标以增强β细胞功能和存活产生影响。
■在移植有功能性人胰岛的人源化小鼠中诱导人β细胞死亡。使用这些带有诱导β细胞死亡的人类胰岛的人源化小鼠，我们通过全转录组鸟枪测序研究了lncRNA的表达。此外,我们系统地确定，characterized,并探索了对人类胰岛细胞功能和存活潜在重要的lncRNAs的调控功能。
■在移植有功能性人胰岛的人源化小鼠中诱导人胰岛细胞死亡。分离的人胰岛的RNA测序分析，来自有和没有诱导细胞死亡的人源化小鼠的胰岛移植物，揭示了一组不同的lncRNAs的异常表达，这些lncRNAs与对β细胞功能和存活相关的细胞过程和分子通路重要的去调节的mRNAs相关。总共10种lncRNA同工型（SCYL1-1：22，POLG2-1：1，CTRB1-1：1，SRPK1-1：1，GTF3C5-1：1，PPY-1：1，CTRB1-1：5，CPA5-1：1，BCAR1-2：1和CTRB1-1：4）被鉴定为高度富集的，对人类胰岛这些lncRNAs在来自不同BMI和2型糖尿病（T2D）供体的人类胰岛中失调，以及在具有葡萄糖刺激和细胞因子诱导的诱导细胞死亡的培养的人胰岛中。在来自用于用细胞因子培养胰岛的培养基的外来体中检测到这些lncRNA的异常表达。
■富含胰岛和特异性的人lncRNAs在人胰岛移植物和培养的人胰岛中失调，诱导细胞死亡。这些lncRNAs可能对于人β细胞功能和存活至关重要，并且可能对鉴定β细胞丢失的生物标志物和发现新的治疗靶标以增强β细胞功能和存活产生影响。
