表观遗传调控对胰岛β细胞发育和功能以及糖尿病发病的影响和机制
|
摘要
背景：糖尿病是一种以血糖升高为特点的慢性代谢性疾病,典型的症状：多尿,多饮,以及多食；因其糖脂代谢紊乱,患并发症如动脉粥样硬化、糖尿病视网膜病变、慢性糖尿病肾病以及糖尿病足等的风险极大地增加。糖尿病的病因为胰岛β细胞不能产生足量的胰岛素、组织细胞对胰岛素失去正常的反应或者是二者皆有。目前认为糖尿病是由基因和环境因素共同作用的结果,但糖尿病发病的病因仍然未知。糖尿病主要有Ⅰ型和Ⅱ型两种。Ⅰ型糖尿病与自身免疫攻击破坏和先天易感因素导致β细胞的丢失,胰岛β细胞的缺乏导致产生的胰岛素量不足为主要特点。在这一过程中,许多基因与其发生有关,因此探寻糖尿病相关基因的调控机制对于发现治疗糖尿病的办法有重大意义。
表观遗传是在不改变DNA序列的情况下改变基因的表达水平。目前发现有如下几种表观遗传分子机制：DNA甲基化,RNA干扰,组蛋白乙酰化和组蛋白修饰。小分子RNA是长度为21-25个核苷酸的非编码单链RNA分子,它能通过目标信使RNA3′非翻译区错配来抑制目的基因信使RNA的翻译从而调控基因的表达。小分子RNA有组织特异性并能在细胞功能中起重要作用。目前已有几种小分子RNA被证明会特异性调节胰岛β细胞的发育和功能。组蛋白通过和DNA结合形成核小体,后者组成包含整个基因组的染色质。组蛋白去乙酰酶(HDACs)能使组蛋白去乙酰化,使其和DNA的结合更加紧密,从而抑制基因转录,进而在包括胰岛素信号传递等多个生理过程中发挥重要作用。HDACs(?)印制剂也被证实可以在炎症过程中防止细胞因子对β细胞的破坏。但是目前HDACs以及HDACs抑制剂对β细胞的直接作用及作用机制仍然未知。本研究从体内体外两部分实验,验证HDAC抑制剂曲古霉素A(TSA)对β细胞的直接作用以及miRNA表达的变化,构建不同miRNA(?)除老鼠观察其对链尿佐菌素(STZ)诱发的糖尿病的敏感度,构建HDAC3胰岛β细胞特异敲除的老鼠研究(?)HDAC3对胰岛β细胞发育以及功能的影响。希望从中明确HDAC与胰岛细胞以及糖尿病发生的关系,为开发糖尿病治疗药物提供理论基础。
研究方法：
1,本研究首先采取不同剂量TSA处理小鼠β细胞株mouse insulinoma (MIN6)不同时间,通过MTT检测和流式细胞仪来观察细胞增殖和凋亡的变化,应用micreRNA array技术确定TSA诱导的β细胞micreRNA表达谱的变化,预测改变的micreRNAs和β细胞凋亡信号因子调节关系。
2,构建miRNA155系统性敲除以及Tie2-Dicerfl/特异性敲除的小鼠,观察它们对多次小剂量STZ诱导糖尿病的敏感度,进而明确miRNAl55,以及总miRNA在骨髓源细胞的缺失在炎症介导糖尿病中的作用。
3,为明确HDAC3对β细胞发生发育和功能的作用,构建胰岛β细胞特异敲除HDAC3的小鼠,监测小鼠体重血糖水平的变化,通过糖耐量实验和葡萄糖刺激的胰岛素分泌来检测小鼠胰岛功能,利用组织学分析和免疫荧光染色来确定其胰岛体积变化和胰岛β细胞的增殖状态,多次小剂量STZ注射观察他们对炎症介导糖尿病的敏感度。通过体外的siRNA(?)敲除HDAC3,实时定量PCR(?)测胰岛素相关基基以及HDAC3潜在靶点基因转录水平,发现细胞因子信号转导抑制因子3(SOCS3)为HDAC3可能的作用靶点,通过双敲除HDAC3和SOCS3验证相关基因表达以及对胰岛素含量和释放的影响。
结果：
1,TSA对MIN6细胞活性有明显的抑制作用,且有明显的时间剂量效应关系,TAS能显著提高MIN6细胞凋亡水平,分别有61和56个miRNA表达下调和上调(|-△△Ct|≥1),其中12个上调的和25个下调的miRNA(?)可以特异调控β细胞凋亡通路的信号因子。
2,miRNA155系统性敲除的小鼠在多次小剂量STZ诱导的糖尿病中发病率和野生型小鼠没有明显区别,但是骨髓源细胞特异Dicer(?)除小鼠却呈现出了明显的低发病率。
3,胰岛β细胞特异性敲除HDAC3小鼠体重较同窝对照小鼠比体重明显降低,血糖值明显升高,且有一定早期自发糖尿病概率,糖耐量实验证实了其葡萄糖不耐受且有胰岛素分泌障碍,组织学证明其胰岛体积并未明显减少,但是其胰腺胰岛素含量以及其处于增,生状态的β细胞比例都显著降低,多次小剂量STZ诱导的糖尿病发病率远高于对照组小鼠。体外通过siRNA敲除HDAC3使MIN6细胞胰岛素基因转录水平明显下.降,通过筛查控制胰岛素合成和分泌以及p细胞增生发育的相关基因,SOCS3被认为是潜在靶点,CHIP证明了HDAC3和(?)SOCS3启动子的结合,通过HDAC3和(?)SOCS3双敲除证明了SOCS3可以或者是部分的改善HDAC3敲除对β细胞胰岛素合成分泌的抑制作用。
结论：
1, HDAC抑制剂对胰岛β细胞有明显生长抑制和促凋亡作用,伴随着多种miRNAs表达的变化,TSA很可能通过niRNA的参与介导了β细胞的凋亡过程,作为目前一种有前途的抗癌药物,TSA对β细胞的负面作用不可忽视,
2, MiRNA155敲除小鼠虽然在别的自身免疫疾病上表现出一定的保护作用,但是却不能降低多次小剂量STZ诱导的糖尿病发生率,说明niRNA在不同的组织和器官炎症活动中有不同作用,骨髓源性细胞通过敲除Dicer导致的miRNA缺失会降低STZ诱导的糖尿病发生率,说明了miRNA对参与胰岛炎症活动的免疫细胞功能必不可少的调节作用。
3, HDAC3敲除会影响β细胞的发育和功能,而且不同于HDACs抑制剂会降低细胞因子介导的胰岛炎症反应,HDAC3(?)的敲除会增加STZ诱导的糖尿病发病率,体外实验也证明了HDAC3(?)沉默会降低胰岛素基因的转录水平以及胰岛素含量,这种作用很可能是通过HDAC3(?)的沉默上调SOCS3来实现的。
Background:Diabetes is a group of chronic metabolic diseases in which a person has high blood glucose level because the pancreatic islets can not produce enough insulin, cells do not respond to the insulin normally or both. High blood glucose levels can cause several classical symptoms, including:polyuria, polydipsia and polyphagia. Chronic diabetes can significantly enhance the risk of long-term complications such as atherosclerosis. Diabetic retinopathy. chronic kidney disease and diabetic foot ulcers. It is believed genes and environmental factors interact to cause diabetes, but the precise etiology of most cases of diabetes is still unknown. There are two main types of diabetes, type1and type2. Type1diabetes is characterized by loss of the insulin-producing β cells in the in the pancreatic islets, leading to insulin deficiency. The bata cell loss is cuased by either autoimmune destruction or idiopathic susceptibility. Many different genes contribute to its onset, so finding the mechanisms that regulate the diabetes-relavent gene expression is of grave importance to the cure of diabetes.
Epigenetic changes can modify the expression of certain genes without changing sequence of DNA. There are several types of epigenetic inheritance systems methylation of DNA, RNA interference, histone acetylation and protein modification. MiRNAs are a class of21-25nucleotide single stranded noncoding small RNAs that function as important regulators of gene expression through inhibiting effective mRNA translation via imperfect base pairing with the3'-untranslated region (3'UTR) of target mRNAs in animals. MiRNAs are tissue-specific and considered to play important roles in cell function. Some microRNAs have shown their specific roles in β cell development and fuction. Histones are small proteins that, by complexing wtih DNA, form the nucleosome core. Repetitive units of this nucleosome led to the chromatin in which all the genome is packaged. Histone deacetylases (HDACs) make histones to wrap the DNA more tightly to inhibit gene transcription, thus to play a regulatory role in many physiological activities including insulin signaling.HDAC inhibitors have shown the effect of protecting β cells from cytokines in the inflammatory process. The effect of HDAC inhibitors and HDACs on β-cells remains unclear. We studied the direct effect of one HDACs inhibitor (TSA) on β cell lines and changed miRNA profiles induced by TSA, generated several miRNA knockout mice strains to observe the sensitivity to Streptozotocin (STZ) induced diabetes, generated βP cell specific HDAC3knockout mice to study the effect of HDAC3on β cell proliferation and function and hope to find the link between HDAC3and β cell as well as diabetes onset to provide theoretical basis for the research and development of drugs for the treatment of diabetes.
Methods:
1, Firstly MIN6cells were treated with different concentrations of TSA for different times, Cell viability was evaluated by the MTT-based cytotoxicity assay, Annexin V-APC and7-AAD staining for apoptosis analysis. miRNAs expression was performed using Taqman MicroRNA assay. Predict the changed microRNAs regulating β cell apoptosis pathway factors.
2, Systemic miRNA155knockout mice and Tie2-Dicerfl/fl mice were generated to test the sensitivity to multiple low-dose streptozotocin-induced diabetes, thus illustrating the function of miRNAs in the onset of cytokine induced diabetes.
3, To investigate the function of HDAC3in the development and function of β cells. Mice with HDAC3specifically depleted in β cells were generated, mice weight and blood glucose levels were monitored and function of islets were assessed using glucose tolerance test and glucose stimulated insulin secretion. β cell number and proliferation were measured by Histological sections and immunoflurescence, multiple low-dose STZ treatment was performed to test the sensitivity to cytokine induced β cell diabetes. HDAC3siRNA transfection was done in vitro to test the changes insulin relavent and HDAC3potential targeted gene expression using realtime PCR. Suppressor of cytokine signaling3(SOCS3) was one of the potential targets of HDAC3, we then used SOCS3and HDAC3double silence to test the insulin relative gene expression and insulin content and secretion.
Results:
1, Cell viability was inhibited as the increasing TSA concentration and the extending of treatment time,TSA significantly elevated cell apoptosis,61miRNAs were down-regulated and56miRNAs were up-regulated (|-ΔΔCt|≥1), among them12up-regulated and25down-regulated miRNAs target specific apoptosis pathway factors.
2, Loss of miR155did not show any difference in the multiple low-dose streptozotocin induced diabetes incidence compared with wide type mice, but loss of total miRNAs in hematopoiesis prevents STZ-induced autoimmune diabetes.
3, Mice with HDAC3depleted β cells showed marked decreased body weight and higher blood glucose level compared with littermate controls, some individuals even developed spontaneous diabetes. They exhibited glucose intolerance, impaired insulin secretion, there was no obvious decrease in the islets volume, but the β cell insulin content as well as proliferation dramatically decreased. They showed significantly enhanced sensitivity to STZ induced diabetes. HDAC3silencing in vitro significantly decreased the mRNA level of insulin, SOCS3was considered to be the potential target of HDAC3after screening all potential genes. CHIP confirmed the binding of HDAC3to the promoter of SOCS3, silencing SOCS3together with HDAC3can, at leat partially attenuated the inhibitive effect of HDAC3silencing to insulin production and secretion.
Conclusions:
1, HDACs inhibitor TSA decreases β cell proliferation, increases apoptosis and altered miRNAs expression, and indicates the potential involvement of miRNAs in TSA mediated MIN6cell apoptosis. As a promising anti-cancer drug, these negative effects of TSA on β cells should also be considered.
2, Unlike prevention in other autoimmune diseases, loss of miR-155does not prevent multiple low-dose STZ induced diabetes development, suggesting that the same miRNA may play different roles in different organs and conditions. Loss of total miRNAs in hematopoiesis prevents STZ-induced diabetes indicating that essential regulatory role of miRNAs in the process of immune cell mediated islets inflammation.
3, HDAC3knockout affects β cell proliferation and function, unlike the protective role of HDAC inhibitors during cytokine mediated islets inflammation, loss of HDAC3in β cells enhances the sensitivity to STZ induced diabetes. HDAC3silencing in vitro reduces the mRNA level of insulin as well as insulin content. Upregulation of SOCS3as a result of HDAC3silence possibly involves in this process.
表观遗传是在不改变DNA序列的情况下改变基因的表达水平。目前发现有如下几种表观遗传分子机制：DNA甲基化,RNA干扰,组蛋白乙酰化和组蛋白修饰。小分子RNA是长度为21-25个核苷酸的非编码单链RNA分子,它能通过目标信使RNA3′非翻译区错配来抑制目的基因信使RNA的翻译从而调控基因的表达。小分子RNA有组织特异性并能在细胞功能中起重要作用。目前已有几种小分子RNA被证明会特异性调节胰岛β细胞的发育和功能。组蛋白通过和DNA结合形成核小体,后者组成包含整个基因组的染色质。组蛋白去乙酰酶(HDACs)能使组蛋白去乙酰化,使其和DNA的结合更加紧密,从而抑制基因转录,进而在包括胰岛素信号传递等多个生理过程中发挥重要作用。HDACs(?)印制剂也被证实可以在炎症过程中防止细胞因子对β细胞的破坏。但是目前HDACs以及HDACs抑制剂对β细胞的直接作用及作用机制仍然未知。本研究从体内体外两部分实验,验证HDAC抑制剂曲古霉素A(TSA)对β细胞的直接作用以及miRNA表达的变化,构建不同miRNA(?)除老鼠观察其对链尿佐菌素(STZ)诱发的糖尿病的敏感度,构建HDAC3胰岛β细胞特异敲除的老鼠研究(?)HDAC3对胰岛β细胞发育以及功能的影响。希望从中明确HDAC与胰岛细胞以及糖尿病发生的关系,为开发糖尿病治疗药物提供理论基础。
研究方法：
1,本研究首先采取不同剂量TSA处理小鼠β细胞株mouse insulinoma (MIN6)不同时间,通过MTT检测和流式细胞仪来观察细胞增殖和凋亡的变化,应用micreRNA array技术确定TSA诱导的β细胞micreRNA表达谱的变化,预测改变的micreRNAs和β细胞凋亡信号因子调节关系。
2,构建miRNA155系统性敲除以及Tie2-Dicerfl/特异性敲除的小鼠,观察它们对多次小剂量STZ诱导糖尿病的敏感度,进而明确miRNAl55,以及总miRNA在骨髓源细胞的缺失在炎症介导糖尿病中的作用。
3,为明确HDAC3对β细胞发生发育和功能的作用,构建胰岛β细胞特异敲除HDAC3的小鼠,监测小鼠体重血糖水平的变化,通过糖耐量实验和葡萄糖刺激的胰岛素分泌来检测小鼠胰岛功能,利用组织学分析和免疫荧光染色来确定其胰岛体积变化和胰岛β细胞的增殖状态,多次小剂量STZ注射观察他们对炎症介导糖尿病的敏感度。通过体外的siRNA(?)敲除HDAC3,实时定量PCR(?)测胰岛素相关基基以及HDAC3潜在靶点基因转录水平,发现细胞因子信号转导抑制因子3(SOCS3)为HDAC3可能的作用靶点,通过双敲除HDAC3和SOCS3验证相关基因表达以及对胰岛素含量和释放的影响。
结果：
1,TSA对MIN6细胞活性有明显的抑制作用,且有明显的时间剂量效应关系,TAS能显著提高MIN6细胞凋亡水平,分别有61和56个miRNA表达下调和上调(|-△△Ct|≥1),其中12个上调的和25个下调的miRNA(?)可以特异调控β细胞凋亡通路的信号因子。
2,miRNA155系统性敲除的小鼠在多次小剂量STZ诱导的糖尿病中发病率和野生型小鼠没有明显区别,但是骨髓源细胞特异Dicer(?)除小鼠却呈现出了明显的低发病率。
3,胰岛β细胞特异性敲除HDAC3小鼠体重较同窝对照小鼠比体重明显降低,血糖值明显升高,且有一定早期自发糖尿病概率,糖耐量实验证实了其葡萄糖不耐受且有胰岛素分泌障碍,组织学证明其胰岛体积并未明显减少,但是其胰腺胰岛素含量以及其处于增,生状态的β细胞比例都显著降低,多次小剂量STZ诱导的糖尿病发病率远高于对照组小鼠。体外通过siRNA敲除HDAC3使MIN6细胞胰岛素基因转录水平明显下.降,通过筛查控制胰岛素合成和分泌以及p细胞增生发育的相关基因,SOCS3被认为是潜在靶点,CHIP证明了HDAC3和(?)SOCS3启动子的结合,通过HDAC3和(?)SOCS3双敲除证明了SOCS3可以或者是部分的改善HDAC3敲除对β细胞胰岛素合成分泌的抑制作用。
结论：
1, HDAC抑制剂对胰岛β细胞有明显生长抑制和促凋亡作用,伴随着多种miRNAs表达的变化,TSA很可能通过niRNA的参与介导了β细胞的凋亡过程,作为目前一种有前途的抗癌药物,TSA对β细胞的负面作用不可忽视,
2, MiRNA155敲除小鼠虽然在别的自身免疫疾病上表现出一定的保护作用,但是却不能降低多次小剂量STZ诱导的糖尿病发生率,说明niRNA在不同的组织和器官炎症活动中有不同作用,骨髓源性细胞通过敲除Dicer导致的miRNA缺失会降低STZ诱导的糖尿病发生率,说明了miRNA对参与胰岛炎症活动的免疫细胞功能必不可少的调节作用。
3, HDAC3敲除会影响β细胞的发育和功能,而且不同于HDACs抑制剂会降低细胞因子介导的胰岛炎症反应,HDAC3(?)的敲除会增加STZ诱导的糖尿病发病率,体外实验也证明了HDAC3(?)沉默会降低胰岛素基因的转录水平以及胰岛素含量,这种作用很可能是通过HDAC3(?)的沉默上调SOCS3来实现的。
Background:Diabetes is a group of chronic metabolic diseases in which a person has high blood glucose level because the pancreatic islets can not produce enough insulin, cells do not respond to the insulin normally or both. High blood glucose levels can cause several classical symptoms, including:polyuria, polydipsia and polyphagia. Chronic diabetes can significantly enhance the risk of long-term complications such as atherosclerosis. Diabetic retinopathy. chronic kidney disease and diabetic foot ulcers. It is believed genes and environmental factors interact to cause diabetes, but the precise etiology of most cases of diabetes is still unknown. There are two main types of diabetes, type1and type2. Type1diabetes is characterized by loss of the insulin-producing β cells in the in the pancreatic islets, leading to insulin deficiency. The bata cell loss is cuased by either autoimmune destruction or idiopathic susceptibility. Many different genes contribute to its onset, so finding the mechanisms that regulate the diabetes-relavent gene expression is of grave importance to the cure of diabetes.
Epigenetic changes can modify the expression of certain genes without changing sequence of DNA. There are several types of epigenetic inheritance systems methylation of DNA, RNA interference, histone acetylation and protein modification. MiRNAs are a class of21-25nucleotide single stranded noncoding small RNAs that function as important regulators of gene expression through inhibiting effective mRNA translation via imperfect base pairing with the3'-untranslated region (3'UTR) of target mRNAs in animals. MiRNAs are tissue-specific and considered to play important roles in cell function. Some microRNAs have shown their specific roles in β cell development and fuction. Histones are small proteins that, by complexing wtih DNA, form the nucleosome core. Repetitive units of this nucleosome led to the chromatin in which all the genome is packaged. Histone deacetylases (HDACs) make histones to wrap the DNA more tightly to inhibit gene transcription, thus to play a regulatory role in many physiological activities including insulin signaling.HDAC inhibitors have shown the effect of protecting β cells from cytokines in the inflammatory process. The effect of HDAC inhibitors and HDACs on β-cells remains unclear. We studied the direct effect of one HDACs inhibitor (TSA) on β cell lines and changed miRNA profiles induced by TSA, generated several miRNA knockout mice strains to observe the sensitivity to Streptozotocin (STZ) induced diabetes, generated βP cell specific HDAC3knockout mice to study the effect of HDAC3on β cell proliferation and function and hope to find the link between HDAC3and β cell as well as diabetes onset to provide theoretical basis for the research and development of drugs for the treatment of diabetes.
Methods:
1, Firstly MIN6cells were treated with different concentrations of TSA for different times, Cell viability was evaluated by the MTT-based cytotoxicity assay, Annexin V-APC and7-AAD staining for apoptosis analysis. miRNAs expression was performed using Taqman MicroRNA assay. Predict the changed microRNAs regulating β cell apoptosis pathway factors.
2, Systemic miRNA155knockout mice and Tie2-Dicerfl/fl mice were generated to test the sensitivity to multiple low-dose streptozotocin-induced diabetes, thus illustrating the function of miRNAs in the onset of cytokine induced diabetes.
3, To investigate the function of HDAC3in the development and function of β cells. Mice with HDAC3specifically depleted in β cells were generated, mice weight and blood glucose levels were monitored and function of islets were assessed using glucose tolerance test and glucose stimulated insulin secretion. β cell number and proliferation were measured by Histological sections and immunoflurescence, multiple low-dose STZ treatment was performed to test the sensitivity to cytokine induced β cell diabetes. HDAC3siRNA transfection was done in vitro to test the changes insulin relavent and HDAC3potential targeted gene expression using realtime PCR. Suppressor of cytokine signaling3(SOCS3) was one of the potential targets of HDAC3, we then used SOCS3and HDAC3double silence to test the insulin relative gene expression and insulin content and secretion.
Results:
1, Cell viability was inhibited as the increasing TSA concentration and the extending of treatment time,TSA significantly elevated cell apoptosis,61miRNAs were down-regulated and56miRNAs were up-regulated (|-ΔΔCt|≥1), among them12up-regulated and25down-regulated miRNAs target specific apoptosis pathway factors.
2, Loss of miR155did not show any difference in the multiple low-dose streptozotocin induced diabetes incidence compared with wide type mice, but loss of total miRNAs in hematopoiesis prevents STZ-induced autoimmune diabetes.
3, Mice with HDAC3depleted β cells showed marked decreased body weight and higher blood glucose level compared with littermate controls, some individuals even developed spontaneous diabetes. They exhibited glucose intolerance, impaired insulin secretion, there was no obvious decrease in the islets volume, but the β cell insulin content as well as proliferation dramatically decreased. They showed significantly enhanced sensitivity to STZ induced diabetes. HDAC3silencing in vitro significantly decreased the mRNA level of insulin, SOCS3was considered to be the potential target of HDAC3after screening all potential genes. CHIP confirmed the binding of HDAC3to the promoter of SOCS3, silencing SOCS3together with HDAC3can, at leat partially attenuated the inhibitive effect of HDAC3silencing to insulin production and secretion.
Conclusions:
1, HDACs inhibitor TSA decreases β cell proliferation, increases apoptosis and altered miRNAs expression, and indicates the potential involvement of miRNAs in TSA mediated MIN6cell apoptosis. As a promising anti-cancer drug, these negative effects of TSA on β cells should also be considered.
2, Unlike prevention in other autoimmune diseases, loss of miR-155does not prevent multiple low-dose STZ induced diabetes development, suggesting that the same miRNA may play different roles in different organs and conditions. Loss of total miRNAs in hematopoiesis prevents STZ-induced diabetes indicating that essential regulatory role of miRNAs in the process of immune cell mediated islets inflammation.
3, HDAC3knockout affects β cell proliferation and function, unlike the protective role of HDAC inhibitors during cytokine mediated islets inflammation, loss of HDAC3in β cells enhances the sensitivity to STZ induced diabetes. HDAC3silencing in vitro reduces the mRNA level of insulin as well as insulin content. Upregulation of SOCS3as a result of HDAC3silence possibly involves in this process.
引文
1. Grunstein, M., Histone acetylation in chromatin structure and transcription. Nature,1997. 389(6649):p.349-52.
2. Choudhary, C., et al., Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science,2009.325(5942):p.834-40.
3. de Ruijter, A.J., et al., Histone deacetylases (HDACs):characterization of the classical HDAC family. Biochem J,2003.370(Pt 3):p.737-49.
4. Haberland, M., R.L. Montgomery, and E.N. Olson, The many roles of histone deacetylases in development and physiology:implications for disease and therapy. Nat Rev Genet,2009.10(1):p.32-42.
5. Bhaskara, S., et al., Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol Cell,2008.30(1):p.61-72.
6. Lundh, M., et al., Lysine deacetylases are produced in pancreatic β cells and are differentially regulated by proinflammatory cytokines. Diabetologia,2010.53(12):p. 2569-78.
7. Li, J., et al., Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J.2000.19(16):p.4342-50.
8. Montgomery, R.L., et al., Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. J Clin Invest,2008.118(11):p.3588-97.
9. Sun, Z.. et al., Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat Med,2012.18(6):p.934-42.
10. Knutson, S.K., et al., Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J,2008.27(7):p.1017-28.
11. Razidlo, D.F., et al., Histone deacetylase 3 depletion in osteo/chondroprogenitor cells decreases bone density and increases marrow fat. PLoS One,2010.5(7):p. e11492.
12. Lewis, E.C., et al., The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet beta cells in vivo and in vitro. Mol Med,2011.17(5-6):p.369-77.
13. Chou, D.H., et al., Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. Chem Biol, 2012. 19(6): p. 669-73.
14. Patel, T., et al., Chromatin remodeling resets the immune system to protect against autoimmune diabetes in mice. Immunol Cell Biol, 2011. 89(5): p. 640-9.
15. Lundh, M., et al., Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and arc differentially regulated in the islets of type 1 diabetic children. Diabctologia, 2012. 55(9): p. 2421-31.
16. Fischle, W., et al., Enzymatic activity associated with class Ⅱ HDACs is dependent on a muliiprotein complex containing HDAC3 and SMRT/N-CoR. Mol Cell, 2002. 9(1): p. 45-57.
17. Guenther, M.G., et al., Assembly of the SMRT-histone deacetylase 3 repression complex requires the TCP-1 ring complex. Genes Dev, 2002. 16(24): p. 3130-5.
18. Slack, J.M., Developmental biology of the pancreas. Development, 1995. 121(6): p. 1569-80.
19. Gannon, M., et al., Analysis of the Cre-mediated recombination driven by rat insulin promoter in embryonic and adult mouse pancreas. Genesis, 2000. 26(2): p. 139-42.
20. Haumaitre, C., O. Lenoir, and R. Scharfmann, Histone deacetyla.se inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors. Mol Cell Biol, 2008. 28(20): p. 6373-83.
21. Lee, H.W., et al., Histone deacetylase 1-mediated histone modification regulates osteoblast differentiation. Mol Endocrinol, 2006. 20(10): p. 2432-43.
22. Yoo, E.J., et al., Down-regulation of histone deacetylases stimulates adipocyte differentiation. J Biol Chem, 2006. 281(10): p. 6608-15.
23. Ortis, F., et al., Cytokines interleukin-1beta and lumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells. Diabetes, 2010. 59(2): p. 358-74.
24. McEvoy, R.C., et al., Multiple low-dose streptozotocin-induced diabetes in the mouse. Evidence for stimulation of a cytotoxic cellular immune response against an insulin-producing beta cell line. J Clin Invest, 1984. 74(3): p. 715-22.
25. Karlsen, A.E., et al., Suppressor of cytokine signalling (SOCS)-3 protects beta cells against IL-1beta-mediated toxicity through inhibition of multiple nuclear factor-kappaB-regulated proapoplotic pathways. Diabetologia. 2004. 47(11): p. 1998-2011.
26. Karlsen. A.E., et al., Suppressor of cytokine signaling 3 (SOCS-3) protects beta -cells against interleukin-Ibeta - and interferon-gamma -mediated toxicity. Proc Natl Acad Sci U SA, 2001. 98(21): p. 12191-6.
27. Borjesson, A., et al., beta-cell specific overexpression of suppressor of cytokine signalling-3 does not protect against multiple low dose streptozotoein induced type 1 diabetes in mice. Immunol Lett, 2011. 136( 1): p. 74-9.
28. Emanuelli, B., et al., The potential role of SOCS-3 in the interleukin-1beta-induced desensitization of insulin signaling in pancreatic beta-cells. Diabetes, 2004. 53 Suppl 3: p. S97-S103.
29. Laubner, K., et al., Inhibition of preproinsulin gene expression by leptin induction of suppressor of cytokine signaling 3 in pancreatic beta-cells. Diabetes. 2005. 54(12): p. 3410-7.
30. Lindberg, K., et al., Regulation of pancreatic beta-cell mass and proliferation by SOCS-3. J Mol Endocrinol,2005.35(2):p.231-43.
31. Howard, J.K., et al., Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med,2004.10(7):p.734-8.
32. Barclay, J.L., et al., SOCS3 as a tumor suppressor in breast cancer cells, and its regulation by PRL. Int J Cancer,2009.124(8):p.1756-66.
33. Jackerott, M., et al., STAT5 activity in pancreatic beta-cells influences the severity of diabetes in animal models of type 1 and 2 diabetes. Diabetes,2006.55(10):p.2705-12.
34. Galsgaard, E.D., et al., Expression of dominant-negative STAT5 inhibits growth hormone-and prolactin-induced proliferation of insulin-producing cells. Diabetes,2001.50 Suppl 1:p. S40-1.
35. Jensen, J., et al., STAT5 activation by human GH protects insulin-producing cells against interleukin-1beta, interferon-gamma and tumour necrosis factor-alpha-induced apoptosis independent of nitric oxide production. J Endocrinol,2005.187(1):p.25-36.
1. Zhang, P., et al., Global healthcare expenditure on diabetes for 2010 and 2030. Diabetes Res Clin Pract,2010.87(3):p.293-301.
2. Shaw, J.E., R.A. Sicree, and P.Z. Zimmet, Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract,2010.87(1):p.4-14.
3. Economic Costs of Diabetes in the U.S. in 2012. Diabetes Care,2013.
4. Rother, K.I., Diabetes treatment--bridging the divide. N Engl J Med,2007.356(15):p. 1499-501.
5. van Belle, T.L., K.T. Coppieters, and M.G. von Herrath, Type 1 diabetes:etiology, immunology, and therapeutic strategies. Physiol Rev,2011.91(1):p.79-118.
6. Eizirik, D.L., M.L. Colli, and F. Ortis, The role of inflammation in insiditis and β-cell loss in type 1 diabetes. Nat Rev Endocrinol,2009.5(4):p.219-26.
7. Mandrup-Poulsen, T., The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia, 1996.39(9):p.1005-29.
8. Mosley, A.L. and S. Ozcan, The pancreatic duodenal homeobox-1 protein (Pdx-1) interacts with histone deacetylases Hdac-1 and Hdac-2 on low levels of glucose. J Biol Chem,2004. 279(52):p.54241-7.
9. Lenoir, O., et al., Specific control of pancreatic endocrine β-and delta-cell mass by class Ⅱa histone deacetylases HDAC4, HDAC5, and HDAC9. Diabetes,2011.60(11):p.2861-71.
10. Haberland, M., R.L. Montgomery, and E.N. Olson, The many roles of histone deacetylases in development and physiology:implications for disease and therapy. Nat Rev Genet,2009. 10(1):p.32-42.
11. Mariadason, J.M., HDACs and HDAC inhibitors in colon cancer. Epigenetics,2008.3(1):p. 28-37.
12. Blanchard, F. and C. Chipoy, Histone deacetylase inhibitors:new drugs for the treatment of inflammatory diseases? Drug Discov Today,2005.10(3):p.197-204.
13. Glauben, R. and B. Siegmund, Molecular basis of histone deacetylase inhibitors as new drugs for the treatment of inflammatory diseases and cancer. Methods Mol Biol,2009.512:p. 365-76.
14. Haumaitre, C., O. Lenoir, and R. Scharfmann, Histone deacetylase inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors. Mol Cell Biol,2008. 28(20):p.6373-83.
15. Larsen, L, et al., Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells. Diabetologia,2007.50(4):p.779-89.
16. Poy, M.N., et al., A pancreatic islet-specific microRNA regulates insulin secretion. Nature, 2004.432(7014):p.226-30.
17. Poy, M.N., et al., miR-375 maintains normal pancreatic alpha- and beta-cell mass. Proc Natl Acad Sci U S A,2009.106(14):p.5813-8.
18. Mi, Q.S., et al., microRNA deficiency in pancreatic islet cells exacerbates streptozotoein-inducedmurine autoimmune diabetes. Cell Cycle,2010.9(15):p.3127-9.
19. Khan, O. and N.B. La Thangue, HDAC inhibitors in cancer biology:emerging mechanisms and clinical applications. Immunol Cell Biol,2012.90(1):p.85-94.
20. Scott, G.K., et al., Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res,2006.66(3):p.1277-81.
21. Hasseine, L.K., et al., miR-139 impacts FoxO1 action by decreasing FoxO1 protein in mouse hepatocytes. Biochem Biophys Res Commun,2009.390(4):p.1278-82.
22. Buteau, J. and D. Accili, Regulation of pancreatic beta-cell function by the forkhead protein FoxO1. Diabetes Obes Metab,2007.9 Suppl 2:p.140-6.
23. Tivnan, A., et al., MicroRNA-184-mediated inhibition of tumour growth in an orthotopic murine model of neurohlastoma. Anticancer Res,2010.30(11):p.4391-5.
24. Bolmeson, C., et al., Differences in islet-enriched miRNAs in healthy and glucose intolerant human subjects. Biochem Biophys Res Commun,2011.404(1):p.16-22.
25. Jeon, H.S., et al., Combining microRNA-449a/b with a HDAC inhibitor has a synergistic effect on growth arrest in lung cancer. Lung Cancer,2012.76(2):p.171-6.
1. Croce, C.M. and G.A. Calin, miRNAs, cancer, and stem cell division. Cell,2005.122(1):p. 6-7.
2. Zhou, L., et al., MicroRNAs are key regulators controlling iNKT and regulatory T-cell development and function. Cell Mol Immunol,2011.8(5):p.380-7.
3. Ha, T.Y., The Role of MicroRNAs in Regulatory T Cells and in the Immune Response. Immune Netw,2011.11(1):p.11-41.
4. Cobb, B.S., et al., A role for Dicer in immune regulation. J Exp Med,2006.203(11):p. 2519-27.
5. Muljo, S.A., et al., Aberrant T cell differentiation in the absence of Dicer. J Exp Med,2005. 202(2):p.261-9.
6. Seo, K.H., et al., Loss of microRNAs in thymus perturbs invariant NKT cell development and function. Cell Mol Immunol,2010.7(6):p.447-53.
7. Zhou, X., et al., Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med,2008.205(9):p.1983-91.
8. Brady, B.L., L.J. Rupp, and C.H. Bassing, Requirement for dicer in survival of proliferating thymocytes experiencing DNA double-strand breaks. J Immunol,2013.190(7):p.3256-66.
9. Wu, K.K, and Y. Huan, Slreptozotocin-induced diabetic models in mice and rats. Curr Protoc Pharmacol,2008. Chapter 5:p. Unit 5 47.
10. Brusko, T. and M. Atkinson, Treg in type 1 diabetes. Cell Biochem Biophys,2007.48(2-3):p. 165-75.
11. Rodriguez, A., et al.. Requirement ofbic/microRNA-155 for normal immune function. Science, 2007.316(5824):p.608-11.
12. Martinez-Nunez, R.T., et al., MicroRNA-155 modulates the pathogen binding ability of dendritic cells (DCs) bv down-regulation of DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN). J Biol Chem,2009.284(24):p.16334-42.
13. O'Connell, R.M., et al., MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity,2010.33(4):p.607-19.
14. Ceppi, M., et al., MicroRNA-155 modulates the inlerleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci U S A,2009.106(8):p.2735-40.
15. Thai, T.H., et al., Regulation of the germinal center response by microRNA-155. Science, 2007.316(5824):p.604-8.
16. O'Connell, R.M., et al., MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A,2007.104(5):p.1604-9.
17. Trotta, R., et al., Overexpression of miR-155 causes expansion, arrest in terminal differentiation and functional activation of mouse natural killer cells. Blood,2013.
18. Jeker, L.T. and J.A. Bluestone, Small RNA regulators of Tcell-mediated autoimmunity. J Clin Immunol,2010.30(3):p.347-57.
19. Kohlhaas, S., et al., Cutting edge:the Foxp3 target miR-155 contributes to the development of regulatory T cells. J Immunol,2009.182(5):p.2578-82.
20. Murugaiyan, G., et al., Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J Immunol,2011.187(5):p.2213-21.
21. Like, A. A. and A.A. Rossini, Streptozotocin-induced pancreatic insulitis:new model of diabetes mellitus. Science,1976.193(4251):p.415-7.
22. Cockfield, S.M., et al., Multiple low dose streptozotocin induces systemic MHC expression in mice by triggering T cells to release IFN-gamma. J Immunol,1989.142(4):p.1120-8.
23. McEvoy, R.C., et al., Multiple low-dose streptozotocin-induced diabetes in the mouse. Evidence for stimulation of a cytotoxic cellular immune response against an insulin-producing beta cell line. J Clin Invest,1984.74(3):p.715-22.
24. Maclaren, N.K., et al., Androgen sensitization of streptozotocin-induced diabetes in mice. Diabetes,1980.29(9):p.710-6.
25. Tian, L., et al., Loss of T cell microRNA provides systemic protection against autoimmune pathology in mice. J Autoimmun,2012.38(1):p.39-48.
2. Choudhary, C., et al., Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science,2009.325(5942):p.834-40.
3. de Ruijter, A.J., et al., Histone deacetylases (HDACs):characterization of the classical HDAC family. Biochem J,2003.370(Pt 3):p.737-49.
4. Haberland, M., R.L. Montgomery, and E.N. Olson, The many roles of histone deacetylases in development and physiology:implications for disease and therapy. Nat Rev Genet,2009.10(1):p.32-42.
5. Bhaskara, S., et al., Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol Cell,2008.30(1):p.61-72.
6. Lundh, M., et al., Lysine deacetylases are produced in pancreatic β cells and are differentially regulated by proinflammatory cytokines. Diabetologia,2010.53(12):p. 2569-78.
7. Li, J., et al., Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J.2000.19(16):p.4342-50.
8. Montgomery, R.L., et al., Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. J Clin Invest,2008.118(11):p.3588-97.
9. Sun, Z.. et al., Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat Med,2012.18(6):p.934-42.
10. Knutson, S.K., et al., Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J,2008.27(7):p.1017-28.
11. Razidlo, D.F., et al., Histone deacetylase 3 depletion in osteo/chondroprogenitor cells decreases bone density and increases marrow fat. PLoS One,2010.5(7):p. e11492.
12. Lewis, E.C., et al., The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet beta cells in vivo and in vitro. Mol Med,2011.17(5-6):p.369-77.
13. Chou, D.H., et al., Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. Chem Biol, 2012. 19(6): p. 669-73.
14. Patel, T., et al., Chromatin remodeling resets the immune system to protect against autoimmune diabetes in mice. Immunol Cell Biol, 2011. 89(5): p. 640-9.
15. Lundh, M., et al., Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and arc differentially regulated in the islets of type 1 diabetic children. Diabctologia, 2012. 55(9): p. 2421-31.
16. Fischle, W., et al., Enzymatic activity associated with class Ⅱ HDACs is dependent on a muliiprotein complex containing HDAC3 and SMRT/N-CoR. Mol Cell, 2002. 9(1): p. 45-57.
17. Guenther, M.G., et al., Assembly of the SMRT-histone deacetylase 3 repression complex requires the TCP-1 ring complex. Genes Dev, 2002. 16(24): p. 3130-5.
18. Slack, J.M., Developmental biology of the pancreas. Development, 1995. 121(6): p. 1569-80.
19. Gannon, M., et al., Analysis of the Cre-mediated recombination driven by rat insulin promoter in embryonic and adult mouse pancreas. Genesis, 2000. 26(2): p. 139-42.
20. Haumaitre, C., O. Lenoir, and R. Scharfmann, Histone deacetyla.se inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors. Mol Cell Biol, 2008. 28(20): p. 6373-83.
21. Lee, H.W., et al., Histone deacetylase 1-mediated histone modification regulates osteoblast differentiation. Mol Endocrinol, 2006. 20(10): p. 2432-43.
22. Yoo, E.J., et al., Down-regulation of histone deacetylases stimulates adipocyte differentiation. J Biol Chem, 2006. 281(10): p. 6608-15.
23. Ortis, F., et al., Cytokines interleukin-1beta and lumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells. Diabetes, 2010. 59(2): p. 358-74.
24. McEvoy, R.C., et al., Multiple low-dose streptozotocin-induced diabetes in the mouse. Evidence for stimulation of a cytotoxic cellular immune response against an insulin-producing beta cell line. J Clin Invest, 1984. 74(3): p. 715-22.
25. Karlsen, A.E., et al., Suppressor of cytokine signalling (SOCS)-3 protects beta cells against IL-1beta-mediated toxicity through inhibition of multiple nuclear factor-kappaB-regulated proapoplotic pathways. Diabetologia. 2004. 47(11): p. 1998-2011.
26. Karlsen. A.E., et al., Suppressor of cytokine signaling 3 (SOCS-3) protects beta -cells against interleukin-Ibeta - and interferon-gamma -mediated toxicity. Proc Natl Acad Sci U SA, 2001. 98(21): p. 12191-6.
27. Borjesson, A., et al., beta-cell specific overexpression of suppressor of cytokine signalling-3 does not protect against multiple low dose streptozotoein induced type 1 diabetes in mice. Immunol Lett, 2011. 136( 1): p. 74-9.
28. Emanuelli, B., et al., The potential role of SOCS-3 in the interleukin-1beta-induced desensitization of insulin signaling in pancreatic beta-cells. Diabetes, 2004. 53 Suppl 3: p. S97-S103.
29. Laubner, K., et al., Inhibition of preproinsulin gene expression by leptin induction of suppressor of cytokine signaling 3 in pancreatic beta-cells. Diabetes. 2005. 54(12): p. 3410-7.
30. Lindberg, K., et al., Regulation of pancreatic beta-cell mass and proliferation by SOCS-3. J Mol Endocrinol,2005.35(2):p.231-43.
31. Howard, J.K., et al., Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med,2004.10(7):p.734-8.
32. Barclay, J.L., et al., SOCS3 as a tumor suppressor in breast cancer cells, and its regulation by PRL. Int J Cancer,2009.124(8):p.1756-66.
33. Jackerott, M., et al., STAT5 activity in pancreatic beta-cells influences the severity of diabetes in animal models of type 1 and 2 diabetes. Diabetes,2006.55(10):p.2705-12.
34. Galsgaard, E.D., et al., Expression of dominant-negative STAT5 inhibits growth hormone-and prolactin-induced proliferation of insulin-producing cells. Diabetes,2001.50 Suppl 1:p. S40-1.
35. Jensen, J., et al., STAT5 activation by human GH protects insulin-producing cells against interleukin-1beta, interferon-gamma and tumour necrosis factor-alpha-induced apoptosis independent of nitric oxide production. J Endocrinol,2005.187(1):p.25-36.
1. Zhang, P., et al., Global healthcare expenditure on diabetes for 2010 and 2030. Diabetes Res Clin Pract,2010.87(3):p.293-301.
2. Shaw, J.E., R.A. Sicree, and P.Z. Zimmet, Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract,2010.87(1):p.4-14.
3. Economic Costs of Diabetes in the U.S. in 2012. Diabetes Care,2013.
4. Rother, K.I., Diabetes treatment--bridging the divide. N Engl J Med,2007.356(15):p. 1499-501.
5. van Belle, T.L., K.T. Coppieters, and M.G. von Herrath, Type 1 diabetes:etiology, immunology, and therapeutic strategies. Physiol Rev,2011.91(1):p.79-118.
6. Eizirik, D.L., M.L. Colli, and F. Ortis, The role of inflammation in insiditis and β-cell loss in type 1 diabetes. Nat Rev Endocrinol,2009.5(4):p.219-26.
7. Mandrup-Poulsen, T., The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia, 1996.39(9):p.1005-29.
8. Mosley, A.L. and S. Ozcan, The pancreatic duodenal homeobox-1 protein (Pdx-1) interacts with histone deacetylases Hdac-1 and Hdac-2 on low levels of glucose. J Biol Chem,2004. 279(52):p.54241-7.
9. Lenoir, O., et al., Specific control of pancreatic endocrine β-and delta-cell mass by class Ⅱa histone deacetylases HDAC4, HDAC5, and HDAC9. Diabetes,2011.60(11):p.2861-71.
10. Haberland, M., R.L. Montgomery, and E.N. Olson, The many roles of histone deacetylases in development and physiology:implications for disease and therapy. Nat Rev Genet,2009. 10(1):p.32-42.
11. Mariadason, J.M., HDACs and HDAC inhibitors in colon cancer. Epigenetics,2008.3(1):p. 28-37.
12. Blanchard, F. and C. Chipoy, Histone deacetylase inhibitors:new drugs for the treatment of inflammatory diseases? Drug Discov Today,2005.10(3):p.197-204.
13. Glauben, R. and B. Siegmund, Molecular basis of histone deacetylase inhibitors as new drugs for the treatment of inflammatory diseases and cancer. Methods Mol Biol,2009.512:p. 365-76.
14. Haumaitre, C., O. Lenoir, and R. Scharfmann, Histone deacetylase inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors. Mol Cell Biol,2008. 28(20):p.6373-83.
15. Larsen, L, et al., Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells. Diabetologia,2007.50(4):p.779-89.
16. Poy, M.N., et al., A pancreatic islet-specific microRNA regulates insulin secretion. Nature, 2004.432(7014):p.226-30.
17. Poy, M.N., et al., miR-375 maintains normal pancreatic alpha- and beta-cell mass. Proc Natl Acad Sci U S A,2009.106(14):p.5813-8.
18. Mi, Q.S., et al., microRNA deficiency in pancreatic islet cells exacerbates streptozotoein-inducedmurine autoimmune diabetes. Cell Cycle,2010.9(15):p.3127-9.
19. Khan, O. and N.B. La Thangue, HDAC inhibitors in cancer biology:emerging mechanisms and clinical applications. Immunol Cell Biol,2012.90(1):p.85-94.
20. Scott, G.K., et al., Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res,2006.66(3):p.1277-81.
21. Hasseine, L.K., et al., miR-139 impacts FoxO1 action by decreasing FoxO1 protein in mouse hepatocytes. Biochem Biophys Res Commun,2009.390(4):p.1278-82.
22. Buteau, J. and D. Accili, Regulation of pancreatic beta-cell function by the forkhead protein FoxO1. Diabetes Obes Metab,2007.9 Suppl 2:p.140-6.
23. Tivnan, A., et al., MicroRNA-184-mediated inhibition of tumour growth in an orthotopic murine model of neurohlastoma. Anticancer Res,2010.30(11):p.4391-5.
24. Bolmeson, C., et al., Differences in islet-enriched miRNAs in healthy and glucose intolerant human subjects. Biochem Biophys Res Commun,2011.404(1):p.16-22.
25. Jeon, H.S., et al., Combining microRNA-449a/b with a HDAC inhibitor has a synergistic effect on growth arrest in lung cancer. Lung Cancer,2012.76(2):p.171-6.
1. Croce, C.M. and G.A. Calin, miRNAs, cancer, and stem cell division. Cell,2005.122(1):p. 6-7.
2. Zhou, L., et al., MicroRNAs are key regulators controlling iNKT and regulatory T-cell development and function. Cell Mol Immunol,2011.8(5):p.380-7.
3. Ha, T.Y., The Role of MicroRNAs in Regulatory T Cells and in the Immune Response. Immune Netw,2011.11(1):p.11-41.
4. Cobb, B.S., et al., A role for Dicer in immune regulation. J Exp Med,2006.203(11):p. 2519-27.
5. Muljo, S.A., et al., Aberrant T cell differentiation in the absence of Dicer. J Exp Med,2005. 202(2):p.261-9.
6. Seo, K.H., et al., Loss of microRNAs in thymus perturbs invariant NKT cell development and function. Cell Mol Immunol,2010.7(6):p.447-53.
7. Zhou, X., et al., Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med,2008.205(9):p.1983-91.
8. Brady, B.L., L.J. Rupp, and C.H. Bassing, Requirement for dicer in survival of proliferating thymocytes experiencing DNA double-strand breaks. J Immunol,2013.190(7):p.3256-66.
9. Wu, K.K, and Y. Huan, Slreptozotocin-induced diabetic models in mice and rats. Curr Protoc Pharmacol,2008. Chapter 5:p. Unit 5 47.
10. Brusko, T. and M. Atkinson, Treg in type 1 diabetes. Cell Biochem Biophys,2007.48(2-3):p. 165-75.
11. Rodriguez, A., et al.. Requirement ofbic/microRNA-155 for normal immune function. Science, 2007.316(5824):p.608-11.
12. Martinez-Nunez, R.T., et al., MicroRNA-155 modulates the pathogen binding ability of dendritic cells (DCs) bv down-regulation of DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN). J Biol Chem,2009.284(24):p.16334-42.
13. O'Connell, R.M., et al., MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity,2010.33(4):p.607-19.
14. Ceppi, M., et al., MicroRNA-155 modulates the inlerleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci U S A,2009.106(8):p.2735-40.
15. Thai, T.H., et al., Regulation of the germinal center response by microRNA-155. Science, 2007.316(5824):p.604-8.
16. O'Connell, R.M., et al., MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A,2007.104(5):p.1604-9.
17. Trotta, R., et al., Overexpression of miR-155 causes expansion, arrest in terminal differentiation and functional activation of mouse natural killer cells. Blood,2013.
18. Jeker, L.T. and J.A. Bluestone, Small RNA regulators of Tcell-mediated autoimmunity. J Clin Immunol,2010.30(3):p.347-57.
19. Kohlhaas, S., et al., Cutting edge:the Foxp3 target miR-155 contributes to the development of regulatory T cells. J Immunol,2009.182(5):p.2578-82.
20. Murugaiyan, G., et al., Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J Immunol,2011.187(5):p.2213-21.
21. Like, A. A. and A.A. Rossini, Streptozotocin-induced pancreatic insulitis:new model of diabetes mellitus. Science,1976.193(4251):p.415-7.
22. Cockfield, S.M., et al., Multiple low dose streptozotocin induces systemic MHC expression in mice by triggering T cells to release IFN-gamma. J Immunol,1989.142(4):p.1120-8.
23. McEvoy, R.C., et al., Multiple low-dose streptozotocin-induced diabetes in the mouse. Evidence for stimulation of a cytotoxic cellular immune response against an insulin-producing beta cell line. J Clin Invest,1984.74(3):p.715-22.
24. Maclaren, N.K., et al., Androgen sensitization of streptozotocin-induced diabetes in mice. Diabetes,1980.29(9):p.710-6.
25. Tian, L., et al., Loss of T cell microRNA provides systemic protection against autoimmune pathology in mice. J Autoimmun,2012.38(1):p.39-48.