miR-34通过自噬作用调控衰老的机制研究
摘要
微小RNA (microRNA, miRNA)是一类功能高度保守的非编码单链小分子RNA,通过与靶基因mRNA的互补配对从而在转录或转录后水平对多个靶mRNAs的表达进行负调控。近年来研究表明,miRNA与发育、衰老、免疫和肿瘤等病理生理过程密切相关。在大鼠和线虫microRNA芯片的研究中发现miR-34随增龄表达上调,体外研究也证实miR-34能通过调控细胞周期等途径加速细胞衰老的进程。自噬是细胞通过溶酶体对自身受损结构的吞噬降解过程,对自噬作用的调控是p53、SIRT1等衰老相关基因调控寿命的关键环节。已有研究显示miR-34参与p53和SIRT1的信号通路,提示自噬可能是miR-34参与衰老调控的重要机制。本研究旨在通过体内外实验阐明miR-34在衰老进程中的确切作用及自噬在介导miR-34调控衰老作用中的分子机制。全文共分三个部分：
第一部分：miR-34对线虫寿命的影响
通过real-time RT-PCR检测大鼠和线虫miR-34随增龄的表达变化特点；并观察miR-34缺失突变对线虫寿命及应激耐受性的影响。结果发现：与3月龄大鼠相比,24月龄wistar大鼠心脏、脑组织、肝脏、胸主动脉和肾脏miR-34a的表达分别增高2.36、1.71、1.85、3.45和2.14倍(p<0.05-0.01)。与1d线虫成虫相比,7d、9d和13d野生型N2株线虫成虫miR-34的表达显著增高(p<0.05-0.01)。相关分析显示,N2株线虫miR-34的表达与增龄呈显著正相关(r=0.856, p<0.0001).线虫寿命分析结果显示,miR-34缺失突变能延缓线虫的衰老进程,使线虫寿命延长42%-62%(p<0.0001),并能改善线虫对热休克和氧化应激的耐受性。同时发现,间断禁食能使野生型N2株线虫寿命延长37%(p<0.0001),但不影响miR-34缺失突变株线虫的寿命。本部分研究结果显示,miR-34能够调控线虫的衰老进程,并提示其机制可能与限食、应激等共同的机制--自噬作用有关。
第二部分：自噬在介导miR-34调控衰老中的作用研究
利用RNAi敲除自噬相关基因,观察抑制自噬对miR-34缺失突变株线虫寿命的影响；并通过体外实验检测miR-34a(人miR-34主要转录本之一)对自噬的调控作用及SIRT1对该作用的影响。结果发现：在野生型N2株线虫,自噬基因RNAi组和对照质粒组之间的寿命无显著差异；而miR-34缺失突变株线虫各RNAi组的寿命较对照质粒组显著缩短(p<0.0001)。体外实验显示,miR-34a能抑制细胞自噬体标志物LC3II的表达(p<0.05)。与对照组相比,SIRT1 siRNA组LC3II的表达显著下调(p<0.05),但SIRT1 siRNA和miR-34a inhibitor共转染组LC3II的表达仍显著升高(p<0.05)。本部分研究结果揭示,miR-34通过抑制细胞的自噬作用而调控衰老,且该作用不完全依赖SIRT1,提示自噬是miR-34调控衰老的重要机制。
第三部分：miR-34通过Atg4B和Atg9A调控自噬的机制研究
利用生物信息学软件预测miR-34a可能的靶基因；通过体外实验验证miR-34a对靶基因表达的影响；进一步采用双荧光素酶报告基因系统检测miR-34a与靶基因3'-UTR序列的相互作用。结果发现：miR-34a共有2904个可能的靶基因,其中Atg4B和Atg9A直接参与自噬体的形成过程。体外实验显示,miR-34a能下调Atg4B和Atg9A蛋白的表达(p<0.05-0.01),但不影响其mRNA的表达水平。双荧光素酶检测结果显示,miR-34a能通过与Atg4B和Atg9A基因3'-UTR序列靶结合位点的相互作用,下调荧光素酶活性(p<0.05-0.01)。本部分研究结果证实,miR-34a能够在转录后水平直接抑制Atg4B和Atg9A蛋白的表达,从而调控自噬作用。
综上所述,本研究从整体动物水平验证了miR-34能够促进衰老进程,而自噬是介导miR-34调控衰老作用的关键环节。并通过体外实验证实,miR-34a能够在转录后水平直接抑制自噬相关蛋白Atg4B和Atg9A的表达,进而调控自噬作用。
MicroRNA (miRNA) are endogenously encoded single-stranded RNAs of about 22 nt in length that are highly conserved and regulate protein expression through interactions with the 3'untranslated region (UTR) of mRNA. The ability of miRNAs to regulate a variety of target genes allows them to induce changes in multiple pathways and processes such as development, senescence, immune system, cancer and other physiological contexts. The evidence for a regulatory role of the miR-34 family in senescence is growing. Recent studies have shown that the expression of miR-34 increases with aging. Overexpression of miR-34 in many cell lines leads to cell cycle arrest, increases the expression of senescence marker, SA-β-Gal (senescence-associatedβ-galactosidase). Autophagy, a highly conserved mechanism of quality control inside cells, plays a critical role in the regulation of aging and age-related degenerative diseases. Recent studies have revealed that the SIRT1 and p53 signaling pathways regulate lifespan via autophagy. miR-34s are direct transcriptional targets of p53. Furthermore, miR-34a can represses SIRT1 translation through a miR-34a-binding site within the 3'-UTR of SIRT1. It suggests that autophagy may be involved in the regulation of aging by miR-34a. However, the exact role of miR-34 in aging in vivo remain unclear. The aim of the present study is to identify the role of miR-34 in aging in vivo, and to examine the mechanisms of autophagy in regulating aging by miR-34, both in vivo and in vitro.
Part I. The role of miR-34 in aging of C.elegans. Real-time RT-PCR was employed to detect the expression of miR-34 in rats and C.elegans. To address the role of miR-34 in the longevity response, we also observed the lifespan in miR-34 loss-off-function mutant alleles (gk437 and n4276) under ad libitum (AL) and intermittent fasting (IF). The results showed that the expression of miR-34a in heart, brain, liver, thoracic aorta, and kidney from 24-month-old rats, compared with the 3-month-old rats, increased by 2.36,1.71,1.85,3.45 and 2.14-fold (p< 0.05～0.01), respectively. The expression of miR-34 wild type N2 worms also increased during aging, and there is a significant positive correlation between the expression of miR-34 and aging (r=0.856,p<0.0001). miR-34 mutant alleles markedly delayed the age-related physiological decline, and increased resistance to heat and oxidative stress. In ad libitum, the lifespan of miR-34 mutant alleles were increased by 42%～62% compared to wild type N2 worms (p＜0.0001) Intermittent fasting significantly extended lifespan of wild type N2 worms (p<0.0001), but didn't influenced the lifespan of miR-34 mutant alleles.
PartⅡ. The role of autophagy in regulation of the aging process by miR-34. To further evaluate whether autophagy is required for extended lifespan in miR-34 mutant alleles, we also tested the effects on the lifespan of RNAi of 5 autophagy genes in C. elegans. In vitro, we examined the role of miR-34a on the autophagy process. We found that RNAi knockdown of the C.elegans orthologs of yeast atg4.1, atg4.2, lggl, bec-1 or atg9 didn't influenced the lifespan in wild type N2 worms, but they significantly suppressed the lifespan extending effect of miR-34 mutant (p＜0.0001). In vitro, Hela and HEK293 cells were respectively transfected with miR-34a mimics or inhibitors, and the results showed that miR-34a affected autophagy, and the effects weren't entirely dependent on SIRT1.
PartⅢ. miR-34a regulating aging by inhibition of autophagy related protein Atg4B and Atg9A. To examine the role of the miR-34a on autophagy related gene (Atg4B or Atg9A) expression, we used mimics and inhibitors of miR-34a. We also used dual luciferase reporter gene assay system to indentify the relationship between the miR-34a and 3'-UTR of Atg4B or Atg9A. Overexpression of miR-34a in Hela cells decreased Atg4B and Atg9A protein levels. By contrast, inhibition of miR-34a in HEK293 cells increased Atg4B and Atg9A protein expression. But, miR-34a had no effect on the expression of Atg4B and Atg9A mRNA. Therefore, miR34a regulated the expression of Atg4B and Atg9A at the post-transcriptional level. Dual luciferase reporter assay confirmed that the miR-34a binding sequences in the 3'-UTR of Atg4B and Atg9A contributed to the modulation of Atg4B and Atg9A expression by miR-34a.
In summary, we found that miR-34 accelerates aging in C.elegans, and autophagy might play a important role in the process. In vitro, our found that miR-34a suppress autophagy by indirectly inhitited autophagy related protein Atg4B and Atg9A.
第一部分：miR-34对线虫寿命的影响
通过real-time RT-PCR检测大鼠和线虫miR-34随增龄的表达变化特点；并观察miR-34缺失突变对线虫寿命及应激耐受性的影响。结果发现：与3月龄大鼠相比,24月龄wistar大鼠心脏、脑组织、肝脏、胸主动脉和肾脏miR-34a的表达分别增高2.36、1.71、1.85、3.45和2.14倍(p<0.05-0.01)。与1d线虫成虫相比,7d、9d和13d野生型N2株线虫成虫miR-34的表达显著增高(p<0.05-0.01)。相关分析显示,N2株线虫miR-34的表达与增龄呈显著正相关(r=0.856, p<0.0001).线虫寿命分析结果显示,miR-34缺失突变能延缓线虫的衰老进程,使线虫寿命延长42%-62%(p<0.0001),并能改善线虫对热休克和氧化应激的耐受性。同时发现,间断禁食能使野生型N2株线虫寿命延长37%(p<0.0001),但不影响miR-34缺失突变株线虫的寿命。本部分研究结果显示,miR-34能够调控线虫的衰老进程,并提示其机制可能与限食、应激等共同的机制--自噬作用有关。
第二部分：自噬在介导miR-34调控衰老中的作用研究
利用RNAi敲除自噬相关基因,观察抑制自噬对miR-34缺失突变株线虫寿命的影响；并通过体外实验检测miR-34a(人miR-34主要转录本之一)对自噬的调控作用及SIRT1对该作用的影响。结果发现：在野生型N2株线虫,自噬基因RNAi组和对照质粒组之间的寿命无显著差异；而miR-34缺失突变株线虫各RNAi组的寿命较对照质粒组显著缩短(p<0.0001)。体外实验显示,miR-34a能抑制细胞自噬体标志物LC3II的表达(p<0.05)。与对照组相比,SIRT1 siRNA组LC3II的表达显著下调(p<0.05),但SIRT1 siRNA和miR-34a inhibitor共转染组LC3II的表达仍显著升高(p<0.05)。本部分研究结果揭示,miR-34通过抑制细胞的自噬作用而调控衰老,且该作用不完全依赖SIRT1,提示自噬是miR-34调控衰老的重要机制。
第三部分：miR-34通过Atg4B和Atg9A调控自噬的机制研究
利用生物信息学软件预测miR-34a可能的靶基因；通过体外实验验证miR-34a对靶基因表达的影响；进一步采用双荧光素酶报告基因系统检测miR-34a与靶基因3'-UTR序列的相互作用。结果发现：miR-34a共有2904个可能的靶基因,其中Atg4B和Atg9A直接参与自噬体的形成过程。体外实验显示,miR-34a能下调Atg4B和Atg9A蛋白的表达(p<0.05-0.01),但不影响其mRNA的表达水平。双荧光素酶检测结果显示,miR-34a能通过与Atg4B和Atg9A基因3'-UTR序列靶结合位点的相互作用,下调荧光素酶活性(p<0.05-0.01)。本部分研究结果证实,miR-34a能够在转录后水平直接抑制Atg4B和Atg9A蛋白的表达,从而调控自噬作用。
综上所述,本研究从整体动物水平验证了miR-34能够促进衰老进程,而自噬是介导miR-34调控衰老作用的关键环节。并通过体外实验证实,miR-34a能够在转录后水平直接抑制自噬相关蛋白Atg4B和Atg9A的表达,进而调控自噬作用。
MicroRNA (miRNA) are endogenously encoded single-stranded RNAs of about 22 nt in length that are highly conserved and regulate protein expression through interactions with the 3'untranslated region (UTR) of mRNA. The ability of miRNAs to regulate a variety of target genes allows them to induce changes in multiple pathways and processes such as development, senescence, immune system, cancer and other physiological contexts. The evidence for a regulatory role of the miR-34 family in senescence is growing. Recent studies have shown that the expression of miR-34 increases with aging. Overexpression of miR-34 in many cell lines leads to cell cycle arrest, increases the expression of senescence marker, SA-β-Gal (senescence-associatedβ-galactosidase). Autophagy, a highly conserved mechanism of quality control inside cells, plays a critical role in the regulation of aging and age-related degenerative diseases. Recent studies have revealed that the SIRT1 and p53 signaling pathways regulate lifespan via autophagy. miR-34s are direct transcriptional targets of p53. Furthermore, miR-34a can represses SIRT1 translation through a miR-34a-binding site within the 3'-UTR of SIRT1. It suggests that autophagy may be involved in the regulation of aging by miR-34a. However, the exact role of miR-34 in aging in vivo remain unclear. The aim of the present study is to identify the role of miR-34 in aging in vivo, and to examine the mechanisms of autophagy in regulating aging by miR-34, both in vivo and in vitro.
Part I. The role of miR-34 in aging of C.elegans. Real-time RT-PCR was employed to detect the expression of miR-34 in rats and C.elegans. To address the role of miR-34 in the longevity response, we also observed the lifespan in miR-34 loss-off-function mutant alleles (gk437 and n4276) under ad libitum (AL) and intermittent fasting (IF). The results showed that the expression of miR-34a in heart, brain, liver, thoracic aorta, and kidney from 24-month-old rats, compared with the 3-month-old rats, increased by 2.36,1.71,1.85,3.45 and 2.14-fold (p< 0.05～0.01), respectively. The expression of miR-34 wild type N2 worms also increased during aging, and there is a significant positive correlation between the expression of miR-34 and aging (r=0.856,p<0.0001). miR-34 mutant alleles markedly delayed the age-related physiological decline, and increased resistance to heat and oxidative stress. In ad libitum, the lifespan of miR-34 mutant alleles were increased by 42%～62% compared to wild type N2 worms (p＜0.0001) Intermittent fasting significantly extended lifespan of wild type N2 worms (p<0.0001), but didn't influenced the lifespan of miR-34 mutant alleles.
PartⅡ. The role of autophagy in regulation of the aging process by miR-34. To further evaluate whether autophagy is required for extended lifespan in miR-34 mutant alleles, we also tested the effects on the lifespan of RNAi of 5 autophagy genes in C. elegans. In vitro, we examined the role of miR-34a on the autophagy process. We found that RNAi knockdown of the C.elegans orthologs of yeast atg4.1, atg4.2, lggl, bec-1 or atg9 didn't influenced the lifespan in wild type N2 worms, but they significantly suppressed the lifespan extending effect of miR-34 mutant (p＜0.0001). In vitro, Hela and HEK293 cells were respectively transfected with miR-34a mimics or inhibitors, and the results showed that miR-34a affected autophagy, and the effects weren't entirely dependent on SIRT1.
PartⅢ. miR-34a regulating aging by inhibition of autophagy related protein Atg4B and Atg9A. To examine the role of the miR-34a on autophagy related gene (Atg4B or Atg9A) expression, we used mimics and inhibitors of miR-34a. We also used dual luciferase reporter gene assay system to indentify the relationship between the miR-34a and 3'-UTR of Atg4B or Atg9A. Overexpression of miR-34a in Hela cells decreased Atg4B and Atg9A protein levels. By contrast, inhibition of miR-34a in HEK293 cells increased Atg4B and Atg9A protein expression. But, miR-34a had no effect on the expression of Atg4B and Atg9A mRNA. Therefore, miR34a regulated the expression of Atg4B and Atg9A at the post-transcriptional level. Dual luciferase reporter assay confirmed that the miR-34a binding sequences in the 3'-UTR of Atg4B and Atg9A contributed to the modulation of Atg4B and Atg9A expression by miR-34a.
In summary, we found that miR-34 accelerates aging in C.elegans, and autophagy might play a important role in the process. In vitro, our found that miR-34a suppress autophagy by indirectly inhitited autophagy related protein Atg4B and Atg9A.
引文
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