抑制Dicer表达对人类细胞染色质结构及相关生理功能的影响
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摘要
Dicer是核糖核酸酶III家族成员之一,在RNAi途径中起着关键作用,具有重要的生物学功能:是miRNA和siRNA生物合成过程中的关键酶,能够调节DNA甲基化和组蛋白修饰,参与维持基因组的稳定性,参与DNA复制时间先后顺序和细胞衰老的调节等等。在小鼠中敲除Dicer导致多方面的异常,包括发育早期干细胞群不能维持、T细胞和B细胞发育异常、卵母细胞有丝分裂停滞、扩张性心肌病、原始生殖细胞和精子发育不良、肾小球疾病、视网膜退化、神经系统疾病等等。
在脊椎动物中,RNAi依赖的染色质沉默不仅仅局限于着丝粒区。为了研究RNAi途径对印迹基因染色质结构的影响,我们在HEK293细胞中抑制Dicer的表达。结果发现干扰Dicer的表达能够诱导PHLDA2(11p15.5处印迹基因区域中的基因之一)的表达上调,该基因位点的组蛋白H3K9乙酰化水平增高,提示该基因的染色质被活化,但是该基因的DNA甲基化水平没有受到影响。同时,我们也发现在血清饥饿或接触抑制的HEK293细胞中PHLDA2的表达明显降低,说明PHLDA2的上调不是敲除Dicer诱导生长抑制的结果,而是染色质活化的结果。
染色质的结构与基因组的稳定性密切相关,在果蝇中Dicer2的缺失通过引起异染色质的解凝聚诱导染色体外环状DNA (eccDNA)的形成;另外DNA损伤修复通路也可能与Dicer2突变细胞中的ecc DNA形成有关。DNA复制时间的先后顺序与染色质结构密切相关,一般来说,常染色质先复制,异染色质后复制。在Dicer缺失的胚胎干细胞中,卫星DNA的复制时间先后顺序发生紊乱,DNA复制时间先后顺序紊乱能诱发DNA损伤。作为基因组的免疫系统,RNAi通路可以抑制转座子的活动,Dicer缺失可能激活转座子,从而导致DNA损伤。为了研究Dicer缺失是否引起DNA损伤,我们用两个不同的siRNA在HEK293T和HepG2细胞中抑制Dicer的表达,结果表明抑制Dicer表达能够诱导DNA损伤,具体表现为:(1)与对照细胞相比,Dicer缺失细胞的γ-H2AX foci阳性率明显增加,复制蛋白A 70(RPA 70)的染色明显增强,并在细胞核中呈点状分布;(2)Dicer缺失细胞中检验点激酶1(Chk1)S345的磷酸化水平明显增加;(3)彗星电泳的结果直接表明,Dicer缺失能够诱导DNA损伤;(4)在Dicer缺失细胞中,一些与DNA损伤有关的基因,包括GADD45A、GADD45B、p21、BTG3、ATF3和EGR1的表达明显升高。
DNA损伤能够诱导天然免疫系统NKG2D配体的表达,抑制Dicer表达能够诱导DNA损伤。为了研究Dicer缺失能否上调NKG2D配体的表达,我们用定量RT-PCR和流式细胞仪检测了主要组织相容性复合物I相关分子A和B(MICA和MICB)的表达。结果表明,在Dicer缺失的细胞中,MICA和MICB的表达明显增加。Dicer缺失诱导的MICA和MICB表达能够被DNA损伤途径组分(包括ATM、ART和Chk1)的抑制剂阻断,说明MICA和MICB表达上调是Dicer缺失诱导DNA损伤的结果。MICA和MICB表达的上调导致HEK293T和HepG2细胞对自然杀伤细胞株NKL的杀伤作用更加敏感。
为了进一步证实异染色质解凝聚能够引起DNA损伤并诱导MICA和MICB的表达,我们用DNA甲基转移酶抑制剂5-氮杂脱氧胞苷(5-aza-dC)处理HEK293T和HepG2细胞。5-aza-dC诱导DNA去甲基化和异染色质解凝聚,并诱导DNA损伤和MICB的表达上调。
Dicer缺失影响内皮细胞的迁移能力,在Dicer缺失的内皮细胞中,纤维粘连蛋白的表达明显增加。EGR1能够与纤维粘连蛋白的启动子结合,诱导纤维粘连蛋白表达,Dicer缺失能够诱导EGR1的表达,因此我们推测Dicer缺失可能通过EGR1诱导纤维粘连蛋白表达。为了证实这个假设,我们在HEK293T细胞中抑制Dicer的表达,结果发现Dicer缺失诱导EGR1依赖的纤维粘连表达增加,纤维粘连蛋白表达增加削弱了HEK293T细胞的迁移能力。另外,我们还发现在Dicer下调的HEK293T细胞中,抑制纤维粘连蛋白表达可诱导细胞凋亡。因此,我们推测纤维粘连蛋白表达增加可能是Dicer缺失的HEK293T细胞不发生凋亡的原因之一。
综上所述,我们提出这样一个模型:Dicer是异染色质形成所必须的,Dicer缺失导致染色质解凝聚,从而打乱了DNA复制时间的先后顺序,诱导DNA损伤;异染色质解凝聚能够激活转座元件,另外Dicer缺失也可能增加来源于转座元件的双链RNA的稳定性,因此提高转座子活性,从而导致DNA损伤。DNA损伤诱导EGR1表达,进而激活纤维粘连蛋白转录,纤维粘连蛋白表达上调能够抑制细胞的迁移能力。另外,DNA损伤还能诱导MICA和MICB的表达,从而导致Dicer缺失的细胞被免疫系统清除。
Dicer is a ribonuclease III-like enzyme that plays a key role in the biogenesis of miRNAs and siRNAs. In addition, Dicer is essential for the regulation of chromatin structure and function, DNA replication timing, genome stability and cellular senescence. Targeted knockout of Dicer leads to the inability to maintain the stem cell population during early mouse development, aberrant T cell differentiation, meiosis arrest of mouse oocytes, dilated cardiomyopathy, poor proliferation of primordial germ cells and spermatogonia, aberrant B cell development, glomerular disease, degeneration of the mouse retina, and neurological disorders.
It has been reported that RNAi-dependent chromatin silencing in vertebrates is not restricted to the centromeres. To address whether RNAi machinery could regulate the chromatin structure of imprinted genes, we knocked down Dicer in HEK293 cells, and found that the expression of PHLDA2, one of the several genes in the imprinted gene domain of 11p15.5, was specifically upregulated. This was accompanied by a shift towards more activated chromatin at PHLDA2 locus as indicated by change in H3K9 acetylation, however, the methylation state at this locus was not affected. Furthermore, we found that PHLDA2 was downregulated in growth-arrested HEK293 cells induced by either serum deprivation or contact inhibition. This suggests that PHLDA2 upregulation might be a direct result of Dicer knockdown-induced chromatin decomdensation rather than the consequence of growth arrest induced by Dicer knockdown.
Chromatin structure plays pivotal roles in maintaining genome stability. Loss of Dicer2, a key enzyme in the RNAi pathway, not only results in decondensation of heterochromatin but also leads to accumulation of extrachromosomal circular (ecc) repeated DNAs. Ligase IV, an essential regulator of nonhomologous end joining, and perhaps other DNA damage repair machinery, participate in ecc DNA formation, this suggests that, in addition to increased accessibility of DNA repair and recombination proteins to repeated DNA caused by heterochromatin decondensation, activation of the DNA damage response may also contribute to the formation of ecc DNA in Dicer2 mutant cells. DNA replication timing is tightly regulated and correlates with chromatin state, and the timing of satellite DNA replication is misregulated in Dicer -deficient embryonic stem cells. Stalled and collapsed replication forks elicit the DNA damage response. In addition, loss of Dicer may activate transposons, which in turn leads to DNA damage. These observations collectively suggest that DNA damage response may be elicited in Dicer -deficient cells. To test this hypothesis, we knocked down Dicer in HEK293 cells and human hepatoma HepG2 cells. DNA damage was measured by immunostaining for the phosphorylated form of histone H2AX (γ-H2AX), a widely used marker for DSBs, and the replication protein A 70 (RPA70), a protein involved in DNA replication, recombination, and repair, that becomes phosphorylated and forms intranuclear foci upon exposure of cells to DNA damage, our results indicated that a much higher percentage of Dicer knockdown cells also displayed intense RPA foci andγ-H2AX foci. Consistent with the RPA andγ-H2AX staining results, an increase in checkpoint kinase 1 (Chk1) phosphorylation on S345, an event associated with DNA damage, was found in Dicer knockdown cells. As a more direct assessment of DNA damage, comet assay revealed that knockdown of Dicer resulted in accumulation of DNA breaks, as indicated by formation of a comet-like tail after single-cell gel electrophoresis. As a consequence of DNA damage, the DNA damage-induced genes, including growth arrest– and DNA damage– inducible geneα(GADD45A), growth arrest– and DNA damage– inducible geneβ(GADD45B), p21, B cell translocation gene 3 (BTG3), activating transcription factor 3 (ATF3), and early growth response 1 (EGR1) were up-regulated in Dicer knockdown cells.
The DNA damage pathway regulates innate immune system ligands for the NKG2D receptor, and human NKG2D ligands are up-regulated by genotoxic stress and stalled DNA replication, conditions known to activate a major DNA damage checkpoint pathway. To test whether Dicer knockdown-induced DNA damage could activate the expression of NKG2D ligands, we checked the expression of major histocompatibility complex class I– related molecules A and B (MICA and MICB), ULBP1, -2, and -3 using quantitative RT-PCR and flow cytometry. Our results indicated that MICA and MICB were upregulated in Dicer knockdown cells, while the expression of ULBP1, -2, and -3 was not affected by Dicer knockdown. Up-regulation of MICA and MICB by Dicer knockdown is prevented by pharmacologic or genetic inhibition of DNA damage pathway components, including ataxia telangiectasia mutated (ATM) kinase, ATM- and Rad3-related kinase, or checkpoint kinase 1, indicating that up-regulation of MICA and MICB is the result of DNA damage response activation caused by Dicer knockdown. As a consequence of MICA and MICB upregulation, Dicer knockdown sensitized HEK293T cells and HepG2 cells to the lysis of NKL, a cell line derived from an aggressive form of human natural killer (NK) cell leukemia.
To further confirm that chromatin decondensation causes DNA damage and induces the expression of MICA and MICB, we treated HEK293T cells and HepG2 cells with 5-Aza-2’-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor. DNA methylation is essential for the heterochromatin condensation, 5-aza-dC treatment induces global DNA demethylation and hence heterochromatin decondensation. Our results demonstrated that 5-aza-dC treatment leads DNA damage and upregulation of MICA and MICB.
Depletion of Dicer was found to impair the migration of endothelial cells, and fibronectin-1 (FN1) was upregulated in Dicer knockdown endothelial cells. EGR1 binds to the fibronectin-1 promoter and induces the expression of fibronectin-1. We found that EGR1 was upregulated in Dicer knockdown cells. Therefore, we hypothesized that Dicer knockdown may induce fibronectin-1 expression via an EGR1-dependant mechanism. To test this hypothesis, we knocked-down Dicer expression in HEK293T cells, and found that decreased Dicer expression induced the expression of fibronectin-1, and that the upregulation of fibronectin-1 in Dicer knockdown cells was caused by EGR1. Knockdown of Dicer sensitized cells to apoptosis induced by fibronectin-1 knockdown. Furthermore, we found that knockdown of Dicer impairs the migratory capacity of HEK293T cells.
We proposed the following model: Dicer is essential for heterochromatin formation, loss of Dicer leads to chromatin decondensation, which in turn disrupts DNA replication timing and induces DNA damage; chromatin decondensation may also activate transponsable elements, in addition, decreased Dicer expression may stabilize the dsRNAs transcribed from transposable elements and hence enhance transposition, activation of transposition leads to DNA damage. DNA damage induces the expression of EGR1, which in turn activates the transcription of fibronectin-1, upregulation of fibronectin-1 impair cell migratory capacity. In addition, Dicer knockdown-induced DNA damage leads to the upregulation of MICA and MICB, and Dicer knockdown cells may be eliminated by immune cells.
在脊椎动物中,RNAi依赖的染色质沉默不仅仅局限于着丝粒区。为了研究RNAi途径对印迹基因染色质结构的影响,我们在HEK293细胞中抑制Dicer的表达。结果发现干扰Dicer的表达能够诱导PHLDA2(11p15.5处印迹基因区域中的基因之一)的表达上调,该基因位点的组蛋白H3K9乙酰化水平增高,提示该基因的染色质被活化,但是该基因的DNA甲基化水平没有受到影响。同时,我们也发现在血清饥饿或接触抑制的HEK293细胞中PHLDA2的表达明显降低,说明PHLDA2的上调不是敲除Dicer诱导生长抑制的结果,而是染色质活化的结果。
染色质的结构与基因组的稳定性密切相关,在果蝇中Dicer2的缺失通过引起异染色质的解凝聚诱导染色体外环状DNA (eccDNA)的形成;另外DNA损伤修复通路也可能与Dicer2突变细胞中的ecc DNA形成有关。DNA复制时间的先后顺序与染色质结构密切相关,一般来说,常染色质先复制,异染色质后复制。在Dicer缺失的胚胎干细胞中,卫星DNA的复制时间先后顺序发生紊乱,DNA复制时间先后顺序紊乱能诱发DNA损伤。作为基因组的免疫系统,RNAi通路可以抑制转座子的活动,Dicer缺失可能激活转座子,从而导致DNA损伤。为了研究Dicer缺失是否引起DNA损伤,我们用两个不同的siRNA在HEK293T和HepG2细胞中抑制Dicer的表达,结果表明抑制Dicer表达能够诱导DNA损伤,具体表现为:(1)与对照细胞相比,Dicer缺失细胞的γ-H2AX foci阳性率明显增加,复制蛋白A 70(RPA 70)的染色明显增强,并在细胞核中呈点状分布;(2)Dicer缺失细胞中检验点激酶1(Chk1)S345的磷酸化水平明显增加;(3)彗星电泳的结果直接表明,Dicer缺失能够诱导DNA损伤;(4)在Dicer缺失细胞中,一些与DNA损伤有关的基因,包括GADD45A、GADD45B、p21、BTG3、ATF3和EGR1的表达明显升高。
DNA损伤能够诱导天然免疫系统NKG2D配体的表达,抑制Dicer表达能够诱导DNA损伤。为了研究Dicer缺失能否上调NKG2D配体的表达,我们用定量RT-PCR和流式细胞仪检测了主要组织相容性复合物I相关分子A和B(MICA和MICB)的表达。结果表明,在Dicer缺失的细胞中,MICA和MICB的表达明显增加。Dicer缺失诱导的MICA和MICB表达能够被DNA损伤途径组分(包括ATM、ART和Chk1)的抑制剂阻断,说明MICA和MICB表达上调是Dicer缺失诱导DNA损伤的结果。MICA和MICB表达的上调导致HEK293T和HepG2细胞对自然杀伤细胞株NKL的杀伤作用更加敏感。
为了进一步证实异染色质解凝聚能够引起DNA损伤并诱导MICA和MICB的表达,我们用DNA甲基转移酶抑制剂5-氮杂脱氧胞苷(5-aza-dC)处理HEK293T和HepG2细胞。5-aza-dC诱导DNA去甲基化和异染色质解凝聚,并诱导DNA损伤和MICB的表达上调。
Dicer缺失影响内皮细胞的迁移能力,在Dicer缺失的内皮细胞中,纤维粘连蛋白的表达明显增加。EGR1能够与纤维粘连蛋白的启动子结合,诱导纤维粘连蛋白表达,Dicer缺失能够诱导EGR1的表达,因此我们推测Dicer缺失可能通过EGR1诱导纤维粘连蛋白表达。为了证实这个假设,我们在HEK293T细胞中抑制Dicer的表达,结果发现Dicer缺失诱导EGR1依赖的纤维粘连表达增加,纤维粘连蛋白表达增加削弱了HEK293T细胞的迁移能力。另外,我们还发现在Dicer下调的HEK293T细胞中,抑制纤维粘连蛋白表达可诱导细胞凋亡。因此,我们推测纤维粘连蛋白表达增加可能是Dicer缺失的HEK293T细胞不发生凋亡的原因之一。
综上所述,我们提出这样一个模型:Dicer是异染色质形成所必须的,Dicer缺失导致染色质解凝聚,从而打乱了DNA复制时间的先后顺序,诱导DNA损伤;异染色质解凝聚能够激活转座元件,另外Dicer缺失也可能增加来源于转座元件的双链RNA的稳定性,因此提高转座子活性,从而导致DNA损伤。DNA损伤诱导EGR1表达,进而激活纤维粘连蛋白转录,纤维粘连蛋白表达上调能够抑制细胞的迁移能力。另外,DNA损伤还能诱导MICA和MICB的表达,从而导致Dicer缺失的细胞被免疫系统清除。
Dicer is a ribonuclease III-like enzyme that plays a key role in the biogenesis of miRNAs and siRNAs. In addition, Dicer is essential for the regulation of chromatin structure and function, DNA replication timing, genome stability and cellular senescence. Targeted knockout of Dicer leads to the inability to maintain the stem cell population during early mouse development, aberrant T cell differentiation, meiosis arrest of mouse oocytes, dilated cardiomyopathy, poor proliferation of primordial germ cells and spermatogonia, aberrant B cell development, glomerular disease, degeneration of the mouse retina, and neurological disorders.
It has been reported that RNAi-dependent chromatin silencing in vertebrates is not restricted to the centromeres. To address whether RNAi machinery could regulate the chromatin structure of imprinted genes, we knocked down Dicer in HEK293 cells, and found that the expression of PHLDA2, one of the several genes in the imprinted gene domain of 11p15.5, was specifically upregulated. This was accompanied by a shift towards more activated chromatin at PHLDA2 locus as indicated by change in H3K9 acetylation, however, the methylation state at this locus was not affected. Furthermore, we found that PHLDA2 was downregulated in growth-arrested HEK293 cells induced by either serum deprivation or contact inhibition. This suggests that PHLDA2 upregulation might be a direct result of Dicer knockdown-induced chromatin decomdensation rather than the consequence of growth arrest induced by Dicer knockdown.
Chromatin structure plays pivotal roles in maintaining genome stability. Loss of Dicer2, a key enzyme in the RNAi pathway, not only results in decondensation of heterochromatin but also leads to accumulation of extrachromosomal circular (ecc) repeated DNAs. Ligase IV, an essential regulator of nonhomologous end joining, and perhaps other DNA damage repair machinery, participate in ecc DNA formation, this suggests that, in addition to increased accessibility of DNA repair and recombination proteins to repeated DNA caused by heterochromatin decondensation, activation of the DNA damage response may also contribute to the formation of ecc DNA in Dicer2 mutant cells. DNA replication timing is tightly regulated and correlates with chromatin state, and the timing of satellite DNA replication is misregulated in Dicer -deficient embryonic stem cells. Stalled and collapsed replication forks elicit the DNA damage response. In addition, loss of Dicer may activate transposons, which in turn leads to DNA damage. These observations collectively suggest that DNA damage response may be elicited in Dicer -deficient cells. To test this hypothesis, we knocked down Dicer in HEK293 cells and human hepatoma HepG2 cells. DNA damage was measured by immunostaining for the phosphorylated form of histone H2AX (γ-H2AX), a widely used marker for DSBs, and the replication protein A 70 (RPA70), a protein involved in DNA replication, recombination, and repair, that becomes phosphorylated and forms intranuclear foci upon exposure of cells to DNA damage, our results indicated that a much higher percentage of Dicer knockdown cells also displayed intense RPA foci andγ-H2AX foci. Consistent with the RPA andγ-H2AX staining results, an increase in checkpoint kinase 1 (Chk1) phosphorylation on S345, an event associated with DNA damage, was found in Dicer knockdown cells. As a more direct assessment of DNA damage, comet assay revealed that knockdown of Dicer resulted in accumulation of DNA breaks, as indicated by formation of a comet-like tail after single-cell gel electrophoresis. As a consequence of DNA damage, the DNA damage-induced genes, including growth arrest– and DNA damage– inducible geneα(GADD45A), growth arrest– and DNA damage– inducible geneβ(GADD45B), p21, B cell translocation gene 3 (BTG3), activating transcription factor 3 (ATF3), and early growth response 1 (EGR1) were up-regulated in Dicer knockdown cells.
The DNA damage pathway regulates innate immune system ligands for the NKG2D receptor, and human NKG2D ligands are up-regulated by genotoxic stress and stalled DNA replication, conditions known to activate a major DNA damage checkpoint pathway. To test whether Dicer knockdown-induced DNA damage could activate the expression of NKG2D ligands, we checked the expression of major histocompatibility complex class I– related molecules A and B (MICA and MICB), ULBP1, -2, and -3 using quantitative RT-PCR and flow cytometry. Our results indicated that MICA and MICB were upregulated in Dicer knockdown cells, while the expression of ULBP1, -2, and -3 was not affected by Dicer knockdown. Up-regulation of MICA and MICB by Dicer knockdown is prevented by pharmacologic or genetic inhibition of DNA damage pathway components, including ataxia telangiectasia mutated (ATM) kinase, ATM- and Rad3-related kinase, or checkpoint kinase 1, indicating that up-regulation of MICA and MICB is the result of DNA damage response activation caused by Dicer knockdown. As a consequence of MICA and MICB upregulation, Dicer knockdown sensitized HEK293T cells and HepG2 cells to the lysis of NKL, a cell line derived from an aggressive form of human natural killer (NK) cell leukemia.
To further confirm that chromatin decondensation causes DNA damage and induces the expression of MICA and MICB, we treated HEK293T cells and HepG2 cells with 5-Aza-2’-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor. DNA methylation is essential for the heterochromatin condensation, 5-aza-dC treatment induces global DNA demethylation and hence heterochromatin decondensation. Our results demonstrated that 5-aza-dC treatment leads DNA damage and upregulation of MICA and MICB.
Depletion of Dicer was found to impair the migration of endothelial cells, and fibronectin-1 (FN1) was upregulated in Dicer knockdown endothelial cells. EGR1 binds to the fibronectin-1 promoter and induces the expression of fibronectin-1. We found that EGR1 was upregulated in Dicer knockdown cells. Therefore, we hypothesized that Dicer knockdown may induce fibronectin-1 expression via an EGR1-dependant mechanism. To test this hypothesis, we knocked-down Dicer expression in HEK293T cells, and found that decreased Dicer expression induced the expression of fibronectin-1, and that the upregulation of fibronectin-1 in Dicer knockdown cells was caused by EGR1. Knockdown of Dicer sensitized cells to apoptosis induced by fibronectin-1 knockdown. Furthermore, we found that knockdown of Dicer impairs the migratory capacity of HEK293T cells.
We proposed the following model: Dicer is essential for heterochromatin formation, loss of Dicer leads to chromatin decondensation, which in turn disrupts DNA replication timing and induces DNA damage; chromatin decondensation may also activate transponsable elements, in addition, decreased Dicer expression may stabilize the dsRNAs transcribed from transposable elements and hence enhance transposition, activation of transposition leads to DNA damage. DNA damage induces the expression of EGR1, which in turn activates the transcription of fibronectin-1, upregulation of fibronectin-1 impair cell migratory capacity. In addition, Dicer knockdown-induced DNA damage leads to the upregulation of MICA and MICB, and Dicer knockdown cells may be eliminated by immune cells.
引文
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