全反式维甲酸（RA）诱导的神经细胞分化中NeuroD1基因调控的分子机制研究
摘要
全反式维甲酸(RA)诱导的神经细胞分化中NeuroD1基因调控的分子机制研究
NeuroD1是一类与神经细胞分化和神经系统发育紧密相关的调控因子,其家族中共有七个成员,分别是NeuroD1～6和PJA2。NeuroD1作为一种神经分化因子在外周和中枢神经系统发育过程中都有的高表达。尽管NeuroD1在神经细胞发育中通常是瞬时表达,但在成年小鼠的小脑与海马区细胞中为持续表达;同时,其表达水平也随神经元细胞的成熟而降低。在神经母细胞中过表达NeuroD1时可引起神经细胞提前成熟;而在向表皮细胞分化的细胞中引入外源过表达的NeuroD1则可导致该细胞发育成为神经元细胞。在12种成神经管细胞瘤、成神经细胞瘤和视网膜成细胞瘤中NeuroD1基因都有表达,并且在受到各种刺激或向神经细胞方向诱导时其表达水平都会有显著升高。NeuroD1(-/-)小鼠在出生后立即死亡;重新转入neuroD1,这种小鼠虽然可继续生长,但其小脑和海马区粒细胞层在分化后会出现严重的神经元缺失。
在真核生物中,组蛋白是染色质基本结构一核小体中的重要组成部分,其N末端氨基酸残基可发生乙酰化等共价修饰。组蛋白乙酰化与转录活性有密切关系:乙酰化组蛋白特异地聚集于活性染色质功能区。组蛋白的乙酰化是一可逆的动态过程,而其稳定状态的维持则是多种组蛋白乙酰基转移酶(HATs)和组蛋白去乙酰基转移酶(HDACs)共同作用的结果。这种可逆的乙酰化修饰作用可使染色质结构发生动态的改变,并对基因的转录产生重要影响。
我们以RA诱导神经母细胞瘤SH-SY5Y分化为模型,低浓度RA处理24小时后,采用染色质免疫沉淀和启动子芯片结合技术研究基因组20,000基因的启动子区组蛋白H3K9和H3K14双乙酰化水平变化。本文中所用的ChIP on chip是染色质免疫沉淀与启动子DNA芯片相结合的一种新技术,作为系统生物学的一种手段去检测全基因组范围内变化,它具有高效性和高通量的特点。我们筛选染色质中通常代表转录活性的两个乙酰化修饰位点的分布及其在诱导前后的变化,并检出阳性位点相关的启动子与基因。初步结果根据log_2Ratio≥1或log_2Ratio≤-1分析,找到了597个乙酰化水平上升的启动子和647个乙酰化水平下降的启动子位点,显示RA的处理在细胞分化早期诱导了上述变化。鉴于RA诱导SH-SY5Y细胞分化一般出现在96小时后,上述乙酰化有改变的启动子不仅提示了神经分化早期的相关基因,还包含着与RA受体活化的效应基因。我们选择了数个乙酰化修饰发生变化的基因进行验证,结果显示其一致性达到70%。如PRKCA启动子区组蛋白H3乙酰化水平下降显著,CGB2、CUL7、ELF3、FOXH1、JARID1A和RARB上升显著,而NRG1,MVP和CSF1R变化不显著,与前七者与ChIP on chip结果一致,而后三者则不一致。值得重视的是发现神经分化标记基因NeuroD1的核心启动子区组蛋白H3的K9/K14的乙酰化水平明显降低,但是其mRNA表达水平却明显升高。为深入探讨其机制,我们开展了以下工作。
为进一步研究NeuroD1调控的分子机制,在RA诱导的P19细胞分化模型中,NeuroD1核心启动子区的组蛋白H3乙酰化水平逐步降低,去除RA后组蛋白乙酰化H3修饰有回升,但在整个过程中神经细胞早期分化标记基因NeuroD1的mRNA水平一直升高;这种组蛋白H3乙酰化修饰和NeuroD1 mRNA变化关系与SH-SY5Y细胞分化模型相似。
NeuroD1具有激活自身的启动子效应,并且对顺式调节元节E1 box依赖;研究表明,用TSA处理时,NeuroD1蛋白水平显著升高,但其激活活性反而受到抑制。免疫荧光结果表明,NeuroD1聚集在细胞核内;在TSA处理时,不仅NeuroD1的蛋白水平发生改变,而且在细胞中的定位发生改变,其蛋白会发生核膜聚集现象。
RA能促进NeuroD1的自身激活作用;组蛋白去乙酰化酶HDAC3对自身激活效应具有协同激活作用,能显著增强自身激活效应。免疫共沉淀结果表明NeuroD1和HDAC3蛋白存在于同一个蛋白复合物中,两者之间可能存在相互作用。其他去乙酰化酶(HDAC),如HDAC1,HDAC2,HDAC4,HDAC5,HDAC6都对NeuroD1的激活没有影响。
外源表达HDAC3在去乙酰化酶抑制剂TSA处理的情况下蛋白被修饰,NeuroD1的加入能阻止HDAC3的修饰。可能的机制是,HDAC3在TSA存在的时,在含HDAC3的蛋白复合物中HDAC3被丝/苏氨酸蛋白磷酸酶PP4c磷酸化;当NeuroD1存在的时候,通过某种方式抑制这种磷酸化修饰。
综上所述,在神经细胞分化进程中,神经分化标记基因neuroD1的表达受NeuroD1以及HDAC3的精确调控来执行其功能。
NeuroD is a family of bHLH transcription factors, which play a pivotal role in neuronal differentiation and neuronal development. There are seven members in the family, named NeuroD1～6, and PJA2. As a neuron differentiation factor, NeuroD1 is expressed predominantly in peripheral nerve and genesis of central nervous system. In spite of NeuroD1 is transiently expressed in differentiating neurons in a subset of neural tissues, it also maintains in the cells of the adult mouse cerebellum and hippocampus. However, the expression level gets lower and lower with the mature process of neuron cells. Xenopus ectoderm can be conversed into neurons by NeuroD1. NeuroD1 is also expressed in medulloblastoma, neuroblastoma, and retinoblastoma cells, and once activated and induced to neuron the expression level of NeuroD1 significantly increased. neuroD1 -null mice die shortly after birth. If rescued them by introducing expression plasmid encoding mouse neuroD1 gene, these mice survive to adulthood but appear neuronal deficit in the granule layers of the cerebellum and hippocampus.
In eukaryote, histone is an important part of nucleosome. Covalent modifications, such as acetylation occur in the N-terminal amino acids of histones. Histone acetylation is enriched in chromatin structure with where gene transcription is functionally active. Acetylation modification of histone is a reversible dynamic process determined by the accurate balance between the histone acetyltransferases (HAT) and the histone deacetyltransferase (HDAC).
In our study, all-trans retinoic acid (RA) treated neuroblastoma SH-SY5Y cells are taken as a model to study mechanisms of neuronal differentiation. The ChIP on Chip assay used here is the association of chromatin immunoprecipitation and promoter DNA array to detect the genome wide distribution of the acetylated residues of both H3k9 and H3K14 with over 20,000 gene promoters covered in one array. We chose to study the acetylation of these lysine residues because they usually stand for an active chromatin structure where transcription machinery is on. Raw data were analyzed by log2 Ratio≥1 or log2 Ratio≤-1, and 597 genes with elevated level of acetylated histone H3 and 647 genes with lowered acetylated histone in the promoter areas were identified. We have selected some genes with changes in acetylation status to check the reliability of the above data and found a consistency of 70%. The significant ones with consistency in both assays are 7 genes, which include the lowered PRKCA and the elevated CGB2, ELF3, CUL7, RARB, FOXH1, JARID1A genes. In contrast, NRG1, MVP and CSF1R promoters showed no marked changes in histone acetylation and thus were inconsistent with the ChIP on Chip results. The most worth mentioning point is that while acetylation of neuroD1 core promoter decreases, its mRNA level elevated. This prompts us to further investigate the mechanism of neuroD1, the neural differentiation marker gene during RA induced neuronal differentiation.
To explore the regulation mechanisms of neuroD1 gene during neuronal differentiation, we take RA treated teratocarcinoma P19 cells as a differentiation model specifically for mechanistic studies on neuroD1 gene. We showed that, as the mRNA of neuroD1 increasing upon RA treatment, the acetylation on H3 sites in the promoter region was getting lower and lower, which was exactly in accordance with the situation of SH-SY5Y cells under RA induced differentiation.
It has been known for years that NeuroD1 is capable of trans activating its own promoter, and the activation was E1 box dependent in cis. We showed in P19 cells that the trans auto-regulation of neuroD1 gene can be enhanced by RA. Additionally, histone deacetyltransferase HDAC3 showed synergic effect on the self-activation of NeuroD1. In vitro co-IP showed that NeuroD1 and HDAC3 coexisted in the same protein complex, whereas other HDACs (1,2, 4～6) were non-effective. Unsimilar with the HDAC3 effect shown above, an HDAC inhibitor, tricostatin A (TSA) inhibited the NeuroD1 auto-activity effect. Western blotting and Immunofluorescence analyses showed that NeuroD1 was dominantly located in the nucleus. However, the higher level of NeuroD1 protein induced by TSA was concentrated on the nuclear membrane.
In conclusion, in neuronal differentiation process, the expression of the marker gene neuroD1 is regulated in several levels and through several pathways accurately. As an auto-regulated gene, NeuroD1 protein enhances its own gene expression, this effect is induced by RA and HDAC3, but inhibited by TSA, which suggests a critical role of HDAC3 both in synergistically induced NeuroD1 expression and to counteract acetylation on H3K9-H3K14 as shown in ChIP on Chip and in the RA induced neuronal differentiation from P19 and SH-SY5Y cells.
NeuroD1是一类与神经细胞分化和神经系统发育紧密相关的调控因子,其家族中共有七个成员,分别是NeuroD1～6和PJA2。NeuroD1作为一种神经分化因子在外周和中枢神经系统发育过程中都有的高表达。尽管NeuroD1在神经细胞发育中通常是瞬时表达,但在成年小鼠的小脑与海马区细胞中为持续表达;同时,其表达水平也随神经元细胞的成熟而降低。在神经母细胞中过表达NeuroD1时可引起神经细胞提前成熟;而在向表皮细胞分化的细胞中引入外源过表达的NeuroD1则可导致该细胞发育成为神经元细胞。在12种成神经管细胞瘤、成神经细胞瘤和视网膜成细胞瘤中NeuroD1基因都有表达,并且在受到各种刺激或向神经细胞方向诱导时其表达水平都会有显著升高。NeuroD1(-/-)小鼠在出生后立即死亡;重新转入neuroD1,这种小鼠虽然可继续生长,但其小脑和海马区粒细胞层在分化后会出现严重的神经元缺失。
在真核生物中,组蛋白是染色质基本结构一核小体中的重要组成部分,其N末端氨基酸残基可发生乙酰化等共价修饰。组蛋白乙酰化与转录活性有密切关系:乙酰化组蛋白特异地聚集于活性染色质功能区。组蛋白的乙酰化是一可逆的动态过程,而其稳定状态的维持则是多种组蛋白乙酰基转移酶(HATs)和组蛋白去乙酰基转移酶(HDACs)共同作用的结果。这种可逆的乙酰化修饰作用可使染色质结构发生动态的改变,并对基因的转录产生重要影响。
我们以RA诱导神经母细胞瘤SH-SY5Y分化为模型,低浓度RA处理24小时后,采用染色质免疫沉淀和启动子芯片结合技术研究基因组20,000基因的启动子区组蛋白H3K9和H3K14双乙酰化水平变化。本文中所用的ChIP on chip是染色质免疫沉淀与启动子DNA芯片相结合的一种新技术,作为系统生物学的一种手段去检测全基因组范围内变化,它具有高效性和高通量的特点。我们筛选染色质中通常代表转录活性的两个乙酰化修饰位点的分布及其在诱导前后的变化,并检出阳性位点相关的启动子与基因。初步结果根据log_2Ratio≥1或log_2Ratio≤-1分析,找到了597个乙酰化水平上升的启动子和647个乙酰化水平下降的启动子位点,显示RA的处理在细胞分化早期诱导了上述变化。鉴于RA诱导SH-SY5Y细胞分化一般出现在96小时后,上述乙酰化有改变的启动子不仅提示了神经分化早期的相关基因,还包含着与RA受体活化的效应基因。我们选择了数个乙酰化修饰发生变化的基因进行验证,结果显示其一致性达到70%。如PRKCA启动子区组蛋白H3乙酰化水平下降显著,CGB2、CUL7、ELF3、FOXH1、JARID1A和RARB上升显著,而NRG1,MVP和CSF1R变化不显著,与前七者与ChIP on chip结果一致,而后三者则不一致。值得重视的是发现神经分化标记基因NeuroD1的核心启动子区组蛋白H3的K9/K14的乙酰化水平明显降低,但是其mRNA表达水平却明显升高。为深入探讨其机制,我们开展了以下工作。
为进一步研究NeuroD1调控的分子机制,在RA诱导的P19细胞分化模型中,NeuroD1核心启动子区的组蛋白H3乙酰化水平逐步降低,去除RA后组蛋白乙酰化H3修饰有回升,但在整个过程中神经细胞早期分化标记基因NeuroD1的mRNA水平一直升高;这种组蛋白H3乙酰化修饰和NeuroD1 mRNA变化关系与SH-SY5Y细胞分化模型相似。
NeuroD1具有激活自身的启动子效应,并且对顺式调节元节E1 box依赖;研究表明,用TSA处理时,NeuroD1蛋白水平显著升高,但其激活活性反而受到抑制。免疫荧光结果表明,NeuroD1聚集在细胞核内;在TSA处理时,不仅NeuroD1的蛋白水平发生改变,而且在细胞中的定位发生改变,其蛋白会发生核膜聚集现象。
RA能促进NeuroD1的自身激活作用;组蛋白去乙酰化酶HDAC3对自身激活效应具有协同激活作用,能显著增强自身激活效应。免疫共沉淀结果表明NeuroD1和HDAC3蛋白存在于同一个蛋白复合物中,两者之间可能存在相互作用。其他去乙酰化酶(HDAC),如HDAC1,HDAC2,HDAC4,HDAC5,HDAC6都对NeuroD1的激活没有影响。
外源表达HDAC3在去乙酰化酶抑制剂TSA处理的情况下蛋白被修饰,NeuroD1的加入能阻止HDAC3的修饰。可能的机制是,HDAC3在TSA存在的时,在含HDAC3的蛋白复合物中HDAC3被丝/苏氨酸蛋白磷酸酶PP4c磷酸化;当NeuroD1存在的时候,通过某种方式抑制这种磷酸化修饰。
综上所述,在神经细胞分化进程中,神经分化标记基因neuroD1的表达受NeuroD1以及HDAC3的精确调控来执行其功能。
NeuroD is a family of bHLH transcription factors, which play a pivotal role in neuronal differentiation and neuronal development. There are seven members in the family, named NeuroD1～6, and PJA2. As a neuron differentiation factor, NeuroD1 is expressed predominantly in peripheral nerve and genesis of central nervous system. In spite of NeuroD1 is transiently expressed in differentiating neurons in a subset of neural tissues, it also maintains in the cells of the adult mouse cerebellum and hippocampus. However, the expression level gets lower and lower with the mature process of neuron cells. Xenopus ectoderm can be conversed into neurons by NeuroD1. NeuroD1 is also expressed in medulloblastoma, neuroblastoma, and retinoblastoma cells, and once activated and induced to neuron the expression level of NeuroD1 significantly increased. neuroD1 -null mice die shortly after birth. If rescued them by introducing expression plasmid encoding mouse neuroD1 gene, these mice survive to adulthood but appear neuronal deficit in the granule layers of the cerebellum and hippocampus.
In eukaryote, histone is an important part of nucleosome. Covalent modifications, such as acetylation occur in the N-terminal amino acids of histones. Histone acetylation is enriched in chromatin structure with where gene transcription is functionally active. Acetylation modification of histone is a reversible dynamic process determined by the accurate balance between the histone acetyltransferases (HAT) and the histone deacetyltransferase (HDAC).
In our study, all-trans retinoic acid (RA) treated neuroblastoma SH-SY5Y cells are taken as a model to study mechanisms of neuronal differentiation. The ChIP on Chip assay used here is the association of chromatin immunoprecipitation and promoter DNA array to detect the genome wide distribution of the acetylated residues of both H3k9 and H3K14 with over 20,000 gene promoters covered in one array. We chose to study the acetylation of these lysine residues because they usually stand for an active chromatin structure where transcription machinery is on. Raw data were analyzed by log2 Ratio≥1 or log2 Ratio≤-1, and 597 genes with elevated level of acetylated histone H3 and 647 genes with lowered acetylated histone in the promoter areas were identified. We have selected some genes with changes in acetylation status to check the reliability of the above data and found a consistency of 70%. The significant ones with consistency in both assays are 7 genes, which include the lowered PRKCA and the elevated CGB2, ELF3, CUL7, RARB, FOXH1, JARID1A genes. In contrast, NRG1, MVP and CSF1R promoters showed no marked changes in histone acetylation and thus were inconsistent with the ChIP on Chip results. The most worth mentioning point is that while acetylation of neuroD1 core promoter decreases, its mRNA level elevated. This prompts us to further investigate the mechanism of neuroD1, the neural differentiation marker gene during RA induced neuronal differentiation.
To explore the regulation mechanisms of neuroD1 gene during neuronal differentiation, we take RA treated teratocarcinoma P19 cells as a differentiation model specifically for mechanistic studies on neuroD1 gene. We showed that, as the mRNA of neuroD1 increasing upon RA treatment, the acetylation on H3 sites in the promoter region was getting lower and lower, which was exactly in accordance with the situation of SH-SY5Y cells under RA induced differentiation.
It has been known for years that NeuroD1 is capable of trans activating its own promoter, and the activation was E1 box dependent in cis. We showed in P19 cells that the trans auto-regulation of neuroD1 gene can be enhanced by RA. Additionally, histone deacetyltransferase HDAC3 showed synergic effect on the self-activation of NeuroD1. In vitro co-IP showed that NeuroD1 and HDAC3 coexisted in the same protein complex, whereas other HDACs (1,2, 4～6) were non-effective. Unsimilar with the HDAC3 effect shown above, an HDAC inhibitor, tricostatin A (TSA) inhibited the NeuroD1 auto-activity effect. Western blotting and Immunofluorescence analyses showed that NeuroD1 was dominantly located in the nucleus. However, the higher level of NeuroD1 protein induced by TSA was concentrated on the nuclear membrane.
In conclusion, in neuronal differentiation process, the expression of the marker gene neuroD1 is regulated in several levels and through several pathways accurately. As an auto-regulated gene, NeuroD1 protein enhances its own gene expression, this effect is induced by RA and HDAC3, but inhibited by TSA, which suggests a critical role of HDAC3 both in synergistically induced NeuroD1 expression and to counteract acetylation on H3K9-H3K14 as shown in ChIP on Chip and in the RA induced neuronal differentiation from P19 and SH-SY5Y cells.
引文
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