特异性敲低海马RNA甲基转移酶Pcif1对空间学习记忆的影响与机制研究

doi:10.11958/20220477

天津医药 ›› 2022, Vol. 50 ›› Issue (8): 802-809.doi: 10.11958/20220477

特异性敲低海马RNA甲基转移酶Pcif1对空间学习记忆的影响与机制研究

孙祖浩¹^,²(), 所信君¹^,², 夏贤友³, 赵爽¹, 窦妍¹, 于春水¹^,²^,^Δ()

1天津医科大学总医院医学影像科（邮编300052）
2天津医科大学医学技术学院
3细胞生物学系

收稿日期:2022-03-29 修回日期:2022-04-11 出版日期:2022-08-15 发布日期:2022-08-12
通讯作者: 于春水 E-mail:sunzuhao2019@163.com;chunshuiyu@tmu.edu.cn
作者简介:孙祖浩（1997）,男,硕士在读,主要从事表观遗传对学习记忆影响方面研究。E-mail： sunzuhao2019@163.com
基金资助:
国家自然科学基金资助项目(82030053);国家自然科学基金资助项目(81971599);国家自然科学基金资助项目(81771818)

The effect and underlying mechanism of hippocampal specific knockdown of RNA methyltransferase Pcif1 on spatial learning and memory

SUN Zuhao¹^,²(), SUO Xinjun¹^,², XIA Xianyou³, ZHAO Shuang¹, DOU Yan¹, YU Chunshui¹^,²^,^Δ()

1 Department of Radiology, Tianjin Medical University General Hospital, Tianjin 300052, China
2 School of Medical Technology, Tianjin Medical University
3 Department of Cell Biology, Tianjin Medical University

Received:2022-03-29 Revised:2022-04-11 Published:2022-08-15 Online:2022-08-12
Contact: YU Chunshui E-mail:sunzuhao2019@163.com;chunshuiyu@tmu.edu.cn

孙祖浩, 所信君, 夏贤友, 赵爽, 窦妍, 于春水. 特异性敲低海马RNA甲基转移酶Pcif1对空间学习记忆的影响与机制研究[J]. 天津医药, 2022, 50(8): 802-809.

SUN Zuhao, SUO Xinjun, XIA Xianyou, ZHAO Shuang, DOU Yan, YU Chunshui. The effect and underlying mechanism of hippocampal specific knockdown of RNA methyltransferase Pcif1 on spatial learning and memory[J]. Tianjin Medical Journal, 2022, 50(8): 802-809.

摘要/Abstract

摘要：

目的探索RNA甲基转移酶Pcif1对海马相关空间学习记忆的影响及分子机制。方法选择27只8周龄的雄性C57BL/6J Nifdc小鼠进行动物实验,随机分为3组（每组9只）：Pcif1敲低组（对小鼠海马立体定位注射1 μL的腺相关病毒包装的靶向Pcif1的shRNA）、假手术组（对小鼠海马立体定位注射1 μL的对照腺相关病毒）、野生组（不做处理）。3周后,Morris水迷宫实验用于测试小鼠的空间学习记忆能力,Western blot检测小鼠海马组织中相关蛋白的表达。选择小鼠海马神经元来源的HT22细胞系进行体外实验,细胞分为2组：HT22-shPcif1组（通过慢病毒包装的靶向Pcif1的shRNA实现细胞Pcif1的敲低）和HT22-Ctrl组（通过对照慢病毒感染细胞）,通过全转录组测序（RNA-seq）、细胞毒性实验（CCK-8）、细胞划痕和流式细胞术研究敲低Pcif1影响学习记忆的机制。结果与野生组和假手术组相比,敲低组小鼠的空间学习记忆能力增强,小鼠海马中的抗凋亡蛋白Bcl-2表达上调。与HT22-Ctrl组相比,HT22-shPcif1组差异表达的基因富集到凋亡、迁移和增殖通路,细胞迁移能力增强,在400 μmol/L H₂O₂条件下细胞增殖能力提高,凋亡水平下降。结论选择性敲低海马Pcif1可以促进小鼠的空间学习记忆,其机制可能与抗凋亡蛋白上调,促进细胞迁移和增殖有关。

关键词: tRNA甲基转移酶类, 海马, 空间学习, 空间记忆, 细胞凋亡, 细胞增殖, Pcif1

Abstract:

Objective To investigate the effect and underlying molecular mechanism of RNA methyltransferase Pcif1 on hippocampus-dependent spatial learning and memory. Methods A total of twenty-seven 8-week-old male C57BL/6J Nifdc mice were selected for animal experiments. Animals were randomly divided into 3 groups (9 animals per group): the Pcif1 knockdown group (1 μL adeno-associated virus packaged shRNA targeting Pcif1 was stereotactic injected into mouse hippocampi), the sham-operation group (1 μL contrast adeno-associated virus was stereotactic injected into mouse hippocampi) and the wild-type group (none treatment). After treatment for 3 weeks, Morris water maze (MWM) was used to test the spatial learning and memory of mice, and Western blot assay was performed to detect the expression of related proteins in hippocampal tissues. HT22 cell line, a mouse hippocampal neuronal cell line, was selected for in vitro experiment. Cells were divided into two groups: the HT22-shPcif1 group (cellular Pcfi1 was knocked down by lentivirus packaged shRNA targeting Pcif1) and the HT22-Ctrl group (cells infected by contrast lentivirus). The whole-transcriptome sequencing (RNA-seq), cell-count-kit-8 (CCK8) assay, cell scratching assay and flow cytometry were used to study the mechanism of Pcif1 knockdown on learning and memory of mice. Results Comparing to the wild type group and the sham-operation group, spatial learning and memory were promoted in the Pcif1 knockdown group, and anti-apoptosis protein Bcl-2 in hippocampi was upregulated. Comparing to HT22-Ctrl cells, differentially expressed genes of HT22-shPcif1 cells were enriched in pathways of cell apoptosis, migration and proliferation. The cell migration of HT22-shPcif1 cells was enhanced. The cell proliferation of HT22-shPcif1 cells was enhanced under 400 μmol/L H₂O₂, and the cell apoptosis under 400 μmol/L H₂O₂ was reduced. Conclusion The selective knockdown of hippocampal Pcif1 facilitates spatial learning and memory of mice, and its mechanisms may be related to the upregulation of anti-apoptosis proteins and the enhancement of cell migration and proliferation.

Key words: tRNA methyltransferases, hippocampus, spatial learning, spatial memory, apoptosis, cell proliferation, Pcif1

中图分类号:

R338.6

图/表 14

图1 Tabula Muris, Human Protein Atlas和Human Brain Transcriptome数据库中有关Pcif1的表达数据 A：Tabula Muris数据库中Pcif1在神经细胞的表达情况;B：Human Protein Atlas数据库中Pcif1在小鼠不同脑区的表达情况;C：Human Brain Transcriptome数据库中Pcif1在人脑中的时空表达;NCX：新皮质;HIP：海马;AMY：杏仁核;STR：纹状体;MD：丘脑背内侧核;CBC：小脑皮质。

Fig.1 Pcif1 related expression data from Tabula Muris, Human Protein Atlas and Human Brain Transcriptome datasets

图2 小鼠冰冻脑切片荧光成像图（×25）

Fig.2 Representative fluorescence image of frozen mouse brain section (×25)

图3 3组小鼠水迷宫测试游泳轨迹图

Fig.3 Representative swimming paths of mice from 3 groups

表1 3组小鼠Morris水迷宫测试结果（n=9）

Tab.1 Morris water maze results of 3 groups of mice

组别	第1天游泳速度（cm/s）	第2天逃避时间（s）		第3天逃避时间（s）	第4天逃避时间（s）
野生组	20.48±1.71	54.95±6.06		51.71±6.04	46.36±9.36
假手术组	20.56±1.10	52.58±8.36		55.56±5.03	53.37±7.00
敲低组	20.28±1.75	49.63±9.90		46.67±16.68	43.02±14.32
F	1.440	0.749		1.263	1.764
组别	第5天逃避时间（s）		第6天逃避时间（s）	第7天目的象限时间（s）	第7天跨平台次数
野生组	44.16±6.26		39.89±7.19	24.67±5.93	1（0,2）
假手术组	49.28±5.91		38.77±8.18	23.44±3.46	1（0,1）
敲低组	34.04±17.01^b		28.71±9.69^a	30.43±4.06^ab	1（0,1.5）
F或H	3.573^＊		3.849^＊	5.243^＊	0.027

表2 HT22-shPcif1差异表达基因

Tab.2 Differentially expressed genes of HT22-shPcif1

染色体	基因名称	基因差异倍数	表达变化	P_adj
chr10	Gm48128	5.91	上调	5.19E-04
chr6	Gm44248	3.00	上调	4.72E-13
chrX	Foxr2	2.79	上调	4.63E-12
chr7	Nlrp4e	2.28	上调	4.59E-08
chr5	Rundc3b	2.24	上调	2.46E-09
chr18	Slc27a6	2.13	上调	3.95E-05
chrX	Rnf128	2.12	上调	1.52E-12
chr5	Steap4	2.11	上调	6.19E-11
chr15	Cdh10	2.11	上调	2.34E-05
chr7	Fgf21	1.86	上调	1.41E-06
chrX	Armcx2	-2.12	下调	6.47E-146
chr19	Ifit3	-2.33	下调	3.54E-14
chr5	Oas2	-2.57	下调	8.54E-14
chr12	Cmpk2	-2.84	下调	3.98E-10
chr5	Gbp6	-2.86	下调	2.52E-09
chr2	Cdh26	-3.36	下调	1.97E-13
chrY	Gm10256	-3.45	下调	8.25E-09
chr5	Oas1a	-3.46	下调	1.52E-17
chr12	Rsad2	-3.58	下调	4.80E-09
chrY	Gm3376	-3.93	下调	3.34E-20

图4 HT22-shPcif1差异表达基因火山图

Fig.4 Volcano plot of differentially expressed genes of HT22-shPcif1

图5 HT22-shPcif1差异表达基因GO分析 A：上调基因GO分析结果;B：下调基因GO分析结果;富集因子指差异表达基因位于某条GO通路中的数量与该通路上所有基因数量的比值。

Fig.5 GO analysis of differentially expressed genes of HT22-shPcif1

图6 Western blot检测HT22-shPcif1和HT22-Ctrl细胞的Pcif1蛋白水平

Fig.6 Protein levels of Pcif1 in HT22-shPcif1 and HT22-Ctrl cells measured by Western blot assay

图7 HT22-shPcif1和HT22-Ctrl细胞迁移的比较（×100）

Fig.7 Comparison of migration between HT22-shPcif1 and HT22-Ctrl cells (×100)

表3 HT22-shPcif1和HT22-Ctrl细胞迁移和凋亡比较（n=3,%,$\bar{x}±s$±s）

Tab.3 Comparison of cell migration and apoptosis of HT22-shPcif1 and HT22-Ctrl cells

组别	细胞迁移率	细胞凋亡率
HT22-Ctrl组	21.4±4.1	28.55±0.11
HT22-shPcif1组	47.2±5.5	24.80±0.13
t	8.893^＊＊	30.893^＊＊

图8 400 µmol/L H2O2条件下HT22-shPcif1和HT22-Ctrl细胞的生长曲线 t（0 h）=0.166,t（12 h）=1.742,t（24 h）=0.867,t（36 h）=2.936＊,t（48 h）=5.886＊＊;＊P<0.05,＊＊P<0.01。

Fig.8 Growing curves of HT22-shPcif1 and HT22-Ctrl cells under 400 µmol/L H2O2 condition

图9 400 µmol/L H2O2条件下流式细胞术检测HT22-shPcif1和HT22-Ctrl细胞凋亡比较

Fig.9 Comparison of apoptosis measured by flow cytometry between HT22-shPcif1 and HT22-Ctrl cells under 400 µmol/L H2O2 condition

图10 Western blot检测3组小鼠海马组织Pcif1、Bcl-2、Bax、Caspase3、BACE-1和PSD95的相对表达

Fig.10 The relative expression of Pcif1, Bcl-2, Bax, Caspase3, BACE-1 and PSD95 in hippocampal tissues of three groups of mice measured by Western blot assay

表4 3组小鼠海马组织Pcif1、Bcl-2、Bax、Caspase3、BACE-1和PSD95蛋白相对水平（n=3,$\bar{x}±s$）

Tab.4 Comparison of hippocampal relative protein levels of Pcif1, Bcl-2, Bax, Caspase3, BACE-1 and PSD95 of three groups of mice

组别	Pcif1/GAPDH	Bcl-2/GAPDH	Bax/GAPDH	Caspase3/GAPDH	BACE-1/GAPDH	PSD95/GAPDH
野生组	0.40±0.04	0.88±0.04	2.09±0.11	0.41±0.03	0.20±0.01	0.35±0.02
假手术组	0.37±0.04	0.62±0.11	1.90±0.02	0.44±0.10	0.15±0.01	0.36±0.01
敲低组	0.15±0.02^ab	1.87±0.20^ab	1.90±0.10	0.37±0.07	0.38±0.05^ab	0.40±0.09
F	23.390^＊＊	49.260^＊＊	3.288	0.423	30.690^＊＊	0.417

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特异性敲低海马RNA甲基转移酶Pcif1对空间学习记忆的影响与机制研究

The effect and underlying mechanism of hippocampal specific knockdown of RNA methyltransferase Pcif1 on spatial learning and memory

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