hil-1基因通过饮食限制通路调节秀丽隐杆线虫寿命

doi:10.12300/j.issn.1674-5817.2022.183

实验动物与比较医学 ›› 2023, Vol. 43 ›› Issue (3): 271-281.DOI: 10.12300/j.issn.1674-5817.2022.183

hil-1基因通过饮食限制通路调节秀丽隐杆线虫寿命

成慧¹(), 方菲¹, 石嘉豪¹, 杨桦¹, 张梦杰¹, 杨平², 费俭¹^,²()()

^1.同济大学生命科学与技术学院, 上海 200082
^2.上海模式动物工程技术研究中心, 上海 201309

收稿日期:2022-11-28 修回日期:2023-02-15 出版日期:2023-06-25 发布日期:2023-07-18
通讯作者: 费俭（1965—），男，博士，教授、博士生导师，研究方向：基因功能的模式生物研究。E-mail： jfei@tongji.edu.cn。ORCID： 0000-0001-7755-0818
作者简介:成慧（1996—），女，硕士，研究方向：遗传与衰老。E-mail： 1931474@tongji.edu.cn
基金资助:
上海市科学技术委员会科研计划项目“上海模式动物工程技术研究中心”(19DZ2280500);“上海市比较医学专业技术服务平台”(18DZ2293500)

H1 Linker Histone Gene Regulates Lifespan via Dietary Restriction Pathways in Caenorhabditis elegans

Hui CHENG¹(), Fei FANG¹, Jiahao SHI¹, Hua YANG¹, Mengjie ZHANG¹, Ping YANG², Jian FEI¹^,²()()

^1.School of Life Sciences and Technology, Tongji University, Shanghai 200082, China
^2.Shanghai Model Animal Engineering Technology Research Center, Shanghai 201309, China

Received:2022-11-28 Revised:2023-02-15 Published:2023-06-25 Online:2023-07-18
Contact: FEI Jian (ORCID: 0000-0001-7755-0818 ), E-mail: jfei@tongji.edu.cn

摘要/Abstract

摘要：

目的揭示H1连接子组蛋白基因（H1 linker histone gene，hil-1）的生理学功能，以及其调控线虫寿命的分子机制。方法以秀丽隐杆线虫为模式生物，采用RNA干扰菌喂食、hil-1（gk229）突变体回交纯化以及过表达质粒显微注射技术来敲降、敲除以及过表达hil-1基因，然后观察线虫存活寿命及产卵情况，通过热耐受实验、百草枯应激实验和重金属Cr⁶⁺应激实验评价hil-1（gk229）突变体的抗逆性，利用实时荧光定量PCR实验以及构建双突变体线虫进一步确定hil-1调控寿命所关联的信号通路和作用靶点。结果与野生型N2线虫相比，RNA干扰后的线虫寿命以及hil-1（gk229）突变体线虫寿命明显缩短（P<0.001），而hil-1全身性过表达后线虫寿命延长（P<0.05）。与野生型N2线虫相比，hil-1（gk229）突变体线虫对热压力和氧化压力的耐受性明显降低（P<0.001，P<0.05），而对重金属的耐受能力无差异（P>0.05）。并且，相比于野生型N2线虫，hil-1（gk229）突变体线虫的发育周期缩短（P<0.001），产卵提前（P<0.001），但产卵总量没有显著变化（P>0.05）。给eat-2（ad465）突变体线虫喂食hil-1 RNA干扰菌后，hil-1表达下调不影响eat-2（ad465）突变体线虫的寿命（P>0.05）。相较于野生型N2线虫，hil-1（gk229）突变体线虫中daf-16表达水平明显下调（P<0.001），其下游基因mtl-1和ctl-1表达也下调（P<0.05，P<0.001）。与daf-2（e1370）突变体相比，daf-2（e1370）；hil-1（gk229）双突变体线虫的寿命无明显变化（P>0.05）；而与daf-16（mu 86）突变体相比，daf-16（mu86）；hil-1（gk229）双突变线虫的寿命明显缩短（P<0.001）。与对照组相比，在表皮和肠道中RNA干扰hil-1基因表达后线虫寿命明显缩短（P<0.001）。结论 hil-1基因缺失明显缩短线虫寿命，同时使线虫对热压力和氧化压力的耐受性降低。hil-1基因可能通过饮食限制信号通路调控秀丽隐杆线虫的寿命，且该作用主要在表皮和肠道。

关键词: 秀丽隐杆线虫, H1连接子组蛋白基因, 衰老, 寿命, 饮食限制通路

Abstract:

Objective To reveal the physiological function of H1 linker histone gene (hil-1) and its molecular mechanism for regulating the lifespan in Caenorhabditis elegans (C. elegans). Methods C. elegans was used as a model organism and hil-1 gene was knock-down, knock-out and over-expressed via RNA interference technology, hil-1(gk229) mutants backcross purification and microinjection technology. Then the survival and oviposition of C. elegans were observed. Physiological tests including heat shock test, paraquat stress test and heavy metal Cr⁶⁺ stress test were conducted to evaluate the stress resistance of hil-1 mutants. After constructing a dual mutant nematode, real-time fluorescence quantitative PCR (RT-qPCR) was used to further identify the signaling pathways and target sites associated with hil-1 gene regulatory lifespan. Results Compared with wild-type N2 worms, the lifespan of C. elegans of RNA interference and hil-1(gk229) mutants were significantly shortened (P<0.001), while overexpression of hil-1 in the whole body increased lifespan (P<0.05). The tolerance of hil-1(gk229) mutants to heat stress and oxidative stress was significantly decreased (P<0.001, P<0.05), but the tolerance to heavy metals was not different compared to wild-type N2 worms (P>0.05). In addition, the developmental cycle of hil-1(gk229) mutants was shortened and the time of oviposition was advanced (P<0.001), but there was no significant change in total number of oviposition (P>0.05). After feeding hil-1 RNA interference bacteria to eat-2(ad465) mutants, the down-regulation of hil-1 expression did not affect the lifespan of eat-2(ad465) mutants (P>0.05). Compared with wild-type N2 worms, the expression level of daf-16 in hil-1(gk229) mutants was significantly down-regulated (P<0.001), and the expressions of downstream genes, mtl-1 and ctl-1, were also down-regulated (P<0.05, P<0.001). Compared with daf-2(e1370) mutants, the lifespan of daf-2 (e1370); hil-1(gk229) mutants did not shortened (P>0.05). Compared with daf-16(mu86) mutants, the lifespan of daf-16(mu86); hil-1(gk229) mutants was significantly shortened (P<0.001). The knockdown of hil-1via RNA interference technology, specifically in epidermis and intestine, was sufficient for lifespan reduction (P<0.001). Conclusion The deletion of hil-1 gene significantly shortened the lifespan of C. elegans and decreased the tolerance to heat and oxidative stress. The hil-1 gene regulates the lifespan of C. elegans via dietary restriction pathway and acts mostly in epidermis and intestine.

Key words: Caenorhabditis elegans, H1 linker histone gene (hil-1), Aging, Lifespan, Dietary restriction pathway

中图分类号:

Q95-33

成慧, 方菲, 石嘉豪, 杨桦, 张梦杰, 杨平, 费俭. hil-1基因通过饮食限制通路调节秀丽隐杆线虫寿命[J]. 实验动物与比较医学, 2023, 43(3): 271-281.

Hui CHENG, Fei FANG, Jiahao SHI, Hua YANG, Mengjie ZHANG, Ping YANG, Jian FEI. H1 Linker Histone Gene Regulates Lifespan via Dietary Restriction Pathways in Caenorhabditis elegans[J]. Laboratory Animal and Comparative Medicine, 2023, 43(3): 271-281.

图/表 8

表1 PCR引物序列

Table 1 Prime sequences for PCR

基因

Gene

引物序列

Sequences of primers

hil-1

Forward: 5’-AATGGAACCGGAAGCAGCAA-3’

Reverse: 5’-TCCGCGAGTCTGTTCAATGT-3’

daf-16

Forward: 5’- GCTCCCTTCACTCGACACTT-3’

Reverse: 5’- TTCGATTGAGTTCGGGGACG-3’

mtl-1

Forward: 5’- GCTTGCAAGTGTGACTGCAA-3’

Reverse: 5’- TTGATGGGTCTTGTCTCCGC-3’

ctl-1

Forward: 5’- TACCGAGGAGGGTAACTGGG-3’

Reverse: 5’- AGTCTGTGGATTGCGCTTCA-3’

act-4

Forward: 5’- GCCACCGCTGCCTCCTCATC-3’

Reverse: 5’- CCGGCAGACTCCATACCCAAGAAG-3’

图1 hil-1参与线虫寿命的调控注：A，野生型N2线虫喂食hil-1 RNA干扰（RNAi）菌的生存曲线［与对照组（喂食L4440）相比，P<0.001］；B，野生型N2线虫与hil-1（gk229）突变体线虫的生存曲线（与N2线虫相比，P<0.001）；C，野生型N2线虫与hil-1全身性过表达线虫（hil-1 OE）的生存曲线（与N2线虫相比，P<0.05）。

Figure 1 hil-1 is involved in regulation of the lifespan in C. elegansNote：A, Survival curves of wild-type N2 worms fed hil-1 RNA interference (RNAi) bacteria [compared with control group (fed L4440), P<0.001]; B, Survival curves of wild-type N2 worms and hil-1(gk229) mutants (compared with N2, P<0.001); C, Survival curves between wild-type N2 nematode and hil-1 systemic overexpression worms (compared with N2 nematode, P<0.05).

表2 线虫寿命实验的数据分析

Table 2 Analysis of experimental data of lifespan in C. elegans

线虫种类 C. elegans strains	线虫数量 Number	平均寿命 Mean lifespan /d
N2	94	22±0.23
hil-1(gk229)	95	18±0.67^***
Whole body hil-1 OE	101	22±0.22^*
daf-2(e1370)	101	47±0.46
daf-2(e1370);hil-1(gk229)	97	47±0.57
daf-16(mu86)	98	15±0.24
daf-16(mu86);hil-1(gk229)	82	14±0.26^▲▲▲
N2-L4440	85	17±0.23
N2-hil-1 RNAi	95	13±0.60^△△△
eat-2(ad465)-L4440	91	26±0.41
eat-2(ad465)-hil-1 RNAi	103	26±0.42
NR350-L4440	90	16±0.56
NR350-hil-1 RNAi	95	16±0.57
TU3311-L4440	101	13±0.28
TU3311-hil-1 RNAi	105	13±0.33
NR222-L4440	105	22±0.27
NR222-hil-1 RNAi	91	17±0.34^aaa
VP303-L4440	91	18±0.62
VP303-hil-1 RNAi	96	13±0.44^bbb
AMJ345-L4440	99	15±0.21
AMJ345-hil-1 RNAi	99	15±0.23^cc

图2 hil-1缺失降低了线虫对热压力和氧化压力的耐受性注：A，野生型N2线虫与hil-1（gk229）突变体线虫从20 ℃转移至35 ℃环境中的生存曲线，P<0.001；B，野生型N2线虫与hil-1（gk229）突变体在50 mmol/L百草枯环境中的生存曲线，*P<0.05；C，野生型N2 线虫与hil-1（gk229）突变体在10 mmol/L K2Cr2O7环境中的生存曲线，P>0.05。

Figure 2 The deletion of hil-1 reduces the tolerance to heat shock and oxidative stress of C. elegansNote：A， Survival curves of wild-type N2 worms and hil-1(gk229) mutant worms transferred from 20 °C to 35 °C, P<0.001; B, Survival curves of wild-type N2 worms and hil-1(gk229) mutant worms exposed to 50 mmol/L paraquat, *P<0.05; C, Survival curves of wild-type N2 worms and hil-1(gk229) mutant worms exposed to 10 mmol/L K2Cr2O7, P>0.05.

图3 hil-1缺失影响线虫发育注：A，分别在卵发育65 h和72 h 时在显微镜下观察野生型N2线虫和hil-1（gk229）突变体线虫（放大倍数100X）；B，野生型N2线虫与hil-1（gk229）突变体线虫从卵发育到产下第一颗卵所用时间，每组各10条线虫，***P<0.001；C，野生型N2线虫与hil-1（gk229）突变体从卵发育开始每12 h平均产卵量，每组均不少于10条线虫；D，野生型N2线虫与hil-1（gk229）突变体平均产卵总量，每组均不少于10条线虫，P>0.05。

Figure 3 The deletion of hil-1 affects the development of C. elegansNote：A, Observing the morphology of eggs of wild-type N2 worms and hil-1(gk229) mutant worms at 65 h and 72 h of development under microscope, with magnification of 100X; B, The duration of wild-type N2 worms and hil-1(gk229) mutant worms from egg to the laying of the first egg, n =10 in each group, ***P<0.001; C, The average number of eggs production every 12 h from egg development in wild-type N2 worms and hil-1(gk229) mutant worms, n > 10 in each group; D, The total number of eggs in wild-type N2 worms and hil-1(gk229) mutant worms. n > 10 in each group, nsP>0.05.

图4 hil-1 敲降不影响eat-2（ad465）突变体寿命注：eat-2（ad465）突变体喂食hil-1 RNA干扰（RNAi）菌的生存曲线。与对照组（喂食L4440）相比，P>0.05。

Figure 4 The knockdown of hil-1 has no significant effect on the lifespan of eat-2（ad465）Note： Survival curves of eat-2（ad465） mutants fed hil-1 RNA interference （RNAi） bacteria. Compared with control group （fed L4440）， P>0.05.

图5 hil-1不完全依赖胰岛素信号通路调控线虫寿命注：A，daf-2（e1370）突变体和daf-2（e1370）；hil-1（gk229）双突变体线虫的生存曲线，P>0.05；B，野生型N2线虫和hil-1（gk229）突变体线虫中daf-16的表达量（与N2相比，***P<0.001）；C，野生型N2线虫和hil-1（gk229）突变体线虫中daf-16下游靶基因mtl-1和ctl-1的表达（与N2相比，*P<0.05，***P<0.001）；D，daf-16 （mu86）突变体和daf-16（mu86）；hil-1（gk229）双突变体线虫的生存曲线，P<0.001。

Figure 5 hil-1 is not completely dependent on insulin signaling pathway to regulate lifespan of C. elegansNote：A, Survival curves of daf-2(e1370) mutant worms and daf-2(e1370);hil-1(gk229) mutant worms, P>0.05; B, Analysis of the expression levels of daf-16 gene in wild-type N2 worms and hil-1(gk229) mutant worms（Compared with wild-type N2 worms, ***P<0.001）; C, Analysis of the expression levels of daf-16 target genes mtl-1 and ctl-1 in wild-type N2 and hil-1(gk229) mutant worms（compared with wild-type N2 worms *P<0.05，***P<0.001）; D, Survival curves of daf-16(mu86) mutant worms and daf-16 (mu86); hil-1(gk229) mutant worms, P<0.001.

图6 hil-1作用于表皮和肠道调控线虫寿命注：A～D分别为肌肉（A）、神经（B）、表皮（C）和肠道（D）组织特异性RNA干扰（RNAi）线虫饲喂hil-1 RNA干扰菌株后的生存曲线。仅在表皮或者肠道组织降敲hil-1基因表达会显著缩短线虫寿命。

Figure 6 hil-1 acts in the hypodermis or intestine to regulate lifespanNote：A-D， Survival curves of worms with tissue-specific knockdown of hil-1in muscle（A）， neuron（B）， hypodermis（C） and intestine（D）， respectively. Lifespan is shortened only in hypodermis-specific RNA interference （RNAi） or intestine-specific RNAi worms.

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hil-1基因通过饮食限制通路调节秀丽隐杆线虫寿命

H1 Linker Histone Gene Regulates Lifespan via Dietary Restriction Pathways in Caenorhabditis elegans

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