遗传 ›› 2021, Vol. 43 ›› Issue (8): 775-791.doi: 10.16288/j.yczz.21-132
收稿日期:
2021-04-11
修回日期:
2021-05-12
出版日期:
2021-08-20
发布日期:
2021-06-30
通讯作者:
黄海燕,吴强
E-mail:wanglingmail0613@163.com;hy_huang@sjtu.edu.cn;qwu123@gmail.com
作者简介:
王玲,硕士研究生,专业方向:生物学。E-mail: 基金资助:
Ling Wang(), Jinhuan Li, Haiyan Huang(
), Qiang Wu(
)
Received:
2021-04-11
Revised:
2021-05-12
Online:
2021-08-20
Published:
2021-06-30
Contact:
Huang Haiyan,Wu Qiang
E-mail:wanglingmail0613@163.com;hy_huang@sjtu.edu.cn;qwu123@gmail.com
Supported by:
摘要:
三维基因组染色质架构蛋白CTCF (CCCTC-binding factor)能够介导增强子与基因启动子的远距离染色质相互作用,也可以结合调控区域的绝缘子发挥增强子绝缘功能,对发育中的基因表达调控具有重要作用。同源框基因家族(Homeobox gene family, Hox)编码一类控制动物发育的关键转录因子,在发育中主要沿胚胎首尾轴(head-to-tail axis)呈时空线性表达。在哺乳动物中,Hox基因分为HoxA、HoxB、HoxC和HoxD四个基因簇,在中枢神经系统、骨骼和四肢发育中发挥重要功能。HoxD基因簇主要调控四肢发育,受位于其两侧调控域内的增强子调节,沿肢体近远轴(proximal-distal axis)呈时空线性表达。在人类基因组中,HOXD基因簇及其两侧的调控区域分布有串联排列的CTCF结合位点(简称CTCF位点),参与9个HOXD基因的表达调控。本研究以HOXD基因簇为模式基因,探究CTCF对发育基因(developmental genes)转录调控的影响。利用CRISPR DNA片段编辑技术在人HEK293T细胞中获得一系列的串联反向CTCF位点删除的单细胞克隆株。RNA-seq实验揭示CTCF位点删除后HOXD基因表达下降。定量高分辨率染色体构象捕获实验显示,HOXD与上游增强子簇的远距离染色质相互作用增强,与下游增强子簇的远距离染色质相互作用减弱。综上所述,串联反向的CTCF位点通过其绝缘子功能维持上下游增强子簇对HOXD基因簇表达调控的平衡,为探究动物发育过程中Hox基因表达的精准调控机制提供参考。
王玲, 李金环, 黄海燕, 吴强. 串联反向CTCF位点的系列删除揭示增强子调控HOXD基因簇表达的平衡[J]. 遗传, 2021, 43(8): 775-791.
Ling Wang, Jinhuan Li, Haiyan Huang, Qiang Wu. Serial deletions of tandem reverse CTCF sites reveal balanced HOXD regulatory landscape of enhancers[J]. Hereditas(Beijing), 2021, 43(8): 775-791.
图1
CTCF位点在Hox基因簇及其调控区域内的分布 A:果蝇及哺乳动物Hox基因家族的基因组结构。果蝇Hox基因簇分为触足复合群(ANT-C)和双胸复合群(BX-C),其中ANT-C包含Antp、Scr、Dfd、pb和lab基因,BX-C包含AbdB、AbdA和Ubx基因。哺乳动物具有4个Hox基因簇:HoxA、HoxB、HoxC和HoxD,共包含39个基因,其中HoxD基因簇包括HoxD1、HoxD3、HoxD4、HoxD8~HoxD13。果蝇及哺乳动物相同颜色的Hox基因为直系同源基因(orthologues),它们起源于同一祖先基因。B:人胚胎肾细胞系HEK293T中的CTCF蛋白、架构蛋白YY1、增强子标记H3K4me1和H3K27ac、启动子标记H3K4me3、转录活性标记PolⅡ和p300在人HOXD基因簇及其调控区域内的分布。红色虚线框指示增强子Island2、Island5、GT2、CS38-41和HOXD基因簇所在区域。哺乳动物的HoxD基因簇位于3′端粒侧TAD (T-DOM)和5′中心粒侧TAD (C-DOM)交界处,并受到上下游增强子簇(upstream enhancer cluster和downstream enhancer cluster)的调控。C:人类HOXD基因簇区域CTCF位点的分布。人肾脏和胚胎肾细胞系HEK293T的CTCF ChIP-seq结合峰分布图:HOXD基因簇C-DOM和T-DOM交界区域均具有串联排列的CTCF位点。红色虚线框依次指示CBS a、b、c和e所在区域。D:小鼠HoxD基因簇区域CTCF位点的分布。小鼠肾脏和第12.5天胚胎肢芽CTCF ChIP-seq数据显示小鼠HoxD基因簇中心粒侧对应的位置具有串联反向排列的4个CTCF位点。图C和D中箭头代表CTCF位点,其中红色箭头代表正向CTCF位点,蓝色箭头代表反向CTCF位点。"
表1
引物序列"
类型 | 引物名称 | 序列(5′→3′) |
---|---|---|
PCR | a1F | TTCCAGCACCTCGGCTTTGTC |
a1R | CCCACTTTCCACCTCTGTCCTG | |
b1F | GTCCGCCCGTGAGCTTCTGAA | |
b1R1 | CTCACAGCAGCCGAAACCG | |
c1F | TGATGCAGCCTCTGTGACCG | |
c1R | AGTTTTCCCGTGGCGTCTGA | |
e1F | TTCCCTGTCCCAGCTTGATTTC | |
e1R | TCAACAGTGAAGGGCGGTGC | |
e2F | CAAGCCACTCTCCCGCCACTA | |
e2R | TCGCTCTCGTCCTCTCTTGGG | |
e2R1 | GGCTCCTGCACTGAGACCACA | |
sgRNA | sgRNA a1F | ACCGCGAAGAGTGCGGGAGAACGG |
sgRNA a1R | AAACCCGTTCTCCCGCACTCTTCG | |
sgRNA b1F | ACCGGGCGCATCAGGAATGTAAG | |
sgRNA b1R | AAACCTTACATTCCTGATGCGCC | |
sgRNA c1F | ACCGCAGGCGAAGTGCGGTTTCCA | |
sgRNA c1R | AAACTGGAAACCGCACTTCGCCTG | |
sgRNA e1F | ACCGAACTGTGCTCAAACGCTCTC | |
sgRNA e1R | AAACGAGAGCGTTTGAGCACAGTT | |
sgRNA e2F | ACCGGAGGCGCAAACAGCTGTTGT | |
sgRNA e2R | AAACACAACAGCTGTTTGCGCCTC | |
Index | Island5-bioprimer | 5′biotin-AAACACAAATGCATCAACCTG |
GT2-bioprimer | 5′biotin-GAGCCAAACTGTACCCCTAGC | |
HOXD9-bioprimer | 5′biotin-ACCGACTAGTTCGCAGGCT | |
Island5-P5 | AATGATACGGCGACCACCGAGATCTACACTCTTTCCCTACACGACGCTCTTCCGATCTATGCATCTCATGAAGCTGGCATCT | |
GT2-P5 | AATGATACGGCGACCACCGAGATCTACACTCTTTCCCTACACGACGCTCTTCCGATCTGTAACTTTAGCTAAACCAAGGCCT | |
HOXD9-P5 | AATGATACGGCGACCACCGAGATCTACACTCTTTCCCTACACGACGCTCTTCCGATCTCTGCAGCCTCCACCATTG | |
P7-index-1 | CAAGCAGAAGACGGCATACGAGATCGAGTAATGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-2 | CAAGCAGAAGACGGCATACGAGATTCTCCGGAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-3 | CAAGCAGAAGACGGCATACGAGATAATGAGCGGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-4 | CAAGCAGAAGACGGCATACGAGATGGAATCTCGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-5 | CAAGCAGAAGACGGCATACGAGATTTCTGAATGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-6 | CAAGCAGAAGACGGCATACGAGATACGAATTCGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-7 | CAAGCAGAAGACGGCATACGAGATAGCTTCAGGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-8 | CAAGCAGAAGACGGCATACGAGATGCGCATTAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-9 | CAAGCAGAAGACGGCATACGAGATCATAGCCGGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-10 | CAAGCAGAAGACGGCATACGAGATTTCGCGGAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-11 | CAAGCAGAAGACGGCATACGAGATGCGCGAGAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-12 | CAAGCAGAAGACGGCATACGAGATCTATCGCTGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-13 | CAAGCAGAAGACGGCATACGAGATAGAGTACTGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-14 | CAAGCAGAAGACGGCATACGAGATGCTCCGTAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-15 | CAAGCAGAAGACGGCATACGAGATCATGAGAGGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-16 | CAAGCAGAAGACGGCATACGAGATTGAATCGCGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-17 | CAAGCAGAAGACGGCATACGAGATGTCTGACTGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-18 | CAAGCAGAAGACGGCATACGAGATCTGAATGCGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-19 | CAAGCAGAAGACGGCATACGAGATCGCTTCTGGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-20 | CAAGCAGAAGACGGCATACGAGATTCGCATGAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-21 | CAAGCAGAAGACGGCATACGAGATAATAGCAGGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-22 | CAAGCAGAAGACGGCATACGAGATGTCGCGTAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-23 | CAAGCAGAAGACGGCATACGAGATACGCGATAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-24 | CAAGCAGAAGACGGCATACGAGATTGATCGATGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-25 | CAAGCAGAAGACGGCATACGAGATCCGCATGAGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-26 | CAAGCAGAAGACGGCATACGAGATCCACAATCGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT | |
P7-index-27 | CAAGCAGAAGACGGCATACGAGATGATGTTCGGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT |
图2
CBS e删除改变增强子与启动子间的远程互作从而影响HOXD基因簇的基因表达 A:利用CRISPR DNA片段编辑技术获得CBS e删除的单细胞克隆株(e#113和e#126)的示意图。针对CBS e设计一对sgRNA(sgRNA e1和sgRNA e2),Cas9核酸酶在sgRNA e1和sgRNA e2的介导下特异性识别CBS e两侧靶向序列后进行切割,形成的两个切口被修复后连接在一起获得CBS e删除的编辑细胞。B:采用特异性引物PCR后进行凝胶电泳实验鉴定单细胞克隆株。引物对e1F/e2R在野生型(WT)细胞中扩增出1560 bp的片段,在e#113和e#126细胞株中扩增出CBS e删除后的729 bp片段(红色虚线框指示目的条带)。C:TA克隆并进行桑格测序确定单细胞克隆株的基因型。引物对e1F/e2R在e#113和e#126细胞株中扩增的产物经TA克隆后的测序结果图。D:RNA-seq数据分析比较WT细胞、e#113和e#126细胞株中HOXD基因簇表达水平。*:P<0.05;**:P<0.01;FPKM:fragments per kilobase of transcript per million mapped reads。E:在染色质构象捕获(QHR-4C)实验中,以增强子Island5为观测点(viewpoint,VP),分析e#113和e#126细胞株中Island5与HOXD基因簇启动子及调控元件Island2、GT2和CS38-41的远程互作。将e#113和e#126细胞株的数据分别与WT进行log2处理,红色实线框内为Island5与HOXD基因簇启动子之间的染色质相互作用,黑色虚线框依次指示调控元件Island2、GT2和CS38-41。F:以增强子GT2为VP,分析CBS e删除后GT2与HOXD基因簇启动子的远程互作。红色实线框内为GT2与HOXD基因簇启动子间的染色质相互作用放大图,黑色虚线框依次指示调控元件Island2、Island5和CS38-41。G:以HOXD9启动子为VP,分析e#113和e#126细胞株中调控元件Island2、Island5、GT2、CS38-41与HOXD9启动子之间的染色质相互作用。黑色虚线框指示Island2,红色实线框内分别为Island5、GT2和CS38-41与HOXD9启动子之间的染色质相互作用放大图。"
图3
CBS c-e删除引起上游增强子与近端HOXD基因相互作用的增强 A:设计一对sgRNA(sgRNA c1和sgRNA e2)对HEK293T野生型细胞进行编辑获得CBS c-e删除的单细胞克隆株(c-e#49和c-e#54)的示意图。B:用引物c1F和e2R PCR鉴定c-e#49和c-e#54单细胞克隆株的凝胶电泳图。C:TA克隆鉴定c-e#49和c-e#54单细胞克隆株基因型的测序结果图。D:RNA-seq数据分析比较WT细胞、c-e#49和c-e#54细胞中HOXD基因簇表达水平。E:QHR-4C实验中,以Island5为VP,分析c-e#49和c-e#54细胞株中Island5与HOXD基因簇启动子的远程互作。红色实线框内为Island5与HOXD基因簇启动子之间的染色质相互作用放大图,黑色虚线框依次指示调控元件Island2、GT2和CS38-41。F:以GT2为VP,分析CBS c- e删除后GT2与HOXD基因簇启动子的远程互作。红色实线框内为GT2与HOXD基因簇启动子间的染色质相互作用放大图,黑色虚线框依次指示调控元件Island2、Island5和CS38-41。G:以HOXD9启动子为VP,c-e#49和c-e#54细胞株中Island2、Island5、GT2、CS38-41与HOXD9启动子之间的染色质相互作用。黑色虚线框指示Island2,红色实线框内分别为Island5、GT2和CS38-41与HOXD9启动子之间的染色质相互作用放大图。"
图4
串联排列CTCF位点对增强子远程互作和HOXD基因表达具有叠加效应 A:利用CRISPR/Cas9编辑系统获得CBS b-e删除的单细胞克隆株(b-e#59和b-e#80)的示意图。B:用引物b1F和e2R1进行PCR鉴定b-e#59和b-e#80单细胞克隆株的凝胶电泳图。C:TA克隆鉴定b-e#59和b-e#80单细胞克隆株基因型的测序结果图。D:RNA-seq数据分析比较WT细胞、b-e#59和b-e#80细胞株细胞中HOXD基因簇表达水平。E:QHR-4C实验中,以Island5为VP,分析CBS b-e删除对Island5与HOXD基因簇启动子远程互作的影响。红色实线框内为Island5与HOXD基因簇启动子之间的染色质相互作用放大图,黑色虚线框依次指示调控元件Island2、GT2和CS38-41。F:以GT2为VP,分析b-e#59和b-e#80细胞株中GT2与HOXD基因簇启动子的远程互作。红色实线框内为GT2与HOXD基因簇启动子间的染色质相互作用放大图,黑色虚线框依次指示调控元件Island2、Island5和CS38-41。G:以HOXD9启动子为VP,分析b-e#59和b-e#80细胞株中Island5、GT2、CS38-41与HOXD9启动子间的染色质相互作用。黑色虚线框指示Island2,红色实线框内分别为Island5、GT2和CS38-41与HOXD9启动子之间的染色质相互作用放大图。"
图5
删除全部反向CTCT位点破坏增强子调控HOXD基因表达的平衡 A:获得CBS a-e删除的单细胞克隆株(a-e#93和a-e#108)的示意图。B:用引物a1F和e2R PCR鉴定a-e#93和a-e#108细胞株的凝胶电泳图。C:TA克隆鉴定a-e#93和a-e#108单细胞克隆株基因型的测序结果图。D:RNA-seq数据分析比较WT细胞、a-e#93和a-e#108细胞株细胞中HOXD基因簇转录水平。E:QHR-4C实验中,以Island5为VP,分析CBS a-e删除对Island5与HOXD基因簇启动子及两侧调控区域染色质相互作用的影响。红色实线框内为Island5与HOXD基因簇启动子之间的染色质相互作用放大图,黑色虚线框依次指示调控元件Island2、GT2和CS38-41。F:以GT2为VP,分析a-e#93和a-e#108细胞株中GT2与HOXD基因簇启动子的染色质相互作用。红色实线框内为GT2与HOXD基因簇启动子间的染色质相互作用放大图,黑色虚线框依次指示调控元件Island2、Island5和CS38-41。G:以HOXD9启动子为VP,分析CBS a-e删除后HOXD9的表达调控模式。黑色虚线框指示Island2,红色实线框内为Island5、GT2、CS38-41与HOXD9基因簇启动子间的染色质相互作用放大图。"
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