U2HR突变致Marie Unna型遗传性稀毛症的分子机制研究
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摘要
Marie Unna遗传性稀毛症(Marie Unna hereditary hypotrichosis,MUHH,MIM146550)是一种毛发周期紊乱导致的遗传病,呈常染色体显性遗传。患者出生后毛发稀少或缺如,儿童期毛发开始生长,质硬、卷曲而无光泽,青春期呈进行性毛发脱落而不再生长。国际上将MUHH基因座定位于人染色体8p21区域,但对此区域中与毛发周期密切相关的Hairless(HR)基因编码区进行突变筛查时都没有发现任何致病性突变。本课题组前期研究证实了MUHH在8p21区域的定位,并于HR基因5'-UTR区4个上游开放读码框(upstream open reading frame,uORFs)(从5'端至3'端分别命名为U1HR、U2HR、U3HR和U4HR)中的第二个uORF(U2HR)发现13种MUHH致病突变。本研究挑选其中7种具有代表性的突变作为研究对象(包括1种起始密码子突变、1种终止密码子突变、1种无义突变和4种不同的错义突变),旨在探讨这7种不同的突变对HR基因表达的影响,以及U2HR对HR基因主要开放读码框(main open reading frame,mORF)表达调控的分子机制。
本课题组在前期工作中发现,U3HR和U4HR都不影响下游报告基因的转录水平和翻译效率。但本研究发现,U1HR和U2HR在分别破坏起始密码子后虽然都不改变下游报告基因的转录水平,但前者使翻译效率降低了近一倍,而后者使翻译效率提高近3倍。提示U1HR和U2HR可能分别作为一种激活性和抑制性元件调控下游HR基因mORF的翻译。
本研究应用萤火虫荧光素酶和EGFP报告基因系统,分析上述7种MUHH致病突变对下游报告基因表达的影响。结果发现,将这7种突变构建体分别转染HeLa细胞后,EGFP报告基因的转录水平与转染野生型后的水平相当,但是荧光素酶和EGFP报告基因的翻译水平却获得2～4倍的升高。该实验结果提示,U2HR的突变不是通过影响HR基因的转录水平,而是通过对HR基因翻译水平的调控来影响HR蛋白在细胞中的含量;同时也提示,MUHH发生的分子机制是:U2HR发生失去功能性突变,从而丧失对下游HR基因mORF翻译的抑制,引起HR蛋白过表达。
在U2HR调控下游HR基因mORF翻译的分子机制研究中,本文首先探讨了这种调控作用是否与U2HR所编码的氨基酸有关。利用定点诱变方法在U2HR编码区C端产生3种同义突变体,与野生型相比,这3种同义突变体在转染细胞后均未能改变荧光素酶和EGFP报告基因的翻译水平,提示U2HR对下游HR基因mORF翻译的调节不是依赖U2HR的核苷酸序列,而是依赖于U2HR所编码的氨基酸序列。
为本研究还通过消除终止密码子的方法将U1HR和U2HR分别与EGFP读码框融合表达融合蛋白,Western Blot分析可见印迹条带分子量大小与预测的相当,这间接提示U1HR和U2HR在生理条件下是可翻译的。
随后在互补实验(complementary test)中,过表达U2HR多肽并不能挽救U2HR无义突变体导致的对下游报告基因表达抑制作用的丧失,也不能增强野生型U2HR对下游报告基因表达的抑制作用,提示U2HR不是通过反式作用,而是通过顺式作用调控下游HR基因mORF的翻译。
为明确是否U2HR编码的其他氨基酸也是调控下游HR基因mORF翻译所必需,本研究在U2HR编码区N端随机选择了两个密码子进行错义突变。随后在报告基因表达水平检测中发现,这两种突变体不影响EGFP报告基因的转录水平,但均使荧光素酶或EGFP的翻译效率提高了2倍左右,提示U2HR编码氨基酸的N端区域对下游HR基因mORF的翻译调控同样重要。
uORF抑制下游mORF翻译的可能机制之一是通过其终止密码子附近的氨基酸阻滞核糖体向下游滑动。为了解U2HR是否可能通过此机制抑制下游HR基因mORF的翻译,本研究采用定点诱变延长U2HR编码区的方法,改变了U2HR终止密码子附近的氨基酸性质,随后将这种突变体转染HeLa细胞,观察其对下游报告基因表达水平的影响。实验结果显示报告基因翻译水平与转染野生型的相比基本没有差异,这提示U2HR终止密码子附近的氨基酸可能不影响核糖体在mRNA上的滑动。本研究还在U2HR起始密码子AUG下游(+4位)插入单碱基G,形成移码突变,改变野生型U2HR编码的包括终止密码子附近氨基酸在内的几乎所有氨基酸。将该突变体转染细胞后发现,与转染野生型的相比,下游报告基因的转录水平基本不变,但翻译效率却升高了近2倍。该结果提示U2HR可能通过其编码的非终止密码子附近的氨基酸序列影响核糖体在mRNA上的滑动,下调HR基因mORF翻译。
如果U2HR在生理条件下翻译为多肽,其可能通过与翻译装置中某些组分发生作用而影响核糖体在mRNA上的滑动。本研究采用酵母双杂交系统和哺乳动物双杂交系统检测了候选蛋白eIF2a、eIF2b、eIF4e和ERF1与U2HR多肽的相互作用,但均获得阴性结果,提示U2HR多肽与这些候选蛋白可能不发生相互作用。
以上研究结果表明,在正常情况下,依赖U2HR编码肽链序列的调控机制使HR蛋白表达水平受到严格调控,U2HR失去功能性突变引起HR蛋白过表达,并最终导致MUHH。这不但为毛发周期中HR基因表达的调控机制,同时也为MUHH的发病机理提供了初步的依据。
Hair growth and shedding occur periodically,characterized by cyclic transformation consisting of phases of rapid growth(anagen),apoptosis-driven regression(catagen),and relative quiescence(telogen).Hair loss and unwanted hair growth(hypertrichosis) emerge owing to disturbance of hair cycle.Marie Unna hereditary hypotrichosis(MUHH) is an autosomal dominant hair loss disorder,with the affected individuals usually born with little or no hair,and coarse twisted hair growth on the scalp in early childhood.In most patients,scalp hair is lost progressively,starting at puberty or beyond.Our previous research and several other studies have mapped the MUHH gene to chromosome 8p21. The mutational screening of the Hairless(HR) gene,which lies in the positioned region and plays a pivotal role in the hair cycling process,however,found no pathogenic change in the coding region.We previously discovered 13 mutations centerlized in the second upstream open reading frame(uORF)(designated as U2HR) region,which is one of the four uORFs(refer to as U1HR,U2HR,U3HR and U4HR,respectively) in the 5'-untranslated region(UTR) of the HR gene.Seven mutations,which consist of mutations in initiation codon or termination codon,as well as one nonsense mutation and four different missense mutations,were chosen for this study to investigate their effects on the downstream HR gene expression regulation.Then we attempted to explore the underlying molecular mechanism regulating the HR gene expression via U2HR.
Cis-acting elements in 5'-UTR generally have negative regulation on expression of downstream cistron.Our previous studies have ruled out the potential effects of U3HR and U4HR on the transcriptional and translational level of downstream reporter genes, whereas disruption of initiation codon in U1HR or U2HR significantly reduced(U1HR) or increased(U2HR) the translation efficiency with nearly no effects on the transcriptional level,suggesting that U1HR and U2HR function as stimulatory and inhibitory translational control elements,respectively.Additionally,we discovered dramatic increase(2～4 folds versus wildtype(WT)) of translational level of reporter genes(Luciferase and EGFP) after transfection of the above seven mutant constructs into HeLa cell line.We found no effects on reporter gene transcriptional level when compared with WT.These findings helped us realize that loss-of-function mutations in U2HR could lead to increased main ORF(mORF) translation of the HR gene,and the underlying mechanism causing MUHH is over-expression of the HR gene.
Inhibitory uORFs may function in nucleotide sequence dependent or nascent peptide sequence dependent way.We generated three synonymous mutants at the C terminal region of U2HR coding sequcence,and no obvious changes were found in the translational level of Luciferase or EGFP reporter gene.This indicated that the translation regulation of HR gene depends on the amino acids encoded from U2HR coding sequence.
We performed site-directed mutagenesis to remove the termination codons of U1HR and U2HR and allow the fusion of EGFP sequence.The observation of efficient translation of the two uORFs in transfected cells,as well as verification of the translation of U2HR using a polyclonal antibody to U2HR,lead us to believe that the functional U1HR and U2HR seem to encode active peptides.
In the complementary test,over-expression of U2HR peptide could not recover or strengthen the inhibitory effect of U2HR on the HR gene mORF translation,indicating that translation regulation of the HR gene mORF via U2HR is the consequence of cis-acting effect.
To further determine whether each amino acid derived from U2HR coding sequence is necessary to regulate downstream mORF expression,we randomly chosed two codons in the N terminal region of U2HR to generate two missense mutants.In the following reporter gene detection,we found that these two mutants increased the translation level of reporter genes by around 2 folds,indicating that N terminal region of U2HR may play the similar role as C terminal region in downstream mORF translation regulation.
Stalling at a codon in a uORF can strongly impact downstream translation.Thus,we used site-directed mutagenesis to lengthen the U2HR from 34 to 49 codons so as to alter the amino acid context around the WT U2HR termination codon.This mutant didn't influence the translation level of the reporter genes,indicating no effects on the scanning ribosomes to move downstream.We then inserted a single nucleotide G into the immediate downstream of U2HR initiation codon,causing frame shift mutation and lengthening the codons up to 49.This mutant thus generally altered the context of amino acids of U2HR.We discovered no obvious effect of such mutant on the transcription activity of reporter gene,whereas up to 2 folds increase of the translation level was detected,consistent with mechanism of nascent peptide sequence dependent translation regulation.
If the U2HR peptide is translated in physical condition,it may influence the movement of scanning ribosomes via interactions with a certain element in the translation machinery. eIF2a,eIF2b,eIF4e and ERF1 were selected as candidates to verify their possible respective interaction with U2HR peptide via yeast two-hybrid system and mammalian two-hybrid system,but the negative results indicated no interaction between U2HR peptide and a certain candidate protein occur.
In summary,these results suggested that the expression level of HR protein in physical condition might be strictly regulated via U2HR.The loss-of-function mutation of U2HR gave rise to over expression of HR gene,and thus caused MUHH.These findings uncover the regulation mechanism underlying HR gene expression,and provide molecular basis for the pathogenesis of MUHH.
本课题组在前期工作中发现,U3HR和U4HR都不影响下游报告基因的转录水平和翻译效率。但本研究发现,U1HR和U2HR在分别破坏起始密码子后虽然都不改变下游报告基因的转录水平,但前者使翻译效率降低了近一倍,而后者使翻译效率提高近3倍。提示U1HR和U2HR可能分别作为一种激活性和抑制性元件调控下游HR基因mORF的翻译。
本研究应用萤火虫荧光素酶和EGFP报告基因系统,分析上述7种MUHH致病突变对下游报告基因表达的影响。结果发现,将这7种突变构建体分别转染HeLa细胞后,EGFP报告基因的转录水平与转染野生型后的水平相当,但是荧光素酶和EGFP报告基因的翻译水平却获得2～4倍的升高。该实验结果提示,U2HR的突变不是通过影响HR基因的转录水平,而是通过对HR基因翻译水平的调控来影响HR蛋白在细胞中的含量;同时也提示,MUHH发生的分子机制是:U2HR发生失去功能性突变,从而丧失对下游HR基因mORF翻译的抑制,引起HR蛋白过表达。
在U2HR调控下游HR基因mORF翻译的分子机制研究中,本文首先探讨了这种调控作用是否与U2HR所编码的氨基酸有关。利用定点诱变方法在U2HR编码区C端产生3种同义突变体,与野生型相比,这3种同义突变体在转染细胞后均未能改变荧光素酶和EGFP报告基因的翻译水平,提示U2HR对下游HR基因mORF翻译的调节不是依赖U2HR的核苷酸序列,而是依赖于U2HR所编码的氨基酸序列。
为本研究还通过消除终止密码子的方法将U1HR和U2HR分别与EGFP读码框融合表达融合蛋白,Western Blot分析可见印迹条带分子量大小与预测的相当,这间接提示U1HR和U2HR在生理条件下是可翻译的。
随后在互补实验(complementary test)中,过表达U2HR多肽并不能挽救U2HR无义突变体导致的对下游报告基因表达抑制作用的丧失,也不能增强野生型U2HR对下游报告基因表达的抑制作用,提示U2HR不是通过反式作用,而是通过顺式作用调控下游HR基因mORF的翻译。
为明确是否U2HR编码的其他氨基酸也是调控下游HR基因mORF翻译所必需,本研究在U2HR编码区N端随机选择了两个密码子进行错义突变。随后在报告基因表达水平检测中发现,这两种突变体不影响EGFP报告基因的转录水平,但均使荧光素酶或EGFP的翻译效率提高了2倍左右,提示U2HR编码氨基酸的N端区域对下游HR基因mORF的翻译调控同样重要。
uORF抑制下游mORF翻译的可能机制之一是通过其终止密码子附近的氨基酸阻滞核糖体向下游滑动。为了解U2HR是否可能通过此机制抑制下游HR基因mORF的翻译,本研究采用定点诱变延长U2HR编码区的方法,改变了U2HR终止密码子附近的氨基酸性质,随后将这种突变体转染HeLa细胞,观察其对下游报告基因表达水平的影响。实验结果显示报告基因翻译水平与转染野生型的相比基本没有差异,这提示U2HR终止密码子附近的氨基酸可能不影响核糖体在mRNA上的滑动。本研究还在U2HR起始密码子AUG下游(+4位)插入单碱基G,形成移码突变,改变野生型U2HR编码的包括终止密码子附近氨基酸在内的几乎所有氨基酸。将该突变体转染细胞后发现,与转染野生型的相比,下游报告基因的转录水平基本不变,但翻译效率却升高了近2倍。该结果提示U2HR可能通过其编码的非终止密码子附近的氨基酸序列影响核糖体在mRNA上的滑动,下调HR基因mORF翻译。
如果U2HR在生理条件下翻译为多肽,其可能通过与翻译装置中某些组分发生作用而影响核糖体在mRNA上的滑动。本研究采用酵母双杂交系统和哺乳动物双杂交系统检测了候选蛋白eIF2a、eIF2b、eIF4e和ERF1与U2HR多肽的相互作用,但均获得阴性结果,提示U2HR多肽与这些候选蛋白可能不发生相互作用。
以上研究结果表明,在正常情况下,依赖U2HR编码肽链序列的调控机制使HR蛋白表达水平受到严格调控,U2HR失去功能性突变引起HR蛋白过表达,并最终导致MUHH。这不但为毛发周期中HR基因表达的调控机制,同时也为MUHH的发病机理提供了初步的依据。
Hair growth and shedding occur periodically,characterized by cyclic transformation consisting of phases of rapid growth(anagen),apoptosis-driven regression(catagen),and relative quiescence(telogen).Hair loss and unwanted hair growth(hypertrichosis) emerge owing to disturbance of hair cycle.Marie Unna hereditary hypotrichosis(MUHH) is an autosomal dominant hair loss disorder,with the affected individuals usually born with little or no hair,and coarse twisted hair growth on the scalp in early childhood.In most patients,scalp hair is lost progressively,starting at puberty or beyond.Our previous research and several other studies have mapped the MUHH gene to chromosome 8p21. The mutational screening of the Hairless(HR) gene,which lies in the positioned region and plays a pivotal role in the hair cycling process,however,found no pathogenic change in the coding region.We previously discovered 13 mutations centerlized in the second upstream open reading frame(uORF)(designated as U2HR) region,which is one of the four uORFs(refer to as U1HR,U2HR,U3HR and U4HR,respectively) in the 5'-untranslated region(UTR) of the HR gene.Seven mutations,which consist of mutations in initiation codon or termination codon,as well as one nonsense mutation and four different missense mutations,were chosen for this study to investigate their effects on the downstream HR gene expression regulation.Then we attempted to explore the underlying molecular mechanism regulating the HR gene expression via U2HR.
Cis-acting elements in 5'-UTR generally have negative regulation on expression of downstream cistron.Our previous studies have ruled out the potential effects of U3HR and U4HR on the transcriptional and translational level of downstream reporter genes, whereas disruption of initiation codon in U1HR or U2HR significantly reduced(U1HR) or increased(U2HR) the translation efficiency with nearly no effects on the transcriptional level,suggesting that U1HR and U2HR function as stimulatory and inhibitory translational control elements,respectively.Additionally,we discovered dramatic increase(2～4 folds versus wildtype(WT)) of translational level of reporter genes(Luciferase and EGFP) after transfection of the above seven mutant constructs into HeLa cell line.We found no effects on reporter gene transcriptional level when compared with WT.These findings helped us realize that loss-of-function mutations in U2HR could lead to increased main ORF(mORF) translation of the HR gene,and the underlying mechanism causing MUHH is over-expression of the HR gene.
Inhibitory uORFs may function in nucleotide sequence dependent or nascent peptide sequence dependent way.We generated three synonymous mutants at the C terminal region of U2HR coding sequcence,and no obvious changes were found in the translational level of Luciferase or EGFP reporter gene.This indicated that the translation regulation of HR gene depends on the amino acids encoded from U2HR coding sequence.
We performed site-directed mutagenesis to remove the termination codons of U1HR and U2HR and allow the fusion of EGFP sequence.The observation of efficient translation of the two uORFs in transfected cells,as well as verification of the translation of U2HR using a polyclonal antibody to U2HR,lead us to believe that the functional U1HR and U2HR seem to encode active peptides.
In the complementary test,over-expression of U2HR peptide could not recover or strengthen the inhibitory effect of U2HR on the HR gene mORF translation,indicating that translation regulation of the HR gene mORF via U2HR is the consequence of cis-acting effect.
To further determine whether each amino acid derived from U2HR coding sequence is necessary to regulate downstream mORF expression,we randomly chosed two codons in the N terminal region of U2HR to generate two missense mutants.In the following reporter gene detection,we found that these two mutants increased the translation level of reporter genes by around 2 folds,indicating that N terminal region of U2HR may play the similar role as C terminal region in downstream mORF translation regulation.
Stalling at a codon in a uORF can strongly impact downstream translation.Thus,we used site-directed mutagenesis to lengthen the U2HR from 34 to 49 codons so as to alter the amino acid context around the WT U2HR termination codon.This mutant didn't influence the translation level of the reporter genes,indicating no effects on the scanning ribosomes to move downstream.We then inserted a single nucleotide G into the immediate downstream of U2HR initiation codon,causing frame shift mutation and lengthening the codons up to 49.This mutant thus generally altered the context of amino acids of U2HR.We discovered no obvious effect of such mutant on the transcription activity of reporter gene,whereas up to 2 folds increase of the translation level was detected,consistent with mechanism of nascent peptide sequence dependent translation regulation.
If the U2HR peptide is translated in physical condition,it may influence the movement of scanning ribosomes via interactions with a certain element in the translation machinery. eIF2a,eIF2b,eIF4e and ERF1 were selected as candidates to verify their possible respective interaction with U2HR peptide via yeast two-hybrid system and mammalian two-hybrid system,but the negative results indicated no interaction between U2HR peptide and a certain candidate protein occur.
In summary,these results suggested that the expression level of HR protein in physical condition might be strictly regulated via U2HR.The loss-of-function mutation of U2HR gave rise to over expression of HR gene,and thus caused MUHH.These findings uncover the regulation mechanism underlying HR gene expression,and provide molecular basis for the pathogenesis of MUHH.
引文
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