A de novo silencer causes elimination of MITF-M expression and profound hearing loss in pigs.
A de novo silencer causes elimination of MITF-M expression and profound hearing loss in pigs.
复制标题
从头消音器导致 MITF-M 表达消除并导致猪严重听力损失
DOI：
10.1186/s12915-016-0273-2
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发表时间：
2016-06-27
期刊：
影响因子：
5.4
通讯作者：
Li N
中科院分区：
文献类型：
--
作者：
Chen L;Guo W;Ren L;Yang M;Zhao Y;Guo Z;Yi H;Li M;Hu Y;Long X;Sun B;Li J;Zhai S;Zhang T;Tian S;Meng Q;Yu N;Zhu D;Tang G;Tang Q;Ren L;Liu K;Zhang S;Che T;Yu Z;Wu N;Jing L;Zhang R;Cong T;Chen S;Zhao Y;Zhang Y;Bai X;Guo Y;Zhao L;Zhang F;Zhao H;Zhang L;Hou Z;Zhao J;Li J;Zhang L;Sun W;Zou X;Wang T;Ge L;Liu Z;Hu X;Wang J;Yang S;Li N
背景：新基因调控模块的发生在很大程度上负责形态和功能的进化。与改变现有顺式调控元件的基因组事件(如转座、启动子切换或共选)相比，新的顺式调节元件(CRE)的从头产生要罕见得多。到目前为止，只有一例在鱼类中报告了从头产生的病例，并且没有涉及表型改变。然而，这一事件可能发生在其他动物中，并有助于推动遗传/表型变异。结果：使用以前没有表征的自发性听力损失的猪模型，我们进行了基因定位和突变筛查，以确定表型的遗传基础。我们在小眼炎相关转录因子(MITF)基因的黑素细胞特异性启动子的非调节区发现了突变，该突变产生了一种新的沉默因子。随之而来的MITF-M亚型表达的缺失导致耳蜗纹血管纹中间细胞的早期退化和严重的听力损失，以及色素脱失，所有这些都类似于人类典型的Waardenburg综合征的表型。该突变仅影响MITF-M，而不影响其他异构体。结论：仅消除MITF-M亚型就足以导致耳聋和色素脱失。据我们所知，这项研究首次提供了在哺乳动物中产生全身功能效应的从头Cre的证据。
Background:Genesis of novel gene regulatory modules is largely responsible for morphological and functional evolution. De novo generation of novel cis-regulatory elements (CREs) is much rarer than genomic events that alter existing CREs such as transposition, promoter switching or co-option. Only one case of de novo generation has been reported to date, in fish and without involvement of phenotype alteration. Yet, this event likely occurs in other animals and helps drive genetic/phenotypic variation.Results:Using a porcine model of spontaneous hearing loss not previously characterized we performed gene mapping and mutation screening to determine the genetic foundation of the phenotype. We identified a mutation in the non-regulatory region of the melanocyte-specific promoter of microphthalmia-associated transcription factor (MITF) gene that generated a novel silencer. The consequent elimination of expression of the MITF-M isoform led to early degeneration of the intermediate cells of the cochlear stria vascularis and profound hearing loss, as well as depigmentation, all of which resemble the typical phenotype of Waardenburg syndrome in humans. The mutation exclusively affected MITF-M and no other isoforms. The essential function of Mitf-m in hearing development was further validated using a knock-out mouse model.Conclusions:Elimination of the MITF-M isoform alone is sufficient to cause deafness and depigmentation. To our knowledge, this study provides the first evidence of a de novo CRE in mammals that produces a systemic functional effect.