A de novo silencer causes elimination of MITF-M expression and profound hearing loss in pigs

BMC Biology

Research Article

Wei Sun¹  Lidong Zhao²  Weiwei Guo²  Ning Yu²  Hui Zhao²  Jianan Li²  Ke Liu²  Lili Ren²  Haijin Yi²  Zhaohui Hou²  Suoqiang Zhai²  Nan Wu²  Yue Zhang²  Shiming Yang²  Tao Cong²  Tiandong Che³  Mingzhou Li³  Qianzi Tang³  Guoqing Tang³  Shilin Tian³  Mingyao Yang³  Boyuan Sun³  Zongyi Guo⁴  Xi Long⁴  Tinghuan Zhang⁴  Liangpeng Ge⁴  Tao Wang⁴  Jiugang Zhao⁴  Xiangang Zou⁴  Zuohua Liu⁴  Siqing Chen⁴  Dan Zhu⁴  Xiaoqing Bai⁴  Liang Zhang⁴  Lan Jing⁴  Lijuan Zhang⁴  Shihua Zhang⁴  Fengming Zhang⁴  Jingyong Wang⁴  Xiaoxiang Hu⁵  Liming Ren⁵  Yiqiang Zhao⁵  Ying Guo⁵  Qingyong Meng⁵  Ning Li⁵  Yiqing Hu⁵  Jinxiu Li⁵  Zhengquan Yu⁵  Yaofeng Zhao⁵  Ran Zhang⁵  Lei Chen⁶ 

[1] Department of Communicative Disorders and Sciences, Center for Hearing and Deafness, State University of New York at Buffalo, Buffalo, New York, USA;Department of Otolaryngology, Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital, 100853, Beijing, China;Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, 625014, Ya’an, Sichuan, China;Key Laboratory of Pig Industry Sciences (Ministry of Agriculture), Chongqing Academy of Animal Science, 402460, Chongqing, China;State Key Laboratory for Agrobiotechnology, College of Biological Sciences, National Engineering Laboratory for Animal Breeding, China Agricultural University, 100193, Beijing, China;State Key Laboratory for Agrobiotechnology, College of Biological Sciences, National Engineering Laboratory for Animal Breeding, China Agricultural University, 100193, Beijing, China;Key Laboratory of Pig Industry Sciences (Ministry of Agriculture), Chongqing Academy of Animal Science, 402460, Chongqing, China;

关键词: De novo silencer;    MITF-M;    Hearing loss;    Waardenburg syndrome;    cis-;    Pig;   

DOI  :  10.1186/s12915-016-0273-2

 received in 2016-02-15, accepted in 2016-06-10,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundGenesis 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.ResultsUsing 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.ConclusionsElimination 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.

【 授权许可】

CC BY   
© Chen et al. 2016