An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.
An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.
复制标题
少突胶质细胞沉默元件是核纤层蛋白 B1 结构变异致病影响的基础。
DOI：
10.1101/2023.08.03.551473
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Gutowski,Nichola
中科院分区：
文献类型：
--
作者：
Nmezi,Bruce;Bey,GuillermoRodriguez;Oranburg,TaliaDeFrancesco;Dudnyk,Kseniia;Lardo,SantanaM;Herdman,Nathan;Jacko,Anastasia;Rubio,Sandy;Alcocer,EmanuelLoeza;Kofler,Julia;Kim,Dongkyeong;Rankin,Julia;Kivuva,Emma;Gutowski,Nichola
非编码调控元件的作用以及它们如何对疾病表型的组织类型特异性做出贡献还知之甚少。常染色体显性遗传性脑白质营养不良(ADLD)是一种以广泛的中枢神经系统脱髓鞘为特征的致死性、成人起病的神经系统疾病。大多数ADLD是由涉及lamin B1基因(LMNB1)的串联基因组复制引起的，但也有一小部分是由该基因上游的基因组缺失引起的。利用最近发现的携带LMNB1基因复制但没有脱髓鞘的家系、ADLD患者组织、CRISPR编辑的细胞系和小鼠模型的数据，我们已经确定了一个在ADLD患者中丢失的、特异性靶向表达的寡突胶质细胞的沉默元件。该元件由CTCF结合位点组成，介导涉及LMNB1的三维染色质环和PRC2转录抑制物复合体的招募。ADLD中沉默元件的缺失确定了非编码调节元件在组织特异性和疾病病因中的作用。
The role of non-coding regulatory elements and how they might contribute to tissue type specificity of disease phenotypes is poorly understood. Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult-onset, neurological disorder that is characterized by extensive CNS demyelination. Most cases of ADLD are caused by tandem genomic duplications involving the lamin B1 gene (LMNB1) while a small subset are caused by genomic deletions upstream of the gene. Utilizing data from recently identified families that carryLMNB1gene duplications but do not exhibit demyelination, ADLD patient tissues, CRISPR edited cell lines and mouse models, we have identified a silencer element that is lost in ADLD patients and that specifically targets expression to oligodendrocytes. This element consists of CTCF binding sites that mediate three-dimensional chromatin looping involvingLMNB1and the recruitment of the PRC2 transcriptional repressor complex. Loss of the silencer element in ADLD identifies a role for non-coding regulatory elements in tissue specificity and disease causation.