Hidden DNA switch explains why brain disease strikes only some carriers
Scientists have identified a regulatory element that controls where a faulty gene causes neurological damage, explaining why some people with the same mutation develop fatal demyelination while others don't. The discovery reshapes how researchers think about genetic disease and could open new treatment angles for brain disorders tied to gene regulation rather than the genes themselves.
Originaltitel: An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants
<p>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 (<em>LMNB1</em>) while a small subset are caused by genomic deletions upstream of the gene. Utilizing data from recently identified families that carry <em>LMNB1</em> gene 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 involving <em>LMNB1</em> and 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.</p>