A Dementia-Associated Risk Variant near TMEM106B Alters Chromatin Architecture and Gene Expression

Abstract

Neurodegenerative diseases pose an extraordinary threat to the world's aging population, yet no disease-modifying therapies are available. Although genome-wide association studies (GWASs) have identified hundreds of risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Here, we investigated the association between common genetic variants at the 7p21 locus and risk of the neurodegenerative disease frontotemporal lobar degeneration. We showed that variants associated with disease risk correlate with increased expression of the 7p21 gene TMEM106B and no other genes; co-localization analyses implicated a common causal variant underlying both association with disease and association with TMEM106B expression in lymphoblastoid cell lines and human brain. Furthermore, increases in the amount of TMEM106B resulted in increases in abnormal lysosomal phenotypes and cell toxicity in both immortalized cell lines and neurons. We then combined fine-mapping, bioinformatics, and bench-based approaches to functionally characterize all candidate causal variants at this locus. This approach identified a noncoding variant, rs1990620, that differentially recruits CTCF in lymphoblastoid cell lines and human brain to influence CTCF-mediated long-range chromatin-looping interactions between multiple cis-regulatory elements, including the TMEM106B promoter. Our findings thus provide an in-depth analysis of the 7p21 locus linked by GWASs to frontotemporal lobar degeneration, nominating a causal variant and causal mechanism for allele-specific expression and disease association at this locus. Finally, we show that genetic variants associated with risk of neurodegenerative diseases beyond frontotemporal lobar degeneration are enriched in CTCF-binding sites found in brain-relevant tissues, implicating CTCF-mediated gene regulation in risk of neurodegeneration more generally.

The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons

“…Overexpression of TMEM106B in cultured cells leads to enlarged dysfunctional lysosomes, as shown in several studies (Arrant et al, 2018;Brady et al, 2013;Chen-Plotkin et al, 2012;Gallagher et al, 2017;Lang et al, 2012), and TMEM106B knockdown leads to a reduced number of lysosomes (Chen-Plotkin et al, 2012;Stagi et al, 2014). Our observation of drastically enlarged, LAMP1-positive organelles in the KO situation appears to be counterintuitive in that regard.…”

“…Whether both situations are caused by the same molecular mechanism(s), however, needs to be formally proven. In this respect, it should also be noted that the lysosome enlargement is dose dependent (Gallagher et al, 2017). These findings have relevance for TMEM106B's role in disease, given that the effect of genetic variants in different disease entities (e.g., on TMEM106B levels) is still obscure.…”

“…The number of MNs in the FMN did not reveal differences between KO animals and controls even at 22 weeks of age ( Figure 1B). Since TMEM106B is a lysosomal protein and TMEM106B overexpression leads to enlarged lysosomes in cultured cells (Brady et al, 2013;Chen-Plotkin et al, 2012;Gallagher et al, 2017;Stagi et al, 2014), we analyzed lysosomes in more detail. Immunofluorescence staining for the lysosomal marker LAMP1 revealed intensely stained, large round or infolded structures in the FMN, trigeminal motor nucleus, and thalamus of Tmem106b KO mice resembling the number, distribution, and size of the vacuoles seen by hematoxylin/eosin (H&E) staining (Figures 1C and S2B).…”

CRISPR-mediated deletion of prostate cancer risk-associated CTCF loop anchors identifies repressive chromatin loops

“…Although the effects of deletion of other GWAS-related CTCF sites have not been reported, Gallager et al have proposed that a CTCF site near a SNP involved in risk for frontotemporal lobar degeneration creates a loop that enhances expression of TMEM106B ; however, because the CTCF site was not deleted, the actual effect of the site on gene expression is not known [ 38 ]. Several groups have studied other disease-related CTCF sites [ 39 ].…”

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

“…The protective effect of p.T185S in TMEM106B may be due to increased degradation of the mutant protein isoform and subsequent reduction of total TMEM106B levels [100]. Cellular assays have shown that overexpression of TMEM106B results in C9orf72-dependent lysosomal defects [14, 41], corroborating a role for reduced TMEM106B expression as protective against FTLD-TDP.…”