Mechanisms of tissue and cell-type specificity in heritable traits and diseases

Hekselman, Idan; Yeger-Lotem, Esti

doi:10.1038/s41576-019-0200-9

Cited by 135 publications

(145 citation statements)

References 161 publications

Supporting

Mentioning

137

Contrasting

Order By: Relevance

“…2A) (63, 64). In some cases, this could be due to the overexpression of causal genes in their disease-manifesting tissue (32,(65)(66)(67), as we observed for muscle diseases (Fig. 2C).…”

Section: Discussionmentioning

confidence: 58%

The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones

Shemesh

Jubran

Abu-Qarn

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

The sensitivity of the protein-folding environment to chaperone disruption can be highly tissue-specific. Yet, the organization of the chaperone system across physiological human tissues has received little attention. Here, we used human tissue RNAsequencing profiles to analyze the expression and organization of chaperones across 29 main tissues. We found that relative to protein-coding genes, chaperones were significantly more ubiquitously and highly expressed across all tissues. Nevertheless, differential expression analysis revealed that most chaperones were up-or downregulated in certain tissues, suggesting that they have tissue-specific roles. In agreement, chaperones that were upregulated in skeletal muscle were highly enriched in mouse myoblasts and in nematode's muscle tissue, and overlapped significantly with chaperones that are causal for muscle diseases. We also identified a distinct subset of chaperones that formed a uniformly-expressed, cross-family core group conducting basic cellular functions that was significantly more essential for cell survival. Altogether, this suggests a layered architecture of chaperones across tissues that is composed of shared core elements that are complemented by variable elements which give rise to tissue-specific functions and sensitivities, thereby contributing to the tissue-specificity of protein misfolding diseases. Significance StatementProtein misfolding diseases, such as neurodegenerative disorders and myopathies, are often manifested in a specific tissue or even a specific cell type. Enigmatically, however, they are typically caused by mutations in widely expressed proteins. Here we focused on chaperones, the main and basic components of the protein-folding machinery of cells. Computational analyses of large scale tissue transcriptomes unveils that the chaperone system is composed of core essential elements that are uniformly expressed across tissues, and of variable elements that are differentially expressed in a tissue-specific manner. This organization allows each tissue to fit the quality control system to its specific requirements and illuminates the mechanisms that underlie a tissue's susceptibility to protein-misfolding diseases.

show abstract

“…2A) (63, 64). In some cases, this could be due to the overexpression of causal genes in their disease-manifesting tissue (32,(65)(66)(67), as we observed for muscle diseases (Fig. 2C).…”

Section: Discussionmentioning

confidence: 58%

The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones

Shemesh

Jubran

Abu-Qarn

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Given the large sample size discrepancies, from the applied TWAS analyses probably the most important findings are the pathways and genes that are associated with the trait, not necessarily the tissue/single cell where they are (the most) significant. This argument is supported by recent research (Hekselman & Yeger‐Lotem, 2020); it shows that while mis‐regulation of gene is causal in one/few tissues, these genes might be mis‐regulated in many other tissues. Consequently, even if we do not assay the gene/pathway in the causal cell types directly, we can find the mis‐regulated genes/pathways by detecting signals in some other tissues and cell types.…”

Section: Discussionmentioning

confidence: 63%

TWAS pathway method greatly enhances the number of leads for uncovering the molecular underpinnings of psychiatric disorders

Chatzinakos

Georgiadis

Lee

et al. 2020

American J of Med Genetics Pt B

View full text Add to dashboard Cite

Genetic signal detection in genome‐wide association studies (GWAS) is enhanced by pooling small signals from multiple Single Nucleotide Polymorphism (SNP), for example, across genes and pathways. Because genes are believed to influence traits via gene expression, it is of interest to combine information from expression Quantitative Trait Loci (eQTLs) in a gene or genes in the same pathway. Such methods, widely referred to as transcriptomic wide association studies (TWAS), already exist for gene analysis. Due to the possibility of eliminating most of the confounding effects of linkage disequilibrium (LD) from TWAS gene statistics, pathway TWAS methods would be very useful in uncovering the true molecular basis of psychiatric disorders. However, such methods are not yet available for arbitrarily large pathways/gene sets. This is possibly due to the quadratic (as a function of the number of SNPs) computational burden for computing LD across large chromosomal regions. To overcome this obstacle, we propose JEPEGMIX2‐P, a novel TWAS pathway method that (a) has a linear computational burden, (b) uses a large and diverse reference panel (33 K subjects), (c) is competitive (adjusts for background enrichment in gene TWAS statistics), and (d) is applicable as‐is to ethnically mixed‐cohorts. To underline its potential for increasing the power to uncover genetic signals over the commonly used nontranscriptomics methods, for example, MAGMA, we applied JEPEGMIX2‐P to summary statistics of most large meta‐analyses from Psychiatric Genetics Consortium (PGC). While our work is just the very first step toward clinical translation of psychiatric disorders, PGC anorexia results suggest a possible avenue for treatment.

show abstract

“…The analysis of developmental transcriptomes further strengthened the apparent paradox of ubiquitously expressed genes often having organ-specific phenotypes (Barshir et al, 2018;Hekselman and Yeger-Lotem, 2020;Lage et al, 2008). We could not distinguish genes associated with organ-specific phenotypes from those associated with multi-organ phenotypes based on the breadth of spatiotemporal profiles, which were similar.…”

Section: Discussionmentioning

confidence: 88%