Abstract
Trisomy of human chromosome 21 (HSA21) causes Down syndrome (DS). The trisomy does not simply result in the upregulation of HSA21--encoded genes but also leads to a genome-wide transcriptomic deregulation, which affect differently each tissue and cell type as a result of epigenetic mechanisms and protein-protein interactions.We performed a meta-analysis integrating the differential expression (DE) analyses of all publicly available transcriptomic datasets, both in human and mouse, comparing trisomic and euploid transcriptomes from different sources. We integrated all these data in a “DS network”.We found that genome wide deregulation as a consequence of trisomy 21 is not arbitrary, but involves deregulation of specific molecular cascades in which both HSA21 genes and HSA21 interactors are more consistently deregulated compared to other genes. In fact, gene deregulation happens in “clusters”, so that groups from 2 to 13 genes are found consistently deregulated. Most of these events of “co-deregulation” involve genes belonging to the same GO category, and genes associated with the same disease class. The most consistent changes are enriched in interferon related categories and neutrophil activation, reinforcing the concept that DS is an inflammatory disease. Our results also suggest that the impact of the trisomy might diverge in each tissue due to the different gene set deregulation, even though the triplicated genes are the same.Our original method to integrate transcriptomic data confirmed not only the importance of known genes, such as SOD1, but also detected new ones that could be extremely useful for generating or confirming hypotheses and supporting new putative therapeutic candidates. We created “metaDEA” an R package that uses our method to integrate every kind of transcriptomic data and therefore could be used with other complex disorders, such as cancer. We also created a user-friendly web application to query Ensembl gene IDs and retrieve all the information of their differential expression across the datasets.
Highlights
Down syndrome (DS) is the most common genetic form of intellectual disability caused by the complete or partial trisomy of human chromosome 21 (HSA21)[1]
The datasets derive from different tissues and organs
We found 6 groups of 3 co-differential expression (DE) genes that were on the same Topologically associated domain (TAD). 9 of these genes mapped on two Human chromosome 21 (HSA21) TADs
Summary
Down syndrome (DS) is the most common genetic form of intellectual disability caused by the complete or partial trisomy of human chromosome 21 (HSA21)[1] This results in a complex syndrome where intellectual disability, one of its main hallmarks, goes along with a series of phenotypes that affect the whole organism. Having three copies instead of two for each HSA21 gene would lead theoretically to an increased transcription by a factor of 1.5 [2]. This dosage imbalance hypothesis is supported by mouse models overexpressing single dosage sensitive genes such as DYRK1A [3], SOD1 [4], or HMGN1 [5] that recapitulate part of the DS phenotype. Genes are transcribed with different efficiency due to the levels of transcription factors and to the epigenetic state that influence chromatin accessibility
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have