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| Status |
Public on Nov 19, 2019 |
| Title |
Analysis of regulatory element evolution between human and mouse reveals a lack of cis-trans compensation |
| Organisms |
Homo sapiens; Mus musculus; synthetic construct |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| Summary |
Gene expression differences between species are driven by both cis and trans effects. Whereas cis effects on gene expression are due to nearby genetic variants, trans effects are due to distal genetic variants that affect diffusible elements such as transcription factors. However, as previous studies have mostly assessed the impacts of cis and trans effects at the gene level, how cis and trans effects differentially impact regulatory elements such as enhancers and promoters remains poorly understood. Here, we used massively parallel reporter assays to directly measure cis and trans effects between human and mouse embryonic stem cells at thousands of individual regulatory elements, including enhancers as well as promoters of both protein-coding and long non-coding RNA genes. Our approach revealed that cis effects are widespread across regulatory elements, and the strongest cis effects are associated with the disruption of motifs recognized by strong transcriptional activators. Conversely, we found that trans effects are rare but stronger in enhancers than promoters, and can be attributed to a subset of transcription factors that are differentially expressed between human and mouse. While previous gene-based studies have found extensive co-occurrence of cis and trans effects in opposite directions that stabilize gene expression between species—or compensatory cis-trans effects—we find that cis-trans compensation is uncommon within individual regulatory elements. Moreover, regulatory elements that do show compensatory cis-trans effects are often less redundant than regulatory elements lacking compensatory cis-trans effects. Thus, our results are consistent with a model wherein compensatory cis-trans effects occur more often through crosstalk between multiple redundant regulatory elements than within a single individual regulatory element. Together, these results indicate that studying the evolution of individual regulatory elements is pivotal to understand the tempo and mode of gene expression evolution.
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| Overall design |
We performed two experiments: (1) a massively parallel reporter assay (MPRA) to assess othologous regulatory elements in hESCs and mESCs, and (2) RNA-sequencing of hESCs and mESCs. For the MPRA data, we provide raw fastqs as well as barcode counts. For the RNA-seq data, we provide raw fastqs and gene featureCounts.
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| Contributor(s) |
Mattioli K, Oliveros W, Gerhardinger C, Andergassen D, Maass PG, Rinn JL, Melé M |
| Citation(s) |
32819422 |
| |
| Submission date |
Nov 18, 2019 |
| Last update date |
Aug 31, 2020 |
| Contact name |
Martha L. Bulyk |
| Organization name |
Brigham and Women's Hospital
|
| Department |
Division of Genetics
|
| Lab |
Bulyk Lab
|
| Street address |
77 Avenue Louis Pasteur, Rm 468
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (3) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL19604 |
Illumina HiSeq 2500 (synthetic construct) |
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| Samples (31)
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| Relations |
| BioProject |
PRJNA590195 |
| SRA |
SRP230424 |
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