Hypothalamic transcriptomes of 99 mouse strains reveal trans eQTL hotspots, splicing QTLs and novel non-coding genes

Hasin-Brumshtein, Yehudit; Ah, Khan; Hormozdiari, Farhad; Pan, Calvin; Parks, Brian W.; Petyuk, Vladislav; Piehowski, Paul; Brümmer, Anneke; Pellegrini, Matteo; Xiao, Xinshu; Eskin, Eleazar; Smith, Richard; Lusis, Aldons J.; Smith, Desmond J.

doi:10.7554/elife.15614

Cited by 38 publications

(37 citation statements)

References 71 publications

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“…Previous work from our lab and others have shown that gene-by-environment interactions can impact both gene expression and complex traits [23,24,25,26,27,28]. While splicing QTLs have been identified both in humans and mice [22,29,30,31], less is known about how gene-by-environment interactions may affect RNA processing. The first step to address this question is to characterize RNA processing in response to environmental perturbations.…”

Section: Introductionmentioning

confidence: 96%

Environmental perturbations lead to extensive directional shifts in RNA processing

Richards

Watza

Findley

et al. 2017

Preprint

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Environmental perturbations have large effects on both organismal and cellular traits, including gene expression, but the extent to which the environment affects RNA processing remains largely uncharacterized. Recent studies have identified a large number of genetic variants associated with variation in RNA processing that also have an important role in complex traits; yet we do not know in which contexts the different underlying isoforms are used. Here, we comprehensively characterized changes in RNA processing events across 89 environments in five human cell types and identified 15,300 event shifts (FDR = 15%) comprised of eight event types in over 4,000 genes. Many of these changes occur consistently in the same direction across conditions, indicative of global regulation by trans factors. Accordingly, we demonstrate that environmental modulation of splicing factor binding predicts shifts in intron retention, and that binding of transcription factors predicts shifts in AFE usage in response to specific treatments. We validated the mechanism hypothesized for AFE in two independent datasets. Using ATAC-seq, we found altered binding of 64 factors in response to selenium at sites of AFE shift, including ELF2 and other factors in the ETS family. We also performed AFE QTL mapping in 373 individuals and found an enrichment for SNPs predicted to disrupt binding of the ELF2 factor. Together, these results demonstrate that RNA processing is dramatically changed in response to environmental perturbations through specific mechanisms regulated by trans factors. 1 peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/119974 doi: bioRxiv preprint first posted online Mar. 24, 2017; Author SummaryChanges in a cell's environment and genetic variation have been shown to impact gene expression. Here, we demonstrate that environmental perturbations also lead to extensive changes in alternative RNA processing across a large number of cellular environments that we investigated. These changes often occur in a non-random manner. For example, many treatments lead to increased intron retention and usage of the downstream first exon. We also show that the changes to first exon usage are likely dependent on changes in transcription factor binding. We provide support for this hypothesis by considering how first exon usage is affected by disruption of binding due to treatment with selenium. We further validate the role of a specific factor by considering the effect of genetic variation in its binding sites on first exon usage. These results help to shed light on the vast number of changes that occur in response to environmental stimuli and will likely aid in understanding the impact of compounds to which we are daily exposed.

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Section: Introductionmentioning

confidence: 96%

Environmental perturbations lead to extensive directional shifts in RNA processing

Richards

Watza

Findley

et al. 2017

Preprint

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“…We also identified 134 Supplemental Fig.S5; Supplemental Table S4). 135 Previous studies in model organisms have identified trans-eQTLs that regulate the expression of 136 many genes (Chesler et al 2005;Hasin-Brumshtein et al 2016;Albert and Kruglyak 2015); we refer to 137 these as 'master eQTLs'. We identified several master eQTLs, including one on chromosome 12 (70.19-138 Figure 4.…”

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confidence: 99%

Genome wide association analysis in a mouse advanced intercross line

Gonzales

Seo

Hernandez-Cordero

et al. 2017

Preprint

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Genome wide association analyses (GWAS) in model organisms have numerous advantages compared 2 to human GWAS, including the ability to use populations with well-defined genetic diversity, the ability to 3 collect tissue for gene expression analysis and the ability to perform experimental manipulations. We 4 examined behavioral, physiological, and gene expression traits in 1,063 male and female mice from a 5 50-generation intercross between two inbred strains (LG/J and SM/J). We used genotyping by 6 sequencing in conjunction with whole genome sequence data from the two founder strains to obtain 7 genotypes at 4.3 million SNPs. As expected, all alleles were common (mean MAF=0.35) and linkage 8 disequilibrium degraded rapidly, providing excellent power and sub-megabase mapping precision. We 9 identified 126 genome-wide significant loci for 50 traits and integrated this information with 7,081 cis-10 eQTLs and 1,476 trans-eQTLs identified in hippocampus, striatum and prefrontal cortex. We replicated 11 several loci that were identified using an earlier generation of this intercross, including an association 12 between locomotor activity and a locus containing a single gene, Csmd1. We also showed that Csmd1 13 mutant mice recapitulated the locomotor phenotype. Our results demonstrate the utility of this population, 14 identify numerous novel associations, and provide examples of replication in an independent cohort, 15 which is customary in human genetics, and replication by experimental manipulation, which is a unique 16 advantage of model organisms.

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“…Moreover, Dong et al (2009) [90] show that specific patterns of gene expression are associated with specific domains where distinct neural projection patterns emerge within the hippocampus, and Wolf et al (2011) [460] show that there is a strong predictive association of neural connections and gene expression within specific brain regions (also see [417]). Superimposed on this complexity are strain-dependent variations in the sexual dimorphism of certain brain nuclei [274, 366], and differences in how gene expression networks in the brain are modulated as a result of expression quantitative trait loci (eQTLs) that are sex-specific [293] (also see [151, 327]). Thus, it is important to consider just what we as scientists lose if we endeavor to extract molecular information from the brain without attempting to preserve the provenance of where the extraction took place.…”

Section: Why Does Location Matter?mentioning

confidence: 99%

Mapping Molecular Datasets Back to the Brain Regions They are Extracted from: Remembering the Native Countries of Hypothalamic Expatriates and Refugees

Khan

Grant

Martínez

et al. 2018

Advances in Neurobiology

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Hypothalamic transcriptomes of 99 mouse strains reveal trans eQTL hotspots, splicing QTLs and novel non-coding genes

Cited by 38 publications

References 71 publications

Environmental perturbations lead to extensive directional shifts in RNA processing

Environmental perturbations lead to extensive directional shifts in RNA processing

Genome wide association analysis in a mouse advanced intercross line

Mapping Molecular Datasets Back to the Brain Regions They are Extracted from: Remembering the Native Countries of Hypothalamic Expatriates and Refugees

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