Abstract Changes in gene expression are important for responses to abiotic stress. Transcriptome profiling of heat- or cold-stressed maize genotypes identifies many changes in transcript abundance. We used comparisons of expression responses in multiple genotypes to identify alleles with variable responses to heat or cold stress and to distinguish examples of cis- or trans-regulatory variation for stress-responsive expression changes. We used motifs enriched near the transcription start sites (TSSs) for thermal stress-responsive genes to develop predictive models of gene expression responses. Prediction accuracies can be improved by focusing only on motifs within unmethylated regions near the TSS and vary for genes with different dynamic responses to stress. Models trained on expression responses in a single genotype and promoter sequences provided lower performance when applied to other genotypes but this could be improved by using models trained on data from all three genotypes tested. The analysis of genes with cis-regulatory variation provides evidence for structural variants that result in presence/absence of transcription factor binding sites in creating variable responses. This study provides insights into cis-regulatory motifs for heat- and cold-responsive gene expression and defines a framework for developing models to predict expression responses across multiple genotypes.
more »
« less
Mapping responsive genomic elements to heat stress in a maize diversity panel
Many plant species exhibit genetic variation for coping with environmental stress. However, there are still limited approaches to effectively uncover the genomic region that regulates distinct responsive patterns of the gene across multiple varieties within the same species under abiotic stress.
By analyzing the transcriptomes of more than 100 maize inbreds, we reveal many
Footprints enriched near proximal regions of characterized heat-responsive genes in a large association panel can be utilized for prioritizing functional genomic regions that regulate genotype-specific responses under heat stress.
- NSF-PAR ID:
- 10379327
- Publisher / Repository:
- Springer Science + Business Media
- Date Published:
- Journal Name:
- Genome Biology
- Volume:
- 23
- Issue:
- 1
- ISSN:
- 1474-760X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
more » « less
Abstract Background Neuropsychiatric disorders afflict a large portion of the global population and constitute a significant source of disability worldwide. Although Genome-wide Association Studies (GWAS) have identified many disorder-associated variants, the underlying regulatory mechanisms linking them to disorders remain elusive, especially those involving distant genomic elements. Expression quantitative trait loci (eQTLs) constitute a powerful means of providing this missing link. However, most eQTL studies in human brains have focused exclusively on cis-eQTLs, which link variants to nearby genes (i.e., those within 1 Mb of a variant). A complete understanding of disease etiology requires a clearer understanding of trans-regulatory mechanisms, which, in turn, entails a detailed analysis of the relationships between variants and expression changes in distant genes.
Methods By leveraging large datasets from the PsychENCODE consortium, we conducted a genome-wide survey of trans-eQTLs in the human dorsolateral prefrontal cortex. We also performed colocalization and mediation analyses to identify mediators in trans-regulation and use trans-eQTLs to link GWAS loci to schizophrenia risk genes.
Results We identified ~80,000 candidate trans-eQTLs (at FDR<0.25) that influence the expression of ~10K target genes (i.e., “trans-eGenes”). We found that many variants associated with these candidate trans-eQTLs overlap with known cis-eQTLs. Moreover, for >60% of these variants (by colocalization), the cis-eQTL’s target gene acts as a mediator for the trans-eQTL SNP's effect on the trans-eGene, highlighting examples of cis-mediation as essential for trans-regulation. Furthermore, many of these colocalized variants fall into a discernable pattern wherein cis-eQTL’s target is a transcription factor or RNA-binding protein, which, in turn, targets the gene associated with the candidate trans-eQTL. Finally, we show that trans-regulatory mechanisms provide valuable insights into psychiatric disorders: beyond what had been possible using only cis-eQTLs, we link an additional 23 GWAS loci and 90 risk genes (using colocalization between candidate trans-eQTLs and schizophrenia GWAS loci).
Conclusions We demonstrate that the transcriptional architecture of the human brain is orchestrated by both cis- and trans-regulatory variants and found that trans-eQTLs provide insights into brain-disease biology.
-
more » « less
Abstract Background Current evidence suggests that
cis -regulatory elements controlling gene expression may be the predominant target of natural selection in humans and other species. Detecting selection acting on these elements is critical to understanding evolution but remains challenging because we do not know which mutations will affect gene regulation.Results To address this, we devise an approach to search for lineage-specific selection on three critical steps in transcriptional regulation: chromatin activity, transcription factor binding, and chromosomal looping. Applying this approach to lymphoblastoid cells from 831 individuals of either European or African descent, we find strong signals of differential chromatin activity linked to gene expression differences between ancestries in numerous contexts, but no evidence of functional differences in chromosomal looping. Moreover, we show that enhancers rather than promoters display the strongest signs of selection associated with sites of differential transcription factor binding.
Conclusions Overall, our study indicates that some
cis -regulatory adaptation may be more easily detected at the level of chromatin than DNA sequence. This work provides a vast resource of genomic interaction data from diverse human populations and establishes a novel selection test that will benefit future study of regulatory evolution in humans and other species. -
The evolution of transcriptional regulatory mechanisms is central to how stress response and tolerance differ between species. However, it remains largely unknown how divergence in cis-regulatory sites and, subsequently, transcription factor (TF) binding specificity contribute to stress-responsive expression divergence, particularly between wild and domesticated spe-cies. By profiling wound-responsive gene transcriptomes in wild Solanum pennellii and do-mesticated S. lycopersicum, we found extensive wound-response divergence and identified 493 S. lycopersicum and 278 S. pennellii putative cis-regulatory elements (pCREs) that were predictive of wound-responsive gene expression. Only 24-52% of these wound-response pCREs (depending on wound-response patterns) were consistently enriched in the putative promoter regions of wound-responsive genes across species. In addition, between these two species, their differences in pCRE site sequences were significantly and positively correlated with differences in wound-responsive gene expression. Furthermore, ~11-39% of pCREs were specific to only one of the species and likely bound by TFs from different families. These findings indicate substantial regulatory divergence in these two plant species that di-verged ~3-7 million years ago. Our study provides insights into the mechanistic basis of how the transcriptional response to wounding is regulated and, importantly, the contribution of cis-regulatory components to variation in wound-responsive gene expression between a wild and a domesticated plant species.more » « less
-
more » « less
Abstract The Heat Shock Factor (HSF) transcription factor family is a central and required component of plant heat stress responses and acquired thermotolerance. The HSF family has dramatically expanded in plant lineages, often including a repertoire of 20 or more genes. Here we assess and compare the composition, heat responsiveness, and chromatin profiles of the HSF families in maize and
Setaria viridis Setaria ), two model C4 panicoid grasses. Both species encode a similar number of HSFs, and examples of both conserved and variable expression responses to a heat stress event were observed between the two species. Chromatin accessibility and genome‐wide DNA‐binding profiles were generated to assess the chromatin of HSF family members with distinct responses to heat stress. We observed significant variability for both chromatin accessibility and promoter occupancy within similarly regulated sets of HSFs betweenSetaria and maize, as well as between syntenic pairs of maize HSFs retained following its most recent genome duplication event. Additionally, we observed the widespread presence of TF binding at HSF promoters in control conditions, even at HSFs that are only expressed in response to heat stress. TF‐binding peaks were typically near putative HSF‐binding sites in HSFs upregulated in response to heat stress, but not in stable or not expressed HSFs. These observations collectively support a complex scenario of expansion and subfunctionalization within this transcription factor family and suggest that within‐family HSF transcriptional regulation is a conserved, defining feature of the family.
