Dataset Information

Complex genetic and epigenetic regulation deviates gene expression from a unifying global transcriptional program.

ABSTRACT: Environmental or genetic perturbations lead to gene expression changes. While most analyses of these changes emphasize the presence of qualitative differences on just a few genes, we now know that changes are widespread. This large-scale variation has been linked to the exclusive influence of a global transcriptional program determined by the new physiological state of the cell. However, given the sophistication of eukaryotic regulation, we expect to have a complex architecture of specific control affecting this program. Here, we examine this architecture. Using data of Saccharomyces cerevisiae expression in different nutrient conditions, we first propose a five-sector genome partition, which integrates earlier models of resource allocation, as a framework to examine the deviations from the global control. In this scheme, we recognize invariant genes, whose regulation is dominated by physiology, specific genes, which substantially depart from it, and two additional classes that contain the frequently assumed growth-dependent genes. Whereas the invariant class shows a considerable absence of specific regulation, the rest is enriched by regulation at the level of transcription factors (TFs) and epigenetic modulators. We nevertheless find markedly different strategies in how these classes deviate. On the one hand, there are TFs that act in a unique way between partition constituents, and on the other, the action of chromatin modifiers is significantly diverse. The balance between regulatory strategies ultimately modulates the action of the general transcription machinery and therefore limits the possibility of establishing a unifying program of expression change at a genomic scale.

SUBMITTER: Chagoyen M

PROVIDER: S-EPMC6764696 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Complex genetic and epigenetic regulation deviates gene expression from a unifying global transcriptional program.

Chagoyen Mónica M Poyatos Juan F JF

PLoS computational biology 20190917 9

Environmental or genetic perturbations lead to gene expression changes. While most analyses of these changes emphasize the presence of qualitative differences on just a few genes, we now know that changes are widespread. This large-scale variation has been linked to the exclusive influence of a global transcriptional program determined by the new physiological state of the cell. However, given the sophistication of eukaryotic regulation, we expect to have a complex architecture of specific contr ...[more]

PMID: 31527866

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Project description:Background:Preeclampsia (PE) is a heterogeneous, hypertensive disorder of pregnancy, with no robust biomarkers or effective treatments. We hypothesized that this heterogeneity is due to the existence of multiple subtypes of PE and, in support of this hypothesis, we recently identified five clusters of placentas within a large gene expression microarray dataset (N = 330), of which four (clusters 1, 2, 3, and 5) contained a substantial number of PE samples. However, while transcriptional analysis of placentas can subtype patients, we propose that the addition of epigenetic information could discern gene regulatory mechanisms behind the distinct PE pathologies, as well as identify clinically useful potential biomarkers. Results:We subjected 48 of our samples from transcriptional clusters 1, 2, 3, and 5 to Infinium HumanMethylation450 arrays. Samples belonging to transcriptional clusters 1-3 still showed visible relationships to each other by methylation, but cluster 5, with known chromosomal abnormalities, no longer formed a cohesive group. Within transcriptional clusters 2 and 3, controlling for fetal sex and gestational age in the identification of differentially methylated sites, compared to the healthier cluster 1, dramatically reduced the number of significant sites, but increased the percentage that demonstrated a strong linear correlation with gene expression (from 5% and 2% to 9% and 8%, respectively). Locations exhibiting a positive relationship between methylation and gene expression were most frequently found in CpG open sea enhancer regions within the gene body, while those with a significant negative correlation were often annotated to the promoter in a CpG shore region. Integrated transcriptome and epigenome analysis revealed modifications in TGF-beta signaling, cell adhesion, oxidative phosphorylation, and metabolism pathways in cluster 2 placentas, and aberrations in antigen presentation, allograft rejection, and cytokine-cytokine receptor interaction in cluster 3 samples. Conclusions:Overall, we have established DNA methylation alterations underlying a portion of the transcriptional development of "canonical" PE in cluster 2 and "immunological" PE in cluster 3. However, a significant number of the observed methylation changes were not associated with corresponding changes in gene expression, and vice versa, indicating that alternate methods of gene regulation will need to be explored to fully comprehend these PE subtypes.

Dataset Information

Complex genetic and epigenetic regulation deviates gene expression from a unifying global transcriptional program.

Publications

Complex genetic and epigenetic regulation deviates gene expression from a unifying global transcriptional program.

Similar Datasets

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