Microbial control of host gene regulation and the evolution of host–microbiome interactions in primates

Recent comparative studies have found evidence consistent with the action of natural selection on gene regulation across primate species. Other recent work has shown that the microbiome can regulate host gene expression in a wide range of relevant tissues, leading to downstream effects on immunity, metabolism and other biological systems in the host. In primates, even closely related host species can have large differences in microbiome composition. One potential consequence of these differences is that host species-specific microbial traits could lead to differences in gene expression that influence primate physiology and adaptation to local environments. Here, we will discuss and integrate recent findings from primate comparative genomics and microbiome research, and explore the notion that the microbiome can influence host evolutionary dynamics by affecting gene regulation across primate host species. This article is part of the theme issue ‘The role of the microbiome in host evolution’.

Download Full-text

Immune Gene Expression Covaries with Gut Microbiome Composition in Stickleback

mBio ◽

10.1128/mbio.00145-21 ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Lauren E. Fuess ◽

Stijn den Haan ◽

Fei Ling ◽

Jesse N. Weber ◽

Natalie C. Steinel ◽

...

Keyword(s):

Gene Expression ◽

Microbial Communities ◽

Gut Microbiome ◽

Alpha Diversity ◽

Host Immunity ◽

Host Gene ◽

Microbiota Composition ◽

Host Gene Expression ◽

Microbiome Composition ◽

Immune Genes

ABSTRACT Commensal microbial communities have immense effects on their vertebrate hosts, contributing to a number of physiological functions, as well as host fitness. In particular, host immunity is strongly linked to microbiota composition through poorly understood bi-directional links. Gene expression may be a potential mediator of these links between microbial communities and host function. However, few studies have investigated connections between microbiota composition and expression of host immune genes in complex systems. Here, we leverage a large study of laboratory-raised fish from the species Gasterosteus aculeatus (three-spined stickleback) to document correlations between gene expression and microbiome composition. First, we examined correlations between microbiome alpha diversity and gene expression. Our results demonstrate robust positive associations between microbial alpha diversity and expression of host immune genes. Next, we examined correlations between host gene expression and abundance of microbial taxa. We identified 15 microbial families that were highly correlated with host gene expression. These families were all tightly correlated with host expression of immune genes and processes, falling into one of three categories—those positively correlated, negatively correlated, and neutrally related to immune processes. Furthermore, we highlight several important immune processes that are commonly associated with the abundance of these taxa, including both macrophage and B cell functions. Further functional characterization of microbial taxa will help disentangle the mechanisms of the correlations described here. In sum, our study supports prevailing hypotheses of intimate links between host immunity and gut microbiome composition. IMPORTANCE Here, we document associations between host gene expression and gut microbiome composition in a nonmammalian vertebrate species. We highlight associations between expression of immune genes and both microbiome diversity and abundance of specific microbial taxa. These findings support other findings from model systems which have suggested that gut microbiome composition and host immunity are intimately linked. Furthermore, we demonstrate that these correlations are truly systemic; the gene expression detailed here was collected from an important fish immune organ (the head kidney) that is anatomically distant from the gut. This emphasizes the systemic impact of connections between gut microbiota and host immune function. Our work is a significant advancement in the understanding of immune-microbiome links in nonmodel, natural systems.

Download Full-text

Host Gene Regulation by Transposable Elements: The New, the Old and the Ugly

Viruses ◽

10.3390/v12101089 ◽

2020 ◽

Vol 12 (10) ◽

pp. 1089 ◽

Cited By ~ 2

Author(s):

Rocio Enriquez-Gasca ◽

Poppy A. Gould ◽

Helen M. Rowe

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Transposable Elements ◽

Essential Gene ◽

Expression Patterns ◽

Genetic Material ◽

Endogenous Retroviruses ◽

Host Gene ◽

New Genes ◽

Host Genes

The human genome has been under selective pressure to evolve in response to emerging pathogens and other environmental challenges. Genome evolution includes the acquisition of new genes or new isoforms of genes and changes to gene expression patterns. One source of genome innovation is from transposable elements (TEs), which carry their own promoters, enhancers and open reading frames and can act as ‘controlling elements’ for our own genes. TEs include LINE-1 elements, which can retrotranspose intracellularly and endogenous retroviruses (ERVs) that represent remnants of past retroviral germline infections. Although once pathogens, ERVs also represent an enticing source of incoming genetic material that the host can then repurpose. ERVs and other TEs have coevolved with host genes for millions of years, which has allowed them to become embedded within essential gene expression programmes. Intriguingly, these host genes are often subject to the same epigenetic control mechanisms that evolved to combat the TEs that now regulate them. Here, we illustrate the breadth of host gene regulation through TEs by focusing on examples of young (The New), ancient (The Old), and disease-causing (The Ugly) TE integrants.

Download Full-text

Intra- and Inter-Specific Investigations of Skeletal DNA Methylation and Femur Morphology in Primates

10.1101/554618 ◽

2019 ◽

Author(s):

Genevieve Housman ◽

Ellen E. Quillen ◽

Anne C. Stone

Keyword(s):

Dna Methylation ◽

Gene Regulation ◽

Biological Effects ◽

Epigenetic Mechanism ◽

Primate Species ◽

Phylogenetic Groups ◽

Skeletal Morphology ◽

Specific Variation ◽

Morphological Variants ◽

Species Specific

AbstractObjectivesEpigenetic mechanisms influence the development and maintenance of complex phenotypes and may also contribute to the evolution of species-specific phenotypes. With respect to skeletal traits, little is known about the gene regulation underlying these hard tissues or how tissue-specific patterns are associated with bone morphology or vary among species. To begin exploring these topics, this study evaluates one epigenetic mechanism, DNA methylation, in skeletal tissues from five nonhuman primate species which display anatomical and locomotor differences representative of their phylogenetic groups.Materials and MethodsFirst, we test whether intra-specific variation in skeletal DNA methylation is associated with intra-specific variation in femur morphology. Second, we identify inter-specific differences in DNA methylation and assess whether these lineage-specific patterns may have contributed to species-specific morphologies. Specifically, we use the Illumina Infinium MethylationEPIC BeadChip to identify DNA methylation patterns in femur trabecular bone from baboons (n=28), macaques (n=10), vervets (n=10), chimpanzees (n=4), and marmosets (n=6).ResultsSignificant differentially methylated positions (DMPs) were associated with a subset of morphological variants, but these likely have small biological effects and may be confounded by other variables associated with morphological variation. Conversely, several species-specific DMPs were identified, and these are found in genes enriched for functions associated with complex skeletal traits.DiscussionOverall, these findings reveal that while intra-specific epigenetic variation is not readily associated with skeletal morphology differences, some inter-specific epigenetic differences in skeletal tissues exist and may contribute to evolutionarily distinct phenotypes. This work forms a foundation for future explorations of gene regulation and skeletal trait evolution in primates.

Download Full-text

Gene expression evolution in pattern-triggered immunity within Arabidopsis thaliana and across Brassicaceae species

10.1101/2020.07.29.227397 ◽

2020 ◽

Author(s):

Thomas M. Winkelmüller ◽

Frederickson Entila ◽

Shajahan Anver ◽

Anna Piasecka ◽

Baoxing Song ◽

...

Keyword(s):

Gene Expression ◽

Arabidopsis Thaliana ◽

Binding Sites ◽

Microbial Control ◽

Purifying Selection ◽

Wrky Transcription Factor ◽

Specific Gene ◽

Specific Expression ◽

Brassicaceae Species ◽

Species Specific

AbstractPlants recognize surrounding microbes by sensing microbe-associated molecular patterns (MAMPs) to activate pattern-triggered immunity (PTI). Despite their significance for microbial control, the evolution of PTI responses remains largely uncharacterized. Employing comparative transcriptomics of six Arabidopsis thaliana accessions and three additional Brassicaceae species for PTI responses to the MAMP flg22, we identified a set of genes with expression changes under purifying selection in the Brassicaceae species and genes exhibiting species-specific expression signatures. Variation in flg22-triggered transcriptome and metabolome responses across Brassicaceae species was incongruent with their phylogeny while expression changes were strongly conserved within A. thaliana, suggesting directional selection for some species-specific gene expression. We found the enrichment of WRKY transcription factor binding sites in 5’-regulatory regions in conserved and species-specific responsive genes, linking the emergence of WRKY-binding sites with the evolution of gene responses in PTI. Our findings advance our understanding of transcriptome evolution during biotic stress.

Download Full-text

Ecological trait differences are associated with gene expression in the primary visual cortex of primates

10.21203/rs.2.20778/v1 ◽

2020 ◽

Author(s):

Trisha Marie Zintel ◽

John J. Ely ◽

Mary Ann Raghanti ◽

William D. Hopkins ◽

Patrick R. Hof ◽

...

Keyword(s):

Gene Expression ◽

Visual Cortex ◽

Visual System ◽

Color Vision ◽

Primary Visual Cortex ◽

Brain Regions ◽

Primate Species ◽

Tissue Samples ◽

Synaptic Signaling ◽

Species Specific

Abstract Background : Primate species differ drastically from most other mammals in how they visually perceive their environments, which is important for foraging, predator avoidance, and detection of social cues. Although it is well established that primates display diversity in color vision and various ecological specializations, it is not understood how visual system characteristics and ecological adaptations may be associated with gene expression levels within the primary visual cortex (V1). Results : We performed RNA-Seq on V1 tissue samples from 28 individuals, representing 13 species of anthropoid primates, including hominoids, cercopithecoids, and platyrrhines. We explored trait-dependent differential expression (DE) by contrasting species with different visual system phenotypes and ecological traits. Between 4-25% of genes were determined to be differentially expressed in primates that varied in type of color vision (trichromatic or polymorphic di/trichromatic), habitat use (arboreal or terrestrial), group size (large or small), and primary diet (frugivorous, folivorous, or omnivorous). DE analyses revealed that humans and chimpanzees showed the most marked differences between any two species, despite the fact that they are only separated by 6-8 million years of independent evolution. Pathway enrichment analyses of DE genes demonstrated that changes in cellular metabolic pathways (e.g. glycolysis) contribute to altered gene expression in primate V1 more than neuron-specific processes (e.g. synaptic signaling). The exception to this trend is between human and chimpanzee, which exhibited DE for a number of processes related to cholinergic and GABAergic synaptic signaling. Conclusions : Our data significantly expand the number of primate species for which V1 expression data exists. These results show a combination of species-specific and trait-dependent differences in the evolution of gene expression in primate V1. We also show that human-specific changes in brain gene expression extend to the primary visual cortex in a manner similar to that reported of other brain regions.

Download Full-text

Human papillomavirus 16 E2 regulates keratinocyte gene expression relevant to cancer and the viral life cycle

10.1101/461715 ◽

2018 ◽

Cited By ~ 2

Author(s):

Michael R Evans ◽

Claire D James ◽

Molly L Bristol ◽

Tara J Nulton ◽

Xu Wang ◽

...

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Radiation Therapy ◽

Life Cycle ◽

Innate Immune ◽

Host Gene ◽

Host Gene Expression ◽

Immune Genes ◽

E6 And E7 ◽

Innate Immune Genes

AbstractHuman papillomaviruses (HPV) are causative agents in ano-genital and oropharyngeal cancers. The virus must reprogram host gene expression to promote infection, and E6 and E7 contribute to this via targeting of cellular transcription factors including p53 and pRb, respectively. The HPV16 E2 protein regulates host gene expression in U2OS cells and in this study we extend these observations into TERT immortalized oral keratinocytes (NOKs) that are capable of supporting late stages of the HPV16 life cycle. We observed repression of innate immune genes by E2 that are also repressed by the intact HPV16 genome in NOKs. RNA-seq data identified 167 up and 395 downregulated genes by E2; there was a highly significant overlap of the E2 regulated genes with those regulated by the intact HPV16 genome in the same cell type. siRNA targeting of E2 reversed repression of E2 targeted genes. The ability of E2 to repress innate immune genes was confirmed in an ano-genital immortalized keratinocyte cell line, N/Tert-1. We present analysis of data from The Cancer Genome Atlas (TCGA) for HPV16 positive and negative head and neck cancers (HNC) suggesting that E2 plays a role in regulation of the host genome in cancers. Patients with HPV16 positive HNC with a loss of E2 expression exhibit a worse clinical outcome and we discuss how this could, at least partially, be related to the loss of E2 host gene regulation.ImportanceHPV16 positive tumors that retain expression of E2 have a better clinical outcome than those that have lost E2 expression. It has been suggested that this is due to a loss of E2 repression of E6 and E7 expression but this is not supported by data from tumors where there is not more E6 and E7 expression in the absence of E2. Here we report that E2 regulates host gene expression and place this regulation in context of the HPV16 life cycle and HPV16 positive head and neck cancers (the majority of which retain E2 expression). We propose that this E2 function may play an important part in the increased response of HPV16 positive cancers to radiation therapy. Therefore, host gene regulation by E2 may be important for promotion of the HPV16 life cycle, and also for the response of HPV16 positive tumors to radiation therapy.

Download Full-text

Transposable element exaptation is the primary source of novelty in the primate gene regulatory landscape

10.1101/083980 ◽

2016 ◽

Cited By ~ 3

Author(s):

Marco Trizzino ◽

YoSon Park ◽

Marcia Holsbach-Beltrame ◽

Katherine Aracena ◽

Katelyn Mika ◽

...

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Phenotypic Diversity ◽

Regulatory Element ◽

Critical Role ◽

Primary Source ◽

Primate Species ◽

Rna Seq ◽

Cell Type Specificity ◽

Regulatory Landscape

AbstractGene regulation plays a critical role in the evolution of phenotypic diversity. We investigated the evolution of liver promoters and enhancers in six primate species. We performed ChlP-seq for two histone modifications and RNA-seq to profile cis-regulatory element (CRE) activity and gene expression. The primate regulatory landscape is largely conserved across the lineage. Conserved CRE function is associated with sequence conservation, proximity to coding genes, cell type specificity of CRE function, and transcription factor binding. Newly evolved CREs are enriched in immune response and neurodevelopmental functions, while conserved CREs bind master regulators. Transposable elements (TEs) are the primary source of novelty in primate gene regulation. Newly evolved CREs are enriched in young TEs that affect gene expression. However, only 17% of conserved CREs overlap a TE, suggesting that target gene expression is under strong selection. Finally, we identified specific genomic features driving the functional recruitment of newly inserted TEs.

Download Full-text

Genes

Examining the Causal Relationship Between Genes, Epigenetics, and Human Health - Advances in Bioinformatics and Biomedical Engineering ◽

10.4018/978-1-5225-8066-9.ch009 ◽

2019 ◽

pp. 186-204

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Expression Patterns ◽

Regulation Of Gene Expression ◽

Regulatory System ◽

The Body ◽

Internal Cell ◽

Wide Range ◽

Tryptophan Operon ◽

Bacterial Genes

Gene expression patterns are dependent on their internal cell environment of their DNA, their immediate internal cell environment, and the integrity of their DNA. It also depends on the cell's external environment comprised of signals from other parts of the body including chemicals, nutrients, and/or mechanical stress. Gene regulation is achieved by a wide range of mechanisms that cells use to control whether genes are transcribed, when they are transcribed, and to regulate the quantity of certain proteins based on the cellular and/or environmental feedback. Proper regulation of gene expression is required by organisms to respond to continually changing environmental conditions. Some bacterial genes are transcribed as a unit under a regulatory system called an operon which contains functionally related genes. Three well studied operons include the lactose operon, histidine operon, and tryptophan operon. Gene regulation in higher organisms can occur at various stages from DNA level to protein assembly. This chapter explores this aspect of genes.

Download Full-text

Immune gene expression covaries with gut microbiome composition in stickleback

10.1101/2020.08.04.236786 ◽

2020 ◽

Author(s):

Lauren Fuess ◽

Stijn den Haan ◽

Fei Ling ◽

Jesse N. Weber ◽

Natalie C. Steinel ◽

...

Keyword(s):

Gene Expression ◽

Microbial Communities ◽

Gut Microbiome ◽

Alpha Diversity ◽

Host Immunity ◽

Host Gene ◽

Microbiota Composition ◽

Host Gene Expression ◽

Microbiome Composition ◽

Immune Genes

ABSTRACTCommensal microbial communities have immense effects on their vertebrate hosts, contributing to a number of physiological functions as well as host fitness. In particular, host immunity is strongly linked to microbiota composition through poorly understood bi-directional links. Gene expression may be a potential mediator of these links between microbial communities and host function. However few studies have investigated connections between microbiota composition and expression of host immune genes in complex systems. Here we leverage a large study of laboratory-raised fish from the species Gasterosteus aculeatus (three-spined stickleback) to document correlations between gene expression and microbiome composition. First, we examined correlations between microbiome alpha diversity and gene expression. Our results demonstrate robust positive associations between microbial alpha diversity and expression of host immunity. Next, we examined correlations between host gene expression and abundance of microbial taxa. We identified 15 microbial families that were highly correlated to host gene expression. These families were all tightly correlated to host expression of immune genes and processes, falling into one of three categories: those positively correlated, negatively correlated, and neutrally related to immune processes. Furthermore, we highlight several important immune processes that are commonly associated with abundance of these taxons, including both macrophage and B cell functions. Further functional characterization of microbial taxa will help disentangle the mechanisms of the correlations described here. In sum, our study supports prevailing hypotheses of intimate links between host immunity and gut microbiome composition.

Download Full-text

Cross-Talk Between Intestinal Microbiota and Host Gene Expression in Gilthead Sea Bream (Sparus aurata) Juveniles: Insights in Fish Feeds for Increased Circularity and Resource Utilization

Frontiers in Physiology ◽

10.3389/fphys.2021.748265 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fernando Naya-Català ◽

Gabriella do Vale Pereira ◽

M. Carla Piazzon ◽

Ana Margarida Fernandes ◽

Josep Alvar Calduch-Giner ◽

...

Keyword(s):

Gene Expression ◽

Gut Microbiota ◽

Head Kidney ◽

Host Gene ◽

Gilthead Sea Bream ◽

Sea Bream ◽

Fish Feed ◽

Host Gene Expression ◽

Gene Markers ◽

Wide Range

New types of fish feed based on processed animal proteins (PAPs), insect meal, yeast, and microbial biomasses have been used with success in gilthead sea bream. However, some drawback effects on feed conversion and inflammatory systemic markers were reported in different degrees with PAP- and non-PAP-based feed formulations. Here, we focused on the effects of control and two experimental diets on gut mucosal-adherent microbiota, and how it correlated with host transcriptomics at the local (intestine) and systemic (liver and head kidney) levels. The use of tissue-specific PCR-arrays of 93 genes in total rendered 13, 12, and 9 differentially expressed (DE) genes in the intestine, liver, and head kidney, respectively. Illumina sequencing of gut microbiota yielded a mean of 125,350 reads per sample, assigned to 1,281 operational taxonomic unit (OTUs). Bacterial richness and alpha diversity were lower in fish fed with the PAP diet, and discriminant analysis displayed 135 OTUs driving the separation between groups with 43 taxa correlating with 27 DE genes. The highest expression of intestinal pcna and alpi was achieved in PAP fish with intermediate values in non-PAP, being the pro-inflammatory action of alpi associated with the presence of Psychrobacter piscatorii. The intestinal muc13 gene was down-regulated in non-PAP fish, with this gene being negatively correlated with anaerobic (Chloroflexi and Anoxybacillus) and metal-reducing (Pelosinus and Psychrosinus) bacteria. Other inflammatory markers (igm, il8, tnfα) were up-regulated in PAP fish, positively correlating the intestinal igm gene with the inflammasome activator Escherichia/Shigella, whereas the systemic expression of il8 and tnfα was negatively correlated with the Bacilli class in PAP fish and positively correlated with Paracoccus yeei in non-PAP fish. Overall changes in the expression pattern of il10, galectins (lgals1, lgals8), and toll-like receptors (tlr2, tlr5, tlr9) reinforced the anti-inflammatory profile of fish fed with the non-PAP diet, with these gene markers being associated with a wide range of OTUs. A gut microbiota-liver axis was also established, linking the microbial generation of short chain fatty acids with the fueling of scd1- and elovl6-mediated lipogenesis. In summary, by correlating the microbiome with host gene expression, we offer new insights in the evaluation of fish diets promoting gut and metabolism homeostasis, and ultimately, the health of farmed fish.

Download Full-text