A comparative analysis of heart microRNAs in vertebrates brings novel insights into the evolution of genetic regulatory networks

Abstract Background During vertebrate evolution, the heart has undergone remarkable changes that lead to morphophysiological differences in the fully formed heart of these species, such as chamber septation, heart rate frequency, blood pressure, and cardiac output volume. Despite these differences, the heart developmental process is guided by a core gene set conserved across vertebrates. Nonetheless, the regulatory mechanisms controlling the expression of genes involved in heart development and maintenance are largely uncharted. MicroRNAs (miRNAs) have been described as important regulatory elements in several biological processes, including heart biology. These small RNA molecules are broadly conserved in sequence and genomic context in metazoans. Mutations may occur in miRNAs and/or genes that contribute to the establishment of distinct repertoires of miRNA-target interactions, thereby favoring the differential control of gene expression and, consequently, the origin of novel phenotypes. In fact, several studies showed that miRNAs are integrated into genetic regulatory networks (GRNs) governing specific developmental programs and diseases. However, studies integrating miRNAs in vertebrate heart GRNs under an evolutionary perspective are still scarce. Results We comprehensively examined and compared the heart miRNome of 20 species representatives of the five major vertebrate groups. We found 54 miRNA families with conserved expression and a variable number of miRNA families with group-specific expression in fishes, amphibians, reptiles, birds, and mammals. We also detected that conserved miRNAs present higher expression levels and a higher number of targets, whereas the group-specific miRNAs present lower expression levels and few targets. Conclusions Both the conserved and group-specific miRNAs can be considered modulators orchestrating the core and peripheral genes of heart GRNs of vertebrates, which can be related to the morphophysiological differences and similarities existing in the heart of distinct vertebrate groups. We propose a hypothesis to explain evolutionary differences in the putative functional roles of miRNAs in the heart GRNs analyzed. Furthermore, we present new insights into the molecular mechanisms that could be helping modulate the diversity of morphophysiology in the heart organ of vertebrate species.

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Molecular mechanisms governing circulating immune cell heterogeneity across different species revealed by single cell sequencing

10.1101/2021.12.17.472326 ◽

2021 ◽

Author(s):

Zhibin Li ◽

chengcheng Sun ◽

Fei Wang ◽

Xiran Wang ◽

Jiacheng Zhu ◽

...

Keyword(s):

Single Cell ◽

Immune Cells ◽

Evolutionary Biology ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Mononuclear Cells ◽

Immune Cell ◽

Cell Types ◽

Genetic Regulatory Networks ◽

Peripheral Blood Mononuclear

Background: Immune cells play important roles in mediating immune response and host defense against invading pathogens. However, insights into the molecular mechanisms governing circulating immune cell diversity among multiple species are limited. Methods: In this study, we compared the single-cell transcriptomes of 77 957 immune cells from 12 species using single-cell RNA-sequencing (scRNA-seq). Distinct molecular profiles were characterized for different immune cell types, including T cells, B cells, natural killer cells, monocytes, and dendritic cells. Results: The results revealed the heterogeneity and compositions of circulating immune cells among 12 different species. Additionally, we explored the conserved and divergent cellular cross-talks and genetic regulatory networks among vertebrate immune cells. Notably, the ligand and receptor pair VIM-CD44 was highly conserved among the immune cells. Conclusions: This study is the first to provide a comprehensive analysis of the cross-species single-cell atlas for peripheral blood mononuclear cells (PBMCs). This research should advance our understanding of the cellular taxonomy and fundamental functions of PBMCs, with important implications in evolutionary biology, developmental biology, and immune system disorders

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DNA Methylation Contributes to the Differential Expression Levels of Mecp2 in Male Mice Neurons and Astrocytes

International Journal of Molecular Sciences ◽

10.3390/ijms20081845 ◽

2019 ◽

Vol 20 (8) ◽

pp. 1845 ◽

Cited By ~ 8

Author(s):

Vichithra R.B. Liyanage ◽

Carl O. Olson ◽

Robby M. Zachariah ◽

James R. Davie ◽

Mojgan Rastegar

Keyword(s):

Dna Methylation ◽

Current Knowledge ◽

Regulatory Element ◽

Regulatory Elements ◽

Autism Spectrum ◽

Brain Cells ◽

Specific Expression ◽

Expression Levels ◽

Mecp2 Duplication Syndrome ◽

Cell Type Specific Expression

Methyl CpG binding protein-2 (MeCP2) isoforms (E1 and E2) are important epigenetic regulators in brain cells. Accordingly, MeCP2 loss- or gain-of-function mutation causes neurodevelopmental disorders, including Rett syndrome (RTT), MECP2 duplication syndrome (MDS), and autism spectrum disorders (ASD). Within different types of brain cells, highest MeCP2 levels are detected in neurons and the lowest in astrocytes. However, our current knowledge of Mecp2/MeCP2 regulatory mechanisms remains largely elusive. It appears that there is a sex-dependent effect in X-linked MeCP2-associated disorders, as RTT primarily affects females, whereas MDS is found almost exclusively in males. This suggests that Mecp2 expression levels in brain cells might be sex-dependent. Here, we investigated the sex- and cell type-specific expression of Mecp2 isoforms in male and female primary neurons and astrocytes isolated from the murine forebrain. Previously, we reported that DNA methylation of six Mecp2 regulatory elements correlated with Mecp2 levels in the brain. We now show that in male brain cells, DNA methylation is significantly correlated with the transcript expression of these two isoforms. We show that both Mecp2 isoforms are highly expressed in male neurons compared to male astrocytes, with Mecp2e1 expressed at higher levels than Mecp2e2. Our data indicate that higher DNA methylation at the Mecp2 regulatory element(s) is associated with lower levels of Mecp2 isoforms in male astrocytes compared to male neurons.

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Comparative transcriptomic analysis of maize ear heterosis during the inflorescence meristem differentiation stage

10.1101/2021.09.28.462161 ◽

2021 ◽

Author(s):

Xia Shi ◽

Weihua li ◽

Zhanyong Guo ◽

Mingbo Wu ◽

Xiangge Zhang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Transcriptomic Analysis ◽

Inflorescence Meristem ◽

Specific Expression ◽

Ear Development ◽

Expression Levels ◽

Transcriptional Variation ◽

Heterotic Locus ◽

Segment Substitution ◽

Maize Ear

AbstractHeterosis is widely used in many crops; however, its genetic mechanisms are only partly understood. Here, we sampled inflorescence meristem (IM) ears from the single-segment substitution maize (Zea mays) line lx9801hlEW2b, containing a heterotic locus hlEW2b associated with ear width, the receptor parent lx9801, the test parent Zheng58, and their corresponding hybrids. After transcriptomic analysis, 1638 genes were identified in at least one hybrid with nonadditively expressed patterns and different expression levels between the two hybrids. In particular, 2263 (12.89%) and 2352 (14.65%) genes showed allele-specific expression (ASE) in Zheng58 × lx9801 and Zheng58 × lx9801hlEW2b, respectively. A functional analysis showed that these genes were enriched in development-related processes and biosynthesis and catabolism processes, which are potentially associated with heterosis. Additionally, nonadditive expression and ASE may fine-tune the expression levels of crucial genes (such as WUS and KNOX that control IM development) controlling auxin metabolism and ear development to optimal states, and transcriptional variation may play important roles in maize ear heterosis. The results provide new information that increases our understanding of the relationship between transcriptional variation and heterosis formation during maize ear development, which may be helpful in clarifying the genetic and molecular mechanisms of heterosis.

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Integrating transcriptome and metabolome reveals molecular networks involved in genetic and environmental variation in tobacco

DNA Research ◽

10.1093/dnares/dsaa006 ◽

2020 ◽

Vol 27 (2) ◽

Author(s):

Pingping Liu ◽

Jie Luo ◽

Qingxia Zheng ◽

Qiansi Chen ◽

Niu Zhai ◽

...

Keyword(s):

Regulatory Networks ◽

Molecular Mechanisms ◽

Developmental Stages ◽

De Novo ◽

Developmental Process ◽

Pearson Correlation ◽

Molecular Networks ◽

Environmental Perturbations ◽

Carotenoid Metabolism ◽

Gene Modules

Abstract Tobacco (Nicotiana tabacum) is one of the most widely cultivated commercial non-food crops with significant social and economic impacts. Here we profiled transcriptome and metabolome from 54 tobacco samples (2–3 replicates; n = 151 in total) collected from three varieties (i.e. genetic factor), three locations (i.e. environmental factor), and six developmental stages (i.e. developmental process). We identified 3,405 differentially expressed (DE) genes (DEGs) and 371 DE metabolites, respectively. We used quantitative real-time PCR to validate 20 DEGs, and confirmed 18/20 (90%) DEGs between three locations and 16/20 (80%) with the same trend across developmental stages. We then constructed nine co-expression gene modules and four co-expression metabolite modules , and defined seven de novo regulatory networks, including nicotine- and carotenoid-related regulatory networks. A novel two-way Pearson correlation approach was further proposed to integrate co-expression gene and metabolite modules to identify joint gene–metabolite relations. Finally, we further integrated DE and network results to prioritize genes by its functional importance and identified a top-ranked novel gene, LOC107773232, as a potential regulator involved in the carotenoid metabolism pathway. Thus, the results and systems-biology approaches provide a new avenue to understand the molecular mechanisms underlying complex genetic and environmental perturbations in tobacco.

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The Genetics of Evolutionary Novelties

Homology, Genes, and Evolutionary Innovation ◽

10.23943/princeton/9780691156460.003.0007 ◽

2014 ◽

Author(s):

Günter P. Wagner

Keyword(s):

Regulatory Networks ◽

Molecular Mechanisms ◽

Regulatory Elements ◽

Complex Problem ◽

Micro Rnas ◽

Sex Comb ◽

Gene Regulatory ◽

Transcription Factor Proteins ◽

Evolutionary Novelties

This chapter examines the molecular genetics of evolutionary novelties. In particular, it investigates which molecular mechanisms might be involved in the origination of novel gene regulatory networks (and, thus, character identity networks) and what these mechanisms imply for the origin of novel characters. The chapter begins with a discussion of the complex problem of the evolution of transcriptional regulation by focusing on the evolution of cis-regulatory elements (CREs) and the evolution of transcription factor proteins. It then asks whether novel pigment spots, such as the Drosophila wing spots, are novelties. It also explores an evolutionary novelty known as sex comb and the role of transposable elements in the origin of novel CREs. Finally, it considers the role of gene duplications, the evolution of micro-RNAs (miRNAs), and the possibility of a mechanistic difference between adaptation and innovation.

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Dynamics of Cardiomyocyte Transcriptome and Chromatin Landscape Demarcates Key Events of Heart Development

10.1101/488593 ◽

2018 ◽

Author(s):

Michal Pawlak ◽

Katarzyna Z. Kedzierska ◽

Maciej Migdal ◽

Karim Abu Nahia ◽

Jordan A. Ramilowski ◽

...

Keyword(s):

Heart Development ◽

Regulatory Networks ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Proximal Promoter ◽

Global Changes ◽

Open Chromatin ◽

Sequence Motifs ◽

Loss Of Function ◽

Heart Looping

ABSTRACTThe development of an organ involves dynamic regulation of gene transcription and complex multipathway interactions. To better understand transcriptional regulatory mechanism driving heart development and the consequences of its disruption, we isolated cardiomyocytes (CMs) from wild-type zebrafish embryos at 24, 48 and 72 hours post fertilization corresponding to heart looping, chamber formation and heart maturation, and from mutant lines carrying loss-of-function mutations in gata5, tbx5a and hand2, transcription factors (TFs) required for proper heart development. The integration of CM transcriptomics (RNA-seq) and genome-wide chromatin accessibility maps (ATAC-seq) unravelled dynamic regulatory networks driving crucial events of heart development. These networks contained key cardiac TFs including Gata5/6, Nkx2.5, Tbx5/20, and Hand2, and are associated with open chromatin regions enriched for DNA sequence motifs belonging to the family of the corresponding TFs. These networks were disrupted in cardiac TF mutants, indicating their importance in proper heart development. The most prominent gene expression changes, which correlated with chromatin accessibility modifications within their proximal promoter regions, occurred between heart looping and chamber formation, and were associated with metabolic and hematopoietic/cardiac switch during CM maturation. Furthermore, loss of function of cardiac TFs Gata5, Tbx5a, and Hand2 affected the cardiac regulatory networks and caused global changes in chromatin accessibility profile. Among regions with differential chromatin accessibility in mutants were highly conserved non-coding elements which represent putative cis regulatory elements with potential role in heart development and disease. Altogether, our results revealed the dynamic regulatory landscape at key stages of heart development and identified molecular drivers of heart morphogenesis.

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PREDetector 2.0: Online and Enhanced Version of the Prokaryotic Regulatory Elements Detector Tool

10.1101/084780 ◽

2016 ◽

Cited By ~ 1

Author(s):

Pierre Tocquin ◽

Aymeric Naômé ◽

Samuel Jourdan ◽

Sinaeda Anderssen ◽

Samuel Hiard ◽

...

Keyword(s):

Binding Sites ◽

Regulatory Networks ◽

Regulatory Elements ◽

Upstream Region ◽

Genomic Context ◽

Bacterial Genomes ◽

Microbial Genomes ◽

Dna Motif ◽

Putative Transcription Factor ◽

Public Repositories

ABSTRACTIn the era that huge numbers of microbial genomes are being released in the databases, it becomes increasingly important to rapidly mine genes as well as predict the regulatory networks that control their expression. To this end, we have developed an improved and online version of the PREDetector software aimed at identifying putative transcription factor-binding sites (TFBS) in bacterial genomes. The original philosophy of PREDetector 1.0 is maintained, i.e. to allow users to freely fix the DNA-motif screening parameters, and to provide a statistical means to estimate the reliability of the prediction output. This new version offers an interactive table as well as graphics to dynamically alter the main screening parameters with automatic update of the list of identified putative TFBS. PREDetector 2.0 also has the following additional options: (i) access to genome sequences from different databases, (ii) access to weight matrices from public repositories, (iii) visualization of the predicted hits in their genomic context, (iv) grouping of hits identified in the same upstream region, (v) possibility to store the performed jobs, and (vi) automated export of the results in various formats. PREDetector 2.0 is available at http://predetector.fsc.ulg.ac.be/.

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Cellular and Molecular Mechanisms Linking Human Cortical Development and Evolution

Annual Review of Genetics ◽

10.1146/annurev-genet-071719-020705 ◽

2021 ◽

Vol 55 (1) ◽

Author(s):

Baptiste Libé-Philippot ◽

Pierre Vanderhaeghen

Keyword(s):

Neural Development ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Regulatory Elements ◽

Annual Review ◽

Publication Date ◽

Human Species ◽

Cellular Mechanisms ◽

Brain Functions ◽

Molecular Features

The cerebral cortex is at the core of brain functions that are thought to be particularly developed in the human species. Human cortex specificities stem from divergent features of corticogenesis, leading to increased cortical size and complexity. Underlying cellular mechanisms include prolonged patterns of neuronal generation and maturation, as well as the amplification of specific types of stem/progenitor cells. While the gene regulatory networks of corticogenesis appear to be largely conserved among all mammals including humans, they have evolved in primates, particularly in the human species, through the emergence of rapidly divergent transcriptional regulatory elements, as well as recently duplicated novel genes. These human-specific molecular features together control key cellular milestones of human corticogenesis and are often affected in neurodevelopmental disorders, thus linking human neural development, evolution, and diseases. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Contributions of 5’HoxA/D regulation to actinodin evolution and the fin-to-limb transition

The International Journal of Developmental Biology ◽

10.1387/ijdb.180248rl ◽

2018 ◽

Vol 62 (11-12) ◽

pp. 705-716 ◽

Cited By ~ 3

Author(s):

Robert L. Lalonde ◽

Marie-Andrée Akimenko

Keyword(s):

Regulatory Networks ◽

Molecular Mechanisms ◽

Morphological Changes ◽

Regulatory Elements ◽

Endochondral Bone ◽

Cis Acting ◽

Advantages And Disadvantages ◽

Regulatory Strategies ◽

Deep Homology ◽

Fish Fins

The evolution of tetrapod limbs from paired fish fins comprised major changes to the appendicular dermal and endochondral skeleton. Fish fin rays were lost, and the endochondral bone was modified and elaborated to form three distinct segments common to all tetrapod limbs: the stylopod, the zeugopod and the autopod. Identifying the molecular mechanisms that contributed to these morphological changes presents a unique insight into our own evolutionary history. This review first summarizes previously identified cis-acting regulatory elements for the 5’HoxA/D genes and actinodin1 that were tested using transgenic swap experiments between fish and tetrapods. Conserved regulatory networks provide evidence for a deep homology between distal fin structures and the autopod, while diverging regulatory strategies highlight potential molecular mechanisms that contributed to the fin-to-limb transition. Next, we summarize studies that performed functional analysis to recapitulate fish-tetrapod diverging regulatory strategies and then discuss their potential morphological consequences during limb evolution. Finally, we also discuss here some of the advantages and disadvantages of using zebrafish to study molecular and morphological changes during the fin-to-limb transition.

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Insights into Gene Regulatory Networks in Chondrocytes

International Journal of Molecular Sciences ◽

10.3390/ijms20246324 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6324 ◽

Cited By ~ 2

Author(s):

Hironori Hojo ◽

Shinsuke Ohba

Keyword(s):

Transcription Factors ◽

Dna Sequences ◽

Regulatory Networks ◽

Developmental Process ◽

Regulatory Elements ◽

Regulatory Mechanisms ◽

Gene Expressions ◽

A Genome ◽

Gene Regulatory Elements ◽

Gene Regulatory

Chondrogenesis is a key developmental process that molds the framework of our body and generates the skeletal tissues by coupling with osteogenesis. The developmental processes are well-coordinated by spatiotemporal gene expressions, which are hardwired with gene regulatory elements. Those elements exist as thousands of modules of DNA sequences on the genome. Transcription factors function as key regulatory proteins by binding to regulatory elements and recruiting cofactors. Over the past 30 years, extensive attempts have been made to identify gene regulatory mechanisms in chondrogenesis, mainly through biochemical approaches and genetics. More recently, newly developed next-generation sequencers (NGS) have identified thousands of gene regulatory elements on a genome scale, and provided novel insights into the multiple layers of gene regulatory mechanisms, including the modes of actions of transcription factors, post-translational histone modifications, chromatin accessibility, the concept of pioneer factors, and three-dimensional chromatin architecture. In this review, we summarize the studies that have improved our understanding of the gene regulatory mechanisms in chondrogenesis, from the historical studies to the more recent works using NGS. Finally, we consider the future perspectives, including efforts to improve our understanding of the gene regulatory landscape in chondrogenesis and potential applications to the treatment of chondrocyte-related diseases.

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