Quantifying the tissue-specific regulatory information within enhancer DNA sequences
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ABSTRACT:
SUBMITTER: Benner P
PROVIDER: S-EPMC8557370 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Transposable element (TE)-derived sequences comprise half of the human genome and DNA methylome and are presumed to be densely methylated and inactive. Examination of genome-wide DNA methylation status within 928 TE subfamilies in human embryonic and adult tissues identified unexpected tissue-specific and subfamily-specific hypomethylation signatures. Genes proximal to tissue-specific hypomethylated TE sequences were enriched for functions important for the relevant tissue type, and their expression correlated strongly with hypomethylation within the TEs. When hypomethylated, these TE sequences gained tissue-specific enhancer marks, including monomethylation of histone H3 at lysine 4 (H3K4me1) and occupancy by p300, and a majority exhibited enhancer activity in reporter gene assays. Many such TEs also harbored binding sites for transcription factors that are important for tissue-specific functions and showed evidence of evolutionary selection. These data suggest that sequences derived from TEs may be responsible for wiring tissue type-specific regulatory networks and may have acquired tissue-specific epigenetic regulation.
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Project description:Enhancers are key players in the spatio-temporal coordination of gene expression during numerous crucial processes, including tissue differentiation across development. Characterizing the transcription factors (TFs) and genes they connect, and the molecular functions underpinned is important to better characterize developmental processes. In plants, the recent molecular characterization of enhancers revealed their capacity to activate the expression of several target genes. Nevertheless, identifying these target genes at a genome-wide level is challenging, particularly for large-genome species, where enhancers and target genes can be hundreds of kilobases away. Therefore, the contribution of enhancers to plant regulatory networks remains poorly understood. Here, we investigate the enhancer-driven regulatory network of two maize tissues at different stages: leaves at seedling stage (V2-IST) and husks (bracts) at flowering. Using systems biology, we integrate genomic, epigenomic, and transcriptomic data to model the regulatory relationships between TFs and their potential target genes, and identify regulatory modules specific to husk and V2-IST. We show that leaves at the V2-IST stage are characterized by the response to hormones and macromolecules biogenesis and assembly, which are regulated by the BBR/BPC and AP2/ERF TF families, respectively. In contrast, husks are characterized by cell wall modification and response to abiotic stresses, which are, respectively, orchestrated by the C2C2/DOF and AP2/EREB families. Analysis of the corresponding enhancer sequences reveals that two different transposable element families (TIR transposon Mutator and MITE Pif/Harbinger) have shaped part of the regulatory network in each tissue, and that MITEs have provided potential new TF binding sites involved in husk tissue-specificity.
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Project description:BackgroundTranscription factors (TFs) and miRNAs are essential for the regulation of gene expression; however, the global view of human gene regulatory networks remains poorly understood. For example, how is the expression of so many genes regulated by limited cohorts of regulators and how are genes differentially expressed in different tissues despite the genetic code being the same in all tissues?ResultsWe analyzed the network properties of housekeeping and tissue-specific genes in gene regulatory networks from seven human tissues. Our results show that different classes of genes behave quite differently in these networks. Tissue-specific miRNAs show a higher average target number compared with non-tissue specific miRNAs, which indicates that tissue-specific miRNAs tend to regulate different sets of targets. Tissue-specific TFs exhibit higher in-degree, out-degree, cluster coefficient and betweenness values, indicating that they occupy central positions in the regulatory network and that they transfer genetic information from upstream genes to downstream genes more quickly than other TFs. Housekeeping TFs tend to have higher cluster coefficients compared with other genes that are neither housekeeping nor tissue specific, indicating that housekeeping TFs tend to regulate their targets synergistically. Several topological properties of disease-associated miRNAs and genes were found to be significantly different from those of non-disease-associated miRNAs and genes.ConclusionsTissue-specific miRNAs, TFs and disease genes have particular topological properties within the transcriptional regulatory networks of the seven human tissues examined. The tendency of tissue-specific miRNAs to regulate different sets of genes shows that a particular tissue-specific miRNA and its target gene set may form a regulatory module to execute particular functions in the process of tissue differentiation. The regulatory patterns of tissue-specific TFs reflect their vital role in regulatory networks and their importance to biological functions in their respective tissues. The topological differences between disease and non-disease genes may aid the discovery of new disease genes or drug targets. Determining the network properties of these regulatory factors will help define the basic principles of human gene regulation and the molecular mechanisms of disease.
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Project description:An increasing number of studies suggest that functionally redundant enhancers safeguard development via buffering gene expression against environmental and genetic perturbations. Here, we identified over-represented clusters of enhancers (enhancer jungles or EJs) in human B lymphoblastoid cells. We found that EJs tend to associate with genes involved in the activation of the immune system response. Although spanning multiple genes, the enhancers within an EJ tend to collaborate with each other on regulating a single gene. The employment of homotypic transcription factor binding sites (TFBSs) in EJ enhancers and heterotypic TFBSs between constituent enhancers within an EJ may safeguard a robust transcriptional output of the target gene. EJ enhancers evolve under a weaker selective pressure compared to regular enhancers (REs), and approximately 35% of EJs do not have orthologues in the mouse genome. In GM12878, these human-specific EJs appear to regulate genes associated with the adaptive immune system response, while the conserved EJs are associated with innate immunity. Recently acquired human EJs are associated with the higher level of target gene expression compared with conserved EJs, thus facilitating the environmental adaptation of the organism during evolution. In short, the existence of EJs is a common regulatory architecture conferring a robust regulatory control for key lineage genes.
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Project description:Enhancers are noncoding regulatory DNA regions that modulate the transcription of target genes, often over large distances along with the genomic sequence. Enhancer alterations have been associated with various pathological conditions, including cancer. However, the identification and characterization of somatic mutations in noncoding regulatory regions with a functional effect on tumorigenesis and prognosis remain a major challenge. Here, we present a strategy for detecting and characterizing enhancer mutations in a genome-wide analysis of patient cohorts, across three lung cancer subtypes. Lung tissue-specific enhancers were defined by integrating experimental data and public epigenomic profiles, and the genome-wide enhancer-target gene regulatory network of lung cells was constructed by integrating chromatin three-dimensional architecture data. Lung cancers possessed a similar mutation burden at tissue-specific enhancers and exons but with differences in their mutation signatures. Functionally relevant alterations were prioritized on the basis of the pathway-level integration of the effect of a mutation and the frequency of mutations on individual enhancers. The genes enriched for mutated enhancers converged on the regulation of key biological processes and pathways relevant to tumor biology. Recurrent mutations in individual enhancers also affected the expression of target genes, with potential relevance for patient prognosis. Together, these findings show that noncoding regulatory mutations have a potential relevance for cancer pathogenesis and can be exploited for patient classification.SignificanceMapping enhancer-target gene regulatory interactions and analyzing enhancer mutations at the level of their target genes and pathways reveal convergence of recurrent enhancer mutations on biological processes involved in tumorigenesis and prognosis.
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Project description:Advances in genome sequencing technologies and lower costs have enabled the exploration of a multitude of known and novel environments and microbiomes. This has led to an exponential growth in the raw sequence data that are deposited in online repositories. Metagenomic and metatranscriptomic data sets are typically analysed with regard to a specific biological question. However, it is widely acknowledged that these data sets are comprised of a proportion of sequences that bear no similarity to any currently known biological sequence, and this so-called "dark matter" is often excluded from downstream analyses. In this study, a systematic framework was developed to assemble, identify, and measure the proportion of unknown sequences present in distinct human microbiomes. This framework was applied to 40 distinct studies, comprising 963 samples, and covering 10 different human microbiomes including fecal, oral, lung, skin, and circulatory system microbiomes. We found that while the human microbiome is one of the most extensively studied, on average 2% of assembled sequences have not yet been taxonomically defined. However, this proportion varied extensively among different microbiomes and was as high as 25% for skin and oral microbiomes that have more interactions with the environment. A rate of taxonomic characterization of 1.64% of unknown sequences being characterized per month was calculated from these taxonomically unknown sequences discovered in this study. A cross-study comparison led to the identification of similar unknown sequences in different samples and/or microbiomes. Both our computational framework and the novel unknown sequences produced are publicly available for future cross-referencing. Our approach led to the discovery of several novel viral genomes that bear no similarity to sequences in the public databases. Some of these are widespread as they have been found in different microbiomes and studies. Hence, our study illustrates how the systematic characterization of unknown sequences can help the discovery of novel microbes, and we call on the research community to systematically collate and share the unknown sequences from metagenomic studies to increase the rate at which the unknown sequence space can be classified.
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Project description:Changes in gene regulation underlie much of phenotypic evolution1. However, our understanding of the potential for regulatory evolution is biased, because most evidence comes from either natural variation or limited experimental perturbations2. Using an automated robotics pipeline, we surveyed an unbiased mutation library for a developmental enhancer in Drosophila melanogaster. We found that almost all mutations altered gene expression and that parameters of gene expression-levels, location, and state-were convolved. The widespread pleiotropic effects of most mutations may constrain the evolvability of developmental enhancers. Consistent with these observations, comparisons of diverse Drosophila larvae revealed apparent biases in the phenotypes influenced by the enhancer. Developmental enhancers may encode a higher density of regulatory information than has been appreciated previously, imposing constraints on regulatory evolution.
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2016-02-08 | PXD002460 | Pride
Project description:The Csf1r locus encodes the receptor for macrophage colony-stimulating factor, which controls the proliferation, differentiation and survival of macrophages. The 300?bp Fms intronic regulatory element (FIRE), within the second intron of Csf1r, is necessary and sufficient to direct macrophage-specific transcription. We have analysed the conservation and divergence of the FIRE DNA sequence in vertebrates. FIRE is present in the same location in the Csf1r locus in reptile, avian and mammalian genomes. Nearest neighbor analysis based upon this element alone largely recapitulates phylogenies inferred from much larger genomic sequence datasets. One core element, containing binding sites for AP1 family and the macrophage-specific transcription factor, PU.1, is conserved from lizards to humans. Around this element, the FIRE sequence is conserved within clades with the most conserved elements containing motifs for known myeloid-expressed transcription factors. Conversely, there is little alignment between clades outside the AP1/PU.1 element. The analysis favours a hybrid between "enhanceosome" and "smorgasbord" models of enhancer function, in which elements cooperate to bind components of the available transcription factor milieu.
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