Shared distal regulatory regions may contribute to the coordinated expression of human ribosomal protein genes.
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ABSTRACT:
SUBMITTER: Wang S
PROVIDER: S-EPMC7217726 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ribosomal protein genes (RPGs) are essential, tightly regulated, and highly expressed during embryonic development and cell growth. Even though their protein sequences are strongly conserved, their mechanism of regulation is not conserved across yeast, Drosophila, and vertebrates. A recent investigation of genomic sequences conserved across both nematode species and associated with different gene groups indicated the existence of several elements in the upstream regions of C. elegans RPGs, providing a new insight regarding the regulation of these genes in C. elegans.In this study, we performed an in-depth examination of C. elegans RPG regulation and found nine highly conserved motifs in the upstream regions of C. elegans RPGs using the motif discovery algorithm DME. Four motifs were partially similar to transcription factor binding sites from C. elegans, Drosophila, yeast, and human. One pair of these motifs was found to co-occur in the upstream regions of 250 transcripts including 22 RPGs. The distance between the two motifs displayed a complex frequency pattern that was related to their relative orientation.We tested the impact of three of these motifs on the expression of rpl-2 using a series of reporter gene constructs and showed that all three motifs are necessary to maintain the high natural expression level of this gene. One of the motifs was similar to the binding site of an orthologue of POP-1, and we showed that RNAi knockdown of pop-1 impacts the expression of rpl-2. We further determined the transcription start site of rpl-2 by 5' RACE and found that the motifs lie 40-90 bases upstream of the start site. We also found evidence that a noncoding RNA, contained within the outron of rpl-2, is co-transcribed with rpl-2 and cleaved during trans-splicing.Our results indicate that C. elegans RPGs are regulated by a complex novel series of regulatory elements that is evolutionarily distinct from those of all other species examined up until now.
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Project description:Ribosomal proteins (RPs) are essential components that translate genetic information from mRNA templates into proteins. Their expressional dysregulation adversely affects the survival and growth of human cells. Nevertheless, little is known about the nucleotide sequences regulating the expression of RPs. Genome-wide associations for expression level of 70 RP genes were conducted across expression stages. Eighteen expression regulatory quantitative trait loci (erQTLs) were identified for protein abundances of 21 RPs (P < 1 × 10-5), but not for their mRNA expression and ribosome occupancy (P > 1 × 10-5). These erQTLs for protein abundance (pQTLs) were all trans-acting. Three of the pQTLs were associated with the expression of long noncoding RNAs (lncRNAs). Target genes of these lncRNAs may produce ribosomal components or may control the metabolic cues for ribosome synthesis. mRNAs of the RP genes extensively interact with miRNAs. The protein-specific erQTLs may become engendered by intensive miRNA controls at the translational stage, which in turn can produce RPs efficient in handling instantaneous cell requirements. This study suggests that the expression levels of RPs may be greatly influenced by trans-acting regulation, presumably via interference of miRNAs and target genes of lncRNAs. Further studies are warranted to examine the molecular functions of pQTLs presented in this study and to understand the underlying regulatory mechanisms of gene expression of RPs.
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Project description:Long-range chromatin interactions are important for transcriptional regulation of genes, many of which are related to complex agronomics traits. However, the pattern of three-dimensional chromatin interactions remains unclear in plants. Here we report the generation of chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) data and the construction of extensive H3K4me3- and H3K27ac-centered chromatin interaction maps in maize. Results show that the interacting patterns between proximal and distal regulatory regions of genes are highly complex and dynamic. Genes with chromatin interactions have higher expression levels than those without interactions. Genes with proximal-proximal interactions prefer to be transcriptionally coordinated. Tissue-specific proximal-distal interactions are associated with tissue-specific expression of genes. Interactions between proximal and distal regulatory regions further interweave into organized network communities that are enriched in specific biological functions. The high-resolution chromatin interaction maps will help to understand the transcription regulation of genes associated with complex agronomic traits of maize.
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Project description:Functioning as signal receivers and transmitters, the integrin ?/? cytoplasmic tails (CT) are pivotal in integrin activation and signaling. 18 ? integrin subunits share a conserved membrane-proximal region but have a highly diverse membrane-distal (MD) region at their CTs. Recent studies demonstrated that the presence of ? CTMD region is essential for talin-induced integrin inside-out activation. However, it remains unknown whether the non-conserved ? CTMD regions differently regulate the inside-out activation of integrin. Using ?IIb?3, ?L?2, and ?5?1 as model integrins and by replacing their ? CTMD regions with those of ? subunits that pair with ?3, ?2, and ?1 subunits, we analyzed the function of CTMD regions of 17 ? subunits in talin-mediated integrin activation. We found that the ? CTMD regions play two roles on integrin, which are activation-supportive and activation-regulatory. The regulatory but not the supportive function depends on the sequence identity of ? CTMD region. A membrane-proximal tyrosine residue present in the CTMD regions of a subset of ? integrins was identified to negatively regulate integrin inside-out activation. Our study provides a useful resource for investigating the function of ? integrin CTMD regions.
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Project description:BackgroundAdjacent gene pairs in the yeast genome have a tendency to express concurrently. Sharing of regulatory elements within the intergenic region of those adjacent gene pairs was often considered the major mechanism responsible for such co-expression. However, it is still in debate to what extent that common transcription factors (TFs) contribute to the co-expression of adjacent genes. In order to resolve the evolutionary aspect of this issue, we investigated the conservation of adjacent pairs in five yeast species. By using the information for TF binding sites in promoter regions available from the MYBS database http://cg1.iis.sinica.edu.tw/~mybs/, the ratios of TF-sharing pairs among all the adjacent pairs in yeast genomes were analyzed. The levels of co-expression in different adjacent patterns were also compared.ResultsOur analyses showed that the proportion of adjacent pairs conserved in five yeast species is relatively low compared to that in the mammalian lineage. The proportion was also low for adjacent gene pairs with shared TFs. Particularly, the statistical analysis suggested that co-expression of adjacent gene pairs was not noticeably associated with the sharing of TFs in these pairs. We further proposed a case of the PAC (polymerase A and C) and RRPE (rRNA processing element) motifs which co-regulate divergent/bidirectional pairs, and found that the shared TFs were not significantly relevant to co-expression of divergent promoters among adjacent genes.ConclusionOur findings suggested that the commonly shared cis-regulatory system does not solely contribute to the co-expression of adjacent gene pairs in yeast genome. Therefore we believe that during evolution yeasts have developed a sophisticated regulatory system that integrates both TF-based and non-TF based mechanisms(s) for concurrent regulation of neighboring genes in response to various environmental changes.
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Project description:HMO1 is a high-mobility group B protein that plays a role in transcription of genes encoding rRNA and ribosomal proteins (RPGs) in Saccharomyces cerevisiae. This study uses genome-wide chromatin immunoprecipitation to study the roles of HMO1, FHL1, and RAP1 in transcription of these genes as well as other RNA polymerase II-transcribed genes in yeast. The results show that HMO1 associates with the 35S rRNA gene in an RNA polymerase I-dependent manner and that RPG promoters (138 in total) can be classified into several distinct groups based on HMO1 abundance at the promoter and the HMO1 dependence of FHL1 and/or RAP1 binding to the promoter. FHL1, a key regulator of RPGs, binds to most of the HMO1-enriched and transcriptionally HMO1-dependent RPG promoters in an HMO1-dependent manner, whereas it binds to HMO1-limited RPG promoters in an HMO1-independent manner, irrespective of whether they are transcribed in an HMO1-dependent manner. Reporter gene assays indicate that these functional properties are determined by the promoter sequence.
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Project description:The gene composition of present-day genomes has been shaped by a complicated evolutionary history, resulting in diverse distributions of genes across genomes. The pattern of presence and absence of a gene in different genomes is called its phylogenetic profile. It has been shown that proteins whose encoding genes have highly similar profiles tend to be functionally related: As these genes were gained and lost together, their encoded proteins can probably only perform their full function if both are present. However, a large proportion of genes encoding interacting proteins do not have matching profiles. In this study, we analysed one possible reason for this, namely that phylogenetic profiles can be affected by multi-functional proteins such as shared subunits of two or more protein complexes. We found that by considering triplets of proteins, of which one protein is multi-functional, a large fraction of disturbed co-occurrence patterns can be explained.
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Project description:The mechanisms of chronic pain are complex, and genetic factors play an essential role in the development of chronic pain. Neuropathic pain (NP) and inflammatory pain (IP) are two primary components of chronic pain. Previous studies have uncovered some common biological processes in NP and IP. However, the shared genetic mechanisms remained poorly studied. We utilized multi-omics systematic analyses to investigate the shared genetic mechanisms of NP and IP. First, by integrating several genome-wide association studies (GWASs) with multi-omics data, we revealed the significant overlap of the gene co-expression modules in NP and IP. Further, we uncovered the shared biological pathways, including the previously reported mitochondrial electron transport and ATP metabolism, and stressed the role of genetic factors in chronic pain with neurodegenerative diseases. Second, we identified 24 conservative key drivers (KDs) contributing to NP and IP, containing two well-established pain genes, IL1B and OPRM1, and some novel potential pain genes, such as C5AR1 and SERPINE1. The subnetwork of those KDs highlighted the processes involving the immune system. Finally, gene expression analysis of the KDs in mouse models underlined two of the KDs, SLC6A15 and KCNQ5, with unidirectional regulatory functions in NP and IP. Our study provides strong evidence to support the current understanding of the shared genetic regulatory networks underlying NP and IP and potentially benefit the future common therapeutic avenues for chronic pain.
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Project description:Molecular biotechnology has made it possible to explore the potential of plants for different purposes. The 3' regulatory regions have a great diversity of cis-regulatory elements directly involved in polyadenylation, stability, transport and mRNA translation, essential to achieve the desired levels of gene expression. A complex interaction between the cleavage and polyadenylation molecular complex and cis-elements determine the polyadenylation site, which may result in the choice of non-canonical sites, resulting in alternative polyadenylation events, involved in the regulation of more than 80% of the genes expressed in plants. In addition, after transcription, a wide array of RNA-binding proteins interacts with cis-acting elements located mainly in the 3' untranslated region, determining the fate of mRNAs in eukaryotic cells. Although a small number of 3' regulatory regions have been identified and validated so far, many studies have shown that plant 3' regulatory regions have a higher potential to regulate gene expression in plants compared to widely used 3' regulatory regions, such as NOS and OCS from Agrobacterium tumefaciens and 35S from cauliflower mosaic virus. In this review, we discuss the role of 3' regulatory regions in gene expression, and the superior potential that plant 3' regulatory regions have compared to NOS, OCS and 35S 3' regulatory regions.
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Project description:Aberrant promoter methylation is a common mechanism for tumor suppressor inactivation in cancer. We develop a set of tools to identify genome-wide DNA methylation in distal regions with causal effect on tumorigenesis called MICMIC. Many predictions are directly validated by dCas9-based epigenetic editing to support the accuracy and efficiency of our tool. Oncogenic and lineage-specific transcription factors are shown to aberrantly shape the methylation landscape by modifying tumor-subtype core regulatory circuitry. Notably, the gene regulatory networks orchestrated by enhancer methylation across different cancer types are seen to converge on a common architecture. MICMIC is available on https://github.com/ZhangJlab/MICMIC .
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