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Functions of Non-coding DNA Regions

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 37678

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Dr. Michał Dąbrowski

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Nencki Institute of Experimental Biology of Polish Academy of Sciences
Interests: cis-regulatory regions; gene regulation; chromosome structure; computational models; regulatory genomics

Special Issue Information

Dear Colleagues,

The term “non-coding DNA” has been established for decades, and, from the beginning, it has been clear that DNA in the genome can serve other functions than encoding the amino-acid sequences of proteins. These other functions include gene regulation—at the levels of transcription, splicing, RNA stability and translation—and maintenance of the chromosomal structure, in particular in the process of DNA replication and recombination, but also during the interphase.

Research in recent decades has begun revealing fascinating inter-relationships between the regulatory and structural roles of non-coding DNA regions, with epigenetic modifications as the key intermediary. An epigenetic modification can affect the DNA region itself or the embedding chromatin segment, leading to a situation where they are usually considered together. Notably, epigenetic modifications include changes in the three-dimensional (3D) structure of the chromatin, leading to non-local interactions, which is are essential feature of information processing (gene regulation) by the genome. Many non-coding DNA regions are transcribed, resulting in several types of non-coding RNAs.

Current research focuses on dynamical aspects of 3D chromatin folding, leading to the notion of the four-dimensional (4D) genome. It is clear that a better understanding of the functions of the non-coding genome requires integration of multiple data types and formulation of quantitative predictive models.

A large fraction of non-coding DNA regions is of retroviral origin, with evidence that many such regions are functional. This constitutes a link between non-coding DNA regions, genetic variation and evolution. Not surprisingly, variation in non-coding regions can lead to diseases.

For this special issue of IJMS, we encourage submissions of original research articles and focused reviews on all aspects of functions of non-coding DNA regions.

Dr. Michał Dąbrowski
Guest Editor

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Keywords

promoter
enhancer
UTR
chromatin loop
chromatin folding
origin of replication
non-coding RNA

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Published Papers (12 papers)

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Research

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14 pages, 7746 KiB

Open AccessArticle

Fragments of rDNA Genes Scattered over the Human Genome Are Targets of Small RNAs

by Nickolai A. Tchurikov, Elena S. Klushevskaya, Ildar R. Alembekov, Anastasiia S. Bukreeva, Antonina N. Kretova, Vladimir R. Chechetkin, Galina I. Kravatskaya and Yuri V. Kravatsky

Int. J. Mol. Sci. 2022, 23(6), 3014; https://doi.org/10.3390/ijms23063014 - 10 Mar 2022

Cited by 3 | Viewed by 2715

Abstract

Small noncoding RNAs of different origins and classes play several roles in the regulation of gene expression. Here, we show that diverged and rearranged fragments of rDNA units are scattered throughout the human genome and that endogenous small noncoding RNAs are processed by the Microprocessor complex from specific regions of ribosomal RNAs shaping hairpins. These small RNAs correspond to particular sites inside the fragments of rDNA that mostly reside in intergenic regions or the introns of about 1500 genes. The targets of these small ribosomal RNAs (srRNAs) are characterized by a set of epigenetic marks, binding sites of Pol II, RAD21, CBP, and P300, DNase I hypersensitive sites, and by enrichment or depletion of active histone marks. In HEK293T cells, genes that are targeted by srRNAs (srRNA target genes) are involved in differentiation and development. srRNA target genes are enriched with more actively transcribed genes. Our data suggest that remnants of rDNA sequences and srRNAs may be involved in the upregulation or downregulation of a specific set of genes in human cells. These results have implications for diverse fields, including epigenetics and gene therapy. Full article

(This article belongs to the Special Issue Functions of Non-coding DNA Regions)

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13 pages, 3139 KiB

Open AccessArticle

Genomic Marks Associated with Chromatin Compartments in the CTCF, RNAPII Loop and Genomic Windows

by Teresa Szczepińska, Ayatullah Faruk Mollah and Dariusz Plewczynski

Int. J. Mol. Sci. 2021, 22(21), 11591; https://doi.org/10.3390/ijms222111591 - 27 Oct 2021

Cited by 2 | Viewed by 2442

Abstract

The nature of genome organization into two basic structural compartments is as yet undiscovered. However, it has been indicated to be a mechanism of gene expression regulation. Using the classification approach, we ranked genomic marks that hint at compartmentalization. We considered a broad range of marks, including GC content, histone modifications, DNA binding proteins, open chromatin, transcription and genome regulatory segmentation in GM12878 cells. Genomic marks were defined over CTCF or RNAPII loops, which are basic elements of genome 3D structure, and over 100 kb genomic windows. Experiments were carried out to empirically assess the whole set of features, as well as the individual features in classification of loops/windows, into compartment A or B. Using Monte Carlo Feature Selection and Analysis of Variance, we constructed a ranking of feature importance for classification. The best simple indicator of compartmentalization is DNase-seq open chromatin measurement for CTCF loops, H3K4me1 for RNAPII loops and H3K79me2 for genomic windows. Among DNA binding proteins, this is RUNX3 transcription factor for loops and RNAPII for genomic windows. Chromatin state prediction methods that indicate active elements like promoters, enhancers or heterochromatin enhance the prediction of loop segregation into compartments. However, H3K9me3, H4K20me1, H3K27me3 histone modifications and GC content poorly indicate compartments. Full article

(This article belongs to the Special Issue Functions of Non-coding DNA Regions)

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13 pages, 681 KiB

Open AccessArticle

HERON: A Novel Tool Enables Identification of Long, Weakly Enriched Genomic Domains in ChIP-seq Data

by Anna Macioszek and Bartek Wilczynski

Int. J. Mol. Sci. 2021, 22(15), 8123; https://doi.org/10.3390/ijms22158123 - 29 Jul 2021

Viewed by 2178

Abstract

The explosive development of next-generation sequencing-based technologies has allowed us to take an unprecedented look at many molecular signatures of the non-coding genome. In particular, the ChIP-seq (Chromatin ImmunoPrecipitation followed by sequencing) technique is now very commonly used to assess the proteins associated with different non-coding DNA regions genome-wide. While the analysis of such data related to transcription factor binding is relatively straightforward, many modified histone variants, such as H3K27me3, are very important for the process of gene regulation but are very difficult to interpret. We propose a novel method, called HERON (HiddEn MaRkov mOdel based peak calliNg), for genome-wide data analysis that is able to detect DNA regions enriched for a certain feature, even in difficult settings of weakly enriched long DNA domains. We demonstrate the performance of our method both on simulated and experimental data. Full article

(This article belongs to the Special Issue Functions of Non-coding DNA Regions)

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15 pages, 3959 KiB

Open AccessArticle

K-mer Content Changes with Node Degree in Promoter–Enhancer Network of Mouse ES Cells

by Kinga Szyman, Bartek Wilczyński and Michał Dąbrowski

Int. J. Mol. Sci. 2021, 22(15), 8067; https://doi.org/10.3390/ijms22158067 - 28 Jul 2021

Viewed by 1916

Abstract

Maps of Hi-C contacts between promoters and enhancers can be analyzed as networks, with cis-regulatory regions as nodes and their interactions as edges. We checked if in the published promoter–enhancer network of mouse embryonic stem (ES) cells the differences in the node type (promoter or enhancer) and the node degree (number of regions interacting with a given promoter or enhancer) are reflected by sequence composition or sequence similarity of the interacting nodes. We used counts of all k-mers (k = 4) to analyze the sequence composition and the Euclidean distance between the k-mer count vectors (k-mer distance) as the measure of sequence (dis)similarity. The results we obtained with 4-mers are interpretable in terms of dinucleotides. Promoters are GC-rich as compared to enhancers, which is known. Enhancers are enriched in scaffold/matrix attachment regions (S/MARs) patterns and depleted of CpGs. Furthermore, we show that promoters are more similar to their interacting enhancers than vice-versa. Most notably, in both promoters and enhancers, the GC content and the CpG count increase with the node degree. As a consequence, enhancers of higher node degree become more similar to promoters, whereas higher degree promoters become less similar to enhancers. We confirmed the key results also for human keratinocytes. Full article

(This article belongs to the Special Issue Functions of Non-coding DNA Regions)

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20 pages, 3664 KiB

Open AccessArticle

Identification of Rhythmically Expressed LncRNAs in the Zebrafish Pineal Gland and Testis

by Shital Kumar Mishra, Taole Liu and Han Wang

Int. J. Mol. Sci. 2021, 22(15), 7810; https://doi.org/10.3390/ijms22157810 - 22 Jul 2021

Cited by 8 | Viewed by 2535

Abstract

Noncoding RNAs have been known to contribute to a variety of fundamental life processes, such as development, metabolism, and circadian rhythms. However, much remains unrevealed in the huge noncoding RNA datasets, which require further bioinformatic analysis and experimental investigation—and in particular, the coding potential of lncRNAs and the functions of lncRNA-encoded peptides have not been comprehensively studied to date. Through integrating the time-course experimentation with state-of-the-art computational techniques, we studied tens of thousands of zebrafish lncRNAs from our own experiments and from a published study including time-series transcriptome analyses of the testis and the pineal gland. Rhythmicity analysis of these data revealed approximately 700 rhythmically expressed lncRNAs from the pineal gland and the testis, and their GO, COG, and KEGG pathway functions were analyzed. Comparative and conservative analyses determined 14 rhythmically expressed lncRNAs shared between both the pineal gland and the testis, and 15 pineal gland lncRNAs as well as 3 testis lncRNAs conserved among zebrafish, mice, and humans. Further, we computationally analyzed the conserved lncRNA-encoded peptides, and revealed three pineal gland and one testis lncRNA-encoded peptides conserved among these three species, which were further investigated for their three-dimensional (3D) structures and potential functions. Our computational findings provided novel annotations and regulatory mechanisms for hundreds of rhythmically expressed pineal gland and testis lncRNAs in zebrafish, and set the stage for their experimental studies in the near future. Full article

(This article belongs to the Special Issue Functions of Non-coding DNA Regions)

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12 pages, 1680 KiB

Open AccessArticle

Role of Non-Coding Regulatory Elements in the Control of GR-Dependent Gene Expression

by Malgorzata Borczyk, Mateusz Zieba, Michał Korostyński and Marcin Piechota

Int. J. Mol. Sci. 2021, 22(8), 4258; https://doi.org/10.3390/ijms22084258 - 20 Apr 2021

Viewed by 2500

Abstract

The glucocorticoid receptor (GR, also known as NR3C1) coordinates molecular responses to stress. It is a potent transcription activator and repressor that influences hundreds of genes. Enhancers are non-coding DNA regions outside of the core promoters that increase transcriptional activity via long-distance interactions. Active GR binds to pre-existing enhancer sites and recruits further factors, including EP300, a known transcriptional coactivator. However, it is not known how the timing of GR-binding-induced enhancer remodeling relates to transcriptional changes. Here we analyze data from the ENCODE project that provides ChIP-Seq and RNA-Seq data at distinct time points after dexamethasone exposure of human A549 epithelial-like cell line. This study aimed to investigate the temporal interplay between GR binding, enhancer remodeling, and gene expression. By investigating a single distal GR-binding site for each differentially upregulated gene, we show that transcriptional changes follow GR binding, and that the largest enhancer remodeling coincides in time with the highest gene expression changes. A detailed analysis of the time course showed that for upregulated genes, enhancer activation persists after gene expression changes settle. Moreover, genes with the largest change in EP300 binding showed the highest expression dynamics before the peak of EP300 recruitment. Overall, our results show that enhancer remodeling may not directly be driving gene expression dynamics but rather be a consequence of expression activation. Full article

(This article belongs to the Special Issue Functions of Non-coding DNA Regions)

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29 pages, 4367 KiB

Open AccessArticle

Distinct miRNA Signatures and Networks Discern Fetal from Adult Erythroid Differentiation and Primary from Immortalized Erythroid Cells

by Panayiota L. Papasavva, Nikoletta Y. Papaioannou, Petros Patsali, Ryo Kurita, Yukio Nakamura, Maria Sitarou, Soteroulla Christou, Marina Kleanthous and Carsten W. Lederer

Int. J. Mol. Sci. 2021, 22(7), 3626; https://doi.org/10.3390/ijms22073626 - 31 Mar 2021

Cited by 12 | Viewed by 5658

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs crucial for post-transcriptional and translational regulation of cellular and developmental pathways. The study of miRNAs in erythropoiesis elucidates underlying regulatory mechanisms and facilitates related diagnostic and therapy development. Here, we used DNA Nanoball (DNB) small RNA sequencing to comprehensively characterize miRNAs in human erythroid cell cultures. Based on primary human peripheral-blood-derived CD34+ (hCD34+) cells and two influential erythroid cell lines with adult and fetal hemoglobin expression patterns, HUDEP-2 and HUDEP-1, respectively, our study links differential miRNA expression to erythroid differentiation, cell type, and hemoglobin expression profile. Sequencing results validated by reverse-transcription quantitative PCR (RT-qPCR) of selected miRNAs indicate shared differentiation signatures in primary and immortalized cells, characterized by reduced overall miRNA expression and reciprocal expression increases for individual lineage-specific miRNAs in late-stage erythropoiesis. Despite the high similarity of same-stage hCD34+ and HUDEP-2 cells, differential expression of several miRNAs highlighted informative discrepancies between both cell types. Moreover, a comparison between HUDEP-2 and HUDEP-1 cells displayed changes in miRNAs, transcription factors (TFs), target genes, and pathways associated with globin switching. In resulting TF-miRNA co-regulatory networks, major therapeutically relevant regulators of globin expression were targeted by many co-expressed miRNAs, outlining intricate combinatorial miRNA regulation of globin expression in erythroid cells. Full article

(This article belongs to the Special Issue Functions of Non-coding DNA Regions)

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14 pages, 466 KiB

Open AccessArticle

Association between HOX Transcript Antisense RNA Single-Nucleotide Variants and Recurrent Implantation Failure

by Jeong Yong Lee, Eun Hee Ahn, Hyeon Woo Park, Ji Hyang Kim, Young Ran Kim, Woo Sik Lee and Nam Keun Kim

Int. J. Mol. Sci. 2021, 22(6), 3021; https://doi.org/10.3390/ijms22063021 - 16 Mar 2021

Cited by 4 | Viewed by 2086

Abstract

Recurrent implantation failure (RIF) refers to the occurrence of more than two failed in vitro fertilization–embryo transfers (IVF-ETs) in the same individual. RIF can occur for many reasons, including embryo characteristics, immunological factors, and coagulation factors. Genetics can also contribute to RIF, with some single-nucleotide variants (SNVs) reported to be associated with RIF occurrence. We examined SNVs in a long non-coding RNA, homeobox (HOX) transcript antisense RNA (HOTAIR), which is known to affect cancer development. HOTAIR regulates epigenetic outcomes through histone modifications and chromatin remodeling. We recruited 155 female RIF patients and 330 healthy controls, and genotyped HOTAIR SNVs, including rs4759314, rs920778, rs7958904, and rs1899663, in all participants. Differences in these SNVs were compared between the patient and control groups. We identified significant differences in the occurrence of heterozygous genotypes and the dominant expression model for the rs1899663 and rs7958904 SNVs between RIF patients and control subjects. These HOTAIR variants were associated with serum hemoglobin (Hgb), luteinizing hormone (LH), total cholesterol (T. chol), and blood urea nitrogen (BUN) levels, as assessed by analysis of variance (ANOVA). We analyzed the four HOTAIR SNVs and found significant differences in haplotype patterns between RIF patients and healthy controls. The results of this study showed that HOTAIR is not only associated with the development of cancer but also with pregnancy-associated diseases. This study represents the first report showing that HOTAIR is correlated with RIF. Full article

(This article belongs to the Special Issue Functions of Non-coding DNA Regions)

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17 pages, 6019 KiB

Open AccessArticle

Characterization and Transcriptome Analysis of Exosomal and Nonexosomal RNAs in Bovine Adipocytes

by Binglin Yue, Haiyan Yang, Jiyao Wu, Jian Wang, Wenxiu Ru, Jie Cheng, Yongzheng Huang, Chuzhao Lei, Xianyong Lan and Hong Chen

Int. J. Mol. Sci. 2020, 21(23), 9313; https://doi.org/10.3390/ijms21239313 - 7 Dec 2020

Cited by 9 | Viewed by 2837

Abstract

Exosomes are endosome-derived extracellular vesicles that allow intercellular communication. However, the biological significance of adipocyte exosomal RNAs remains unclear. To determine the role of RNAs from bovine adipocytes and exosomes in bovine adipogenesis, exosomal and nonexosomal RNAs were extracted from three bovine primary white adipocyte samples and then profiles were generated using DNBSEQ/BGISEQ-500 technology. The RNAome of adipocytes consisted of 12,082 mRNAs, 8589 lncRNAs, and 378 miRNAs for a higher complexity that that detected in exosomes, with 1083 mRNAs, 105 lncRNAs, and 48 miRNAs. Exosomal miRNA-mRNA and lncRNA–miRNA–mRNA networks were constructed and enrichment analysis was performed to predict functional roles and regulatory mechanisms. Our study provides the first characterization of RNAs from bovine adipocyte and exosomes. The findings reveal that some RNAs are specifically packaged in adipocyte-derived exosomes, potentially enabling crosstalk between adipocytes and/or other cells that is mediated by exosomes. Our results greatly expand our understanding of exosomal RNAs from bovine adipocytes, and provide a reference for future functional investigations of adipocyte exosomal RNAs under normal physiological conditions. Full article

(This article belongs to the Special Issue Functions of Non-coding DNA Regions)

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14 pages, 2852 KiB

Open AccessArticle

Genome-Wide Analysis Reveals Changes in Long Noncoding RNAs in the Differentiation of Canine BMSCs into Insulin-Producing Cells

by Jinglu Wang, Pengxiu Dai, Dengke Gao, Xia Zhang, Chenmei Ruan, Jiakai Li, Yijing Chen, Luwen Zhang and Yihua Zhang

Int. J. Mol. Sci. 2020, 21(15), 5549; https://doi.org/10.3390/ijms21155549 - 3 Aug 2020

Cited by 6 | Viewed by 2594

Abstract

Long noncoding RNAs (lncRNAs) have been extensively explored over the past decade, including mice and humans. However, their impact on the transdifferentiation of canine bone marrow mesenchymal stem cells (cBMSCs) into insulin-producing cells (IPCs) is largely unknown. In this study, we used a three-step induction procedure to induce cBMSCs into IPCs, and samples (two biological replicates each) were obtained after each step; the samples consisted of “BMSCs” (B), “stage 1” (S1), “stage 2” (S2), “stage 3” (S3), and “islets” (I). After sequencing, 15,091 lncRNAs were identified, and we screened 110, 41, 23, and 686 differentially expressed lncRNAs (p_adjusted < 0.05) in B vs. S1, S1 vs. S2, S2 vs. S3, and I vs. S3 pairwise comparisons, respectively. In lncRNA target prediction, there were 166,623 colocalized targets and 2,976,362 correlated targets. Gene Ontology (GO) analysis showed that binding represented the main molecular functions of both the cis- and trans-modes. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that the insulin signaling pathway, Rap1 signaling pathway, tight junctions, MAPK signaling pathway, and cell cycle were enriched for these relative genes. The expression of lncRNAs was verified using qRT-PCR. This study provides a lncRNA catalog for future research concerning the mechanism of the transdifferentiation of cBMSCs into IPCs. Full article

(This article belongs to the Special Issue Functions of Non-coding DNA Regions)

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Review

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31 pages, 1299 KiB

Open AccessReview

Fish-Ing for Enhancers in the Heart

by Costantino Parisi, Shikha Vashisht and Cecilia Lanny Winata

Int. J. Mol. Sci. 2021, 22(8), 3914; https://doi.org/10.3390/ijms22083914 - 10 Apr 2021

Cited by 5 | Viewed by 4585

Abstract

Precise control of gene expression is crucial to ensure proper development and biological functioning of an organism. Enhancers are non-coding DNA elements which play an essential role in regulating gene expression. They contain specific sequence motifs serving as binding sites for transcription factors which interact with the basal transcription machinery at their target genes. Heart development is regulated by intricate gene regulatory network ensuring precise spatiotemporal gene expression program. Mutations affecting enhancers have been shown to result in devastating forms of congenital heart defect. Therefore, identifying enhancers implicated in heart biology and understanding their mechanism is key to improve diagnosis and therapeutic options. Despite their crucial role, enhancers are poorly studied, mainly due to a lack of reliable way to identify them and determine their function. Nevertheless, recent technological advances have allowed rapid progress in enhancer discovery. Model organisms such as the zebrafish have contributed significant insights into the genetics of heart development through enabling functional analyses of genes and their regulatory elements in vivo. Here, we summarize the current state of knowledge on heart enhancers gained through studies in model organisms, discuss various approaches to discover and study their function, and finally suggest methods that could further advance research in this field. Full article

(This article belongs to the Special Issue Functions of Non-coding DNA Regions)

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21 pages, 1922 KiB

Open AccessReview

Long Noncoding RNAs—Crucial Players Organizing the Landscape of the Neuronal Nucleus

by Hanna Sas-Nowosielska and Adriana Magalska

Int. J. Mol. Sci. 2021, 22(7), 3478; https://doi.org/10.3390/ijms22073478 - 27 Mar 2021

Cited by 5 | Viewed by 3581

Abstract

The ability to regulate chromatin organization is particularly important in neurons, which dynamically respond to external stimuli. Accumulating evidence shows that lncRNAs play important architectural roles in organizing different nuclear domains like inactive chromosome X, splicing speckles, paraspeckles, and Gomafu nuclear bodies. LncRNAs are abundantly expressed in the nervous system where they may play important roles in compartmentalization of the cell nucleus. In this review we will describe the architectural role of lncRNAs in the nuclei of neuronal cells. Full article

(This article belongs to the Special Issue Functions of Non-coding DNA Regions)

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