Genomic Variants and Multilevel Regulation of ABCA1, ABCG1, and SCARB1 Expression in Atherogenesis

Atheroprotective properties of human plasma high-density lipoproteins (HDLs) are determined by their involvement in reverse cholesterol transport (RCT) from the macrophage to the liver. ABCA1, ABCG1, and SR-BI cholesterol transporters are involved in cholesterol efflux from macrophages to lipid-free ApoA-I and HDL as a first RCT step. Molecular determinants of RCT efficiency that may possess diagnostic and therapeutic meaning remain largely unknown. This review summarizes the progress in studying the genomic variants of ABCA1, ABCG1, and SCARB1, and the regulation of their function at transcriptional and post-transcriptional levels in atherosclerosis. Defects in the structure and function of ABCA1, ABCG1, and SR-BI are caused by changes in the gene sequence, such as single nucleotide polymorphism or various mutations. In the transcription initiation of transporter genes, in addition to transcription factors, long noncoding RNA (lncRNA), transcription activators, and repressors are also involved. Furthermore, transcription is substantially influenced by the methylation of gene promoter regions. Post-transcriptional regulation involves microRNAs and lncRNAs, including circular RNAs. The potential biomarkers and targets for atheroprotection, based on molecular mechanisms of expression regulation for three transporter genes, are also discussed in this review.

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Circular RNAs: Biogenesis, Mechanism, and Function in Human Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms20163926 ◽

2019 ◽

Vol 20 (16) ◽

pp. 3926 ◽

Cited By ~ 25

Author(s):

Xing Zhao ◽

Yujie Cai ◽

Jianzhen Xu

Keyword(s):

Noncoding Rna ◽

Binding Proteins ◽

Molecular Mechanisms ◽

Rna Binding ◽

Rna Binding Proteins ◽

Cancer Development ◽

Circular Rnas ◽

Open Questions ◽

Circular Configuration ◽

And Function

CircRNAs are a class of noncoding RNA species with a circular configuration that is formed by either typical spliceosome-mediated or lariat-type splicing. The expression of circRNAs is usually abnormal in many cancers. Several circRNAs have been demonstrated to play important roles in carcinogenesis. In this review, we will first provide an introduction of circRNAs biogenesis, especially the regulation of circRNA by RNA-binding proteins, then we will focus on the recent findings of circRNA molecular mechanisms and functions in cancer development. Finally, some open questions are also discussed.

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The Roles of the Histone Protein Modifier EZH2 in the Uterus and Placenta

Epigenomes ◽

10.3390/epigenomes4030020 ◽

2020 ◽

Vol 4 (3) ◽

pp. 20

Author(s):

Ana M. Mesa ◽

Cheryl S. Rosenfeld ◽

Geetu Tuteja ◽

Theresa I. Medrano ◽

Paul S. Cooke

Keyword(s):

Critical Role ◽

Histone H3 ◽

Gene Promoter ◽

Epigenetic Changes ◽

Promoter Regions ◽

Polycomb Repressive Complex 2 ◽

Gene Sets ◽

Ezh2 Expression ◽

And Function ◽

Transcription Enhancer

Epigenetic modifications regulate normal physiological, as well as pathological processes in various organs, including the uterus and placenta. Both organs undergo dramatic and rapid restructuring that depends upon precise orchestration of events. Epigenetic changes that alter transcription and translation of gene-sets regulate such responses. Histone modifications alter the chromatin structure, thereby affecting transcription factor access to gene promoter regions. Binding of histones to DNA is regulated by addition or removal of subunit methyl and other groups, which can inhibit or stimulate transcription. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) and subsequently suppresses transcription of genes bound by such histones. Uterine EZH2 expression exerts a critical role in development and function of this organ with deletion of this gene resulting in uterine hyperplasia and expression of cancer-associated transcripts. Elucidating the roles of EZH2 in uterus and placenta is essential as EZH2 dysregulation is associated with several uterine and placental pathologies. Herein, we discuss EZH2 functions in uterus and placenta, emphasizing its physiological and pathological importance.

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Sophisticated Gene Regulation for a Complex Physiological System: The Role of Non-coding RNAs in Photoreceptor Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.629158 ◽

2021 ◽

Vol 8 ◽

Author(s):

Sabrina Carrella ◽

Sandro Banfi ◽

Marianthi Karali

Keyword(s):

Molecular Mechanisms ◽

Developmental Process ◽

Photoreceptor Cells ◽

Sensory Transduction ◽

Circular Rnas ◽

Therapeutic Implications ◽

Physiological Processes ◽

Non Coding Rnas ◽

And Function

Photoreceptors (PRs) are specialized neuroepithelial cells of the retina responsible for sensory transduction of light stimuli. In the highly structured vertebrate retina, PRs have a highly polarized modular structure to accommodate the demanding processes of phototransduction and the visual cycle. Because of their function, PRs are exposed to continuous cellular stress. PRs are therefore under pressure to maintain their function in defiance of constant environmental perturbation, besides being part of a highly sophisticated developmental process. All this translates into the need for tightly regulated and responsive molecular mechanisms that can reinforce transcriptional programs. It is commonly accepted that regulatory non-coding RNAs (ncRNAs), and in particular microRNAs (miRNAs), are not only involved but indeed central in conferring robustness and accuracy to developmental and physiological processes. Here we integrate recent findings on the role of regulatory ncRNAs (e.g., miRNAs, lncRNAs, circular RNAs, and antisense RNAs), and of their contribution to PR pathophysiology. We also outline the therapeutic implications of translational studies that harness ncRNAs to prevent PR degeneration and promote their survival and function.

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Mechanisms of Long Non-Coding RNAs in Cancers and Their Dynamic Regulations

Cancers ◽

10.3390/cancers12051245 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1245 ◽

Cited By ~ 13

Author(s):

Xiao-Zhen Zhang ◽

Hao Liu ◽

Su-Ren Chen

Keyword(s):

Noncoding Rna ◽

Translational Regulation ◽

Molecular Mechanisms ◽

Biological Activities ◽

Cancer Therapies ◽

Search Terms ◽

Non Coding Rna ◽

Pubmed Database ◽

And Function ◽

Long Non Coding Rna

Long non-coding RNA (lncRNA), which is a kind of noncoding RNA, is generally characterized as being more than 200 nucleotide transcripts in length. LncRNAs exhibit many biological activities, including, but not limited to, cancer development. In this review, a search of the PubMed database was performed to identify relevant studies published in English. The term “lncRNA or long non-coding RNA” was combined with a range of search terms related to the core focus of the review: mechanism, structure, regulation, and cancer. The eligibility of the retrieved studies was mainly based on the abstract. The decision as to whether or not the study was included in this review was made after a careful assessment of its content. The reference lists were also checked to identify any other study that could be relevant to this review. We first summarized the molecular mechanisms of lncRNAs in tumorigenesis, including competing endogenous RNA (ceRNA) mechanisms, epigenetic regulation, decoy and scaffold mechanisms, mRNA and protein stability regulation, transcriptional and translational regulation, miRNA processing regulation, and the architectural role of lncRNAs, which will help a broad audience better understand how lncRNAs work in cancer. Second, we introduced recent studies to elucidate the structure of lncRNAs, as there is a link between lncRNA structure and function and visualizing the architectural domains of lncRNAs is vital to understanding their function. Third, we explored emerging evidence for regulators of lncRNA expression, lncRNA turnover, and lncRNA modifications (including 5-methylcytidine, N6-methyladenosine, and adenosine to inosine editing), highlighting the dynamics of lncRNAs. Finally, we used autophagy in cancer as an example to interpret the diverse mechanisms of lncRNAs and introduced clinical trials of lncRNA-based cancer therapies.

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Functional long non-coding and circular RNAs in zebrafish

Briefings in Functional Genomics ◽

10.1093/bfgp/elab014 ◽

2021 ◽

Author(s):

Gyan Ranjan ◽

Paras Sehgal ◽

Disha Sharma ◽

Vinod Scaria ◽

Sridhar Sivasubbu

Keyword(s):

Noncoding Rna ◽

Molecular Mechanisms ◽

Cellular Level ◽

Model Organisms ◽

Circular Rnas ◽

Computational Techniques ◽

Modeling And Analysis ◽

Novel Transcript ◽

Disease Biology ◽

Analysis Of Function

AbstractThe utility of model organisms to understand the function of a novel transcript/genes has allowed us to delineate their molecular mechanisms in maintaining cellular homeostasis. Organisms such as zebrafish have contributed a lot in the field of developmental and disease biology. Attributable to advancement and deep transcriptomics, many new transcript isoforms and non-coding RNAs such as long noncoding RNA (lncRNA) and circular RNAs (circRNAs) have been identified and cataloged in multiple databases and many more are yet to be identified. Various methods and tools have been utilized to identify lncRNAs/circRNAs in zebrafish using deep sequencing of transcriptomes as templates. Functional analysis of a few candidates such as tie1-AS, ECAL1 and CDR1as in zebrafish provides a prospective outline to approach other known or novel lncRNA/circRNA. New genetic alteration tools like TALENS and CRISPRs have helped in probing for the molecular function of lncRNA/circRNA in zebrafish. Further latest improvements in experimental and computational techniques offer the identification of lncRNA/circRNA counterparts in humans and zebrafish thereby allowing easy modeling and analysis of function at cellular level.

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circAkap17b acts as a miR-7 family molecular sponge to regulate FSH secretion in rat pituitary cells

Journal of Molecular Endocrinology ◽

10.1530/jme-20-0036 ◽

2020 ◽

Vol 65 (4) ◽

pp. 135-148

Author(s):

Chang-Jiang Wang ◽

Fei Gao ◽

Yi-Jie Huang ◽

Dong-Xu Han ◽

Yi Zheng ◽

...

Keyword(s):

Noncoding Rna ◽

Molecular Mechanisms ◽

Target Genes ◽

Luciferase Reporter ◽

Circular Rnas ◽

Pituitary Cells ◽

Rat Pituitary ◽

Rna Immunoprecipitation ◽

Rat Pituitary Cells

The pituitary gland functions as a prominent regulator of diverse physiologic processes by secreting multiple hormones. Circular RNAs (circRNAs) are an emerging novel type of endogenous noncoding RNA that have recently been recognized as powerful regulators participating in various biological processes. However, the physiological roles and molecular mechanisms of circRNAs in pituitary remain largely unclear. Herein, we concentrated on expounding the biological function and molecular mechanism of circRNA in rat pituitary. In this study, we identified a novel circRNA in pituitary tissue, circAkap17b, which was pituitary- and stage-specific. Then, we designed circAkap17b siRNA and constructed an overexpression plasmid to evaluate the effect of loss- and gain-of-circAkap17b function on FSH secretion. Interestingly, silencing circAkakp17b significantly inhibited FSH expression and secretion, while overexpression of circAkap17b enhanced FSH expression and secretion. Furthermore, dual luciferase reporter and RNA immunoprecipitation (RIP) assays confirmed that circAkap17b could serve as miR-7 sponge to regulate target genes. Additionally, miR-7b suppressed FSH expression and secretion by directly targeting Fshb through the dual luciferase reporter and RT-qPCR analysis. Additionally, rescue experiments showed that circAkap17b could regulate FSH secretion in pituitary cells through a circAkap17b-miR-7-Fshb axis. Collectively, we demonstrated that circAkap17b could act as a molecular sponge of miR-7 to upregulate expression of the target gene Fshb and facilitate FSH secretion. These findings provide evidence for a novel regulatory role of circRNAs in pituitary.

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The Regulatory Activity of Noncoding RNAs in ILCs

Cells ◽

10.3390/cells10102742 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2742

Author(s):

Alessio Grimaldi ◽

Giuseppe Pietropaolo ◽

Helena Stabile ◽

Andrea Kosta ◽

Cristina Capuano ◽

...

Keyword(s):

Noncoding Rna ◽

Rna Stability ◽

Lymphoid Cells ◽

Circular Rnas ◽

Transcriptional Networks ◽

Regulatory Activity ◽

Protein Coding ◽

Host Protection ◽

Microbial Infections ◽

And Function

Innate lymphoid cells (ILCs) are innate lymphocytes playing essential functions in protection against microbial infections and participate in both homeostatic and pathological contexts, including tissue remodeling, cancer, and inflammatory disorders. A number of lineage-defining transcription factors concur to establish transcriptional networks which determine the identity and the activity of the distinct ILC subsets. However, the contribution of other regulatory molecules in controlling ILC development and function is also recently emerging. In this regard, noncoding RNA (ncRNAs) represent key elements of the complex regulatory network of ILC biology and host protection. ncRNAs mostly lack protein-coding potential, but they are endowed with a relevant regulatory activity in immune and nonimmune cells because of their ability to control chromatin structure, RNA stability, and/or protein synthesis. Herein, we summarize recent studies describing how distinct types of ncRNAs, mainly microRNAs, long ncRNAs, and circular RNAs, act in the context of ILC biology. In particular, we comment on how ncRNAs can exert key effects in ILCs by controlling gene expression in a cell- or state-specific manner and how this tunes distinct functional outputs in ILCs.

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Molecular Mechanisms and Function Prediction of Long Noncoding RNA

The Scientific World JOURNAL ◽

10.1100/2012/541786 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 47

Author(s):

Handong Ma ◽

Yun Hao ◽

Xinran Dong ◽

Qingtian Gong ◽

Jingqi Chen ◽

...

Keyword(s):

Computational Methods ◽

Genetic Information ◽

Noncoding Rna ◽

Recent Progress ◽

Molecular Mechanisms ◽

Noncoding Rnas ◽

Whole Genome ◽

Biological Functions ◽

Large Numbers ◽

And Function

The central dogma of gene expression considers RNA as the carrier of genetic information from DNA to protein. However, it has become more and more clear that RNA plays more important roles than simply being the information carrier. Recently, whole genome transcriptomic analyses have identified large numbers of dynamically expressed long noncoding RNAs (lncRNAs), many of which are involved in a variety of biological functions. Even so, the functions and molecular mechanisms of most lncRNAs still remain elusive. Therefore, it is necessary to develop computational methods to predict the function of lncRNAs in order to accelerate the study of lncRNAs. Here, we review the recent progress in the identification of lncRNAs, the molecular functions and mechanisms of lncRNAs, and the computational methods for predicting the function of lncRNAs.

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Epigenetic Regulation of Polymerase II Transcription Initiation in Trypanosoma cruzi: Modulation of Nucleosome Abundance, Histone Modification, and Polymerase Occupancy by O-Linked Thymine DNA Glucosylation

Eukaryotic Cell ◽

10.1128/ec.05185-11 ◽

2011 ◽

Vol 10 (11) ◽

pp. 1465-1472 ◽

Cited By ~ 32

Author(s):

Dilrukshi Ekanayake ◽

Robert Sabatini

Keyword(s):

Gene Expression ◽

Trypanosoma Cruzi ◽

Epigenetic Regulation ◽

Chromatin Structure ◽

Transcription Initiation ◽

Gene Promoter ◽

Gene Organization ◽

Promoter Regions ◽

Pol Ii ◽

Content Type

ABSTRACT Very little is understood regarding how transcription is initiated/regulated in the early-diverging eukaryote Trypanosoma cruzi . Unusually for a eukaryote, genes transcribed by RNA polymerase (Pol) II in T. cruzi are arranged in polycistronic transcription units (PTUs). On the basis of this gene organization, it was previously thought that trypanosomes rely solely on posttranscriptional processes to regulate gene expression. We recently localized a novel glucosylated thymine DNA base, called base J, to potential promoter regions of PTUs throughout the trypanosome genome. Loss of base J, following the deletion of JBP1, a thymidine hydroxylase involved with synthesis, led to a global increase in the Pol II transcription rate and gene expression. In order to determine the mechanism by which base J regulates transcription, we have characterized changes in chromatin structure and Pol II recruitment to promoter regions following the loss of base J. The loss of base J coincides with a decrease in nucleosome abundance, increased histone H3/H4 acetylation, and increased Pol II occupancy at promoter regions, including the well-characterized spliced leader RNA gene promoter. These studies present the first direct evidence for epigenetic regulation of Pol II transcription initiation via DNA modification and chromatin structure in kinetoplastids as well as provide a mechanism for regulation of trypanosome gene expression via the novel hypermodified base J.

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Early-Life Stress Induced Epigenetic Changes of Corticotropin-Releasing Factor Gene in Anorexic Low Body Weight–Selected Chicks

Life ◽

10.3390/life10050051 ◽

2020 ◽

Vol 10 (5) ◽

pp. 51

Author(s):

Yang Xiao ◽

Jinxin Wang ◽

Paul B. Siegel ◽

Mark A. Cline ◽

Elizabeth R. Gilbert

Keyword(s):

Body Weight ◽

Life Stress ◽

Dna Methyltransferase ◽

Molecular Mechanisms ◽

Gene Promoter ◽

Early Life Stress ◽

Binding Domain ◽

Corticotropin Releasing Factor ◽

Stressful Events ◽

Promoter Regions

The expression of neuropeptide Y (NPY) in the arcuate nucleus (ARC) and corticotropin-releasing factor (CRF) in the paraventricular nucleus (PVN) were increased when low body weight–selected (LWS) line chicks, which are predisposed to anorexia, were subjected to a combination of nutritional and thermal stressors at hatch. We hypothesized that such changes resulted from epigenetic modifications. We determined global DNA methylation, DNA methyltransferase (DNMT) activity, and methylation near the promoter regions of NPY and CRF, in the hypothalamus of LWS chicks on day 5 post-hatch. Stress exposure at hatch induced global hypermethylation and increased DNMT activity in the ARC but not PVN. In the PVN of stressed LWS chicks, there was decreased methylation of a CpG site located at the core binding domain of methyl cytosine binding domain protein 2 (MBD2), near the CRF gene promoter. We then demonstrated that this was associated with disrupted binding of MBD2. There was also reduced utilization of yolk reserves and lean and fat masses in chicks that were stress-exposed. These findings provide novel insights on molecular mechanisms through which stressful events induce or intensify anorexia in predisposed individuals and a novel molecular target for further studies.

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