scholarly journals Enhancing gonadotrope gene expression through regulatory lncRNAs

Endocrinology ◽  
2021 ◽  
Author(s):  
Tal Refael ◽  
Philippa Melamed
Keyword(s):  
Gene Expression ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Transcriptional Enhancers ◽  
Open Questions ◽  
A Cell ◽  
Non Coding Rnas ◽  
Distal Regulatory Elements ◽  
Gonadotropic Hormones ◽  
Shed Light

Abstract The world of long non-coding RNAs (lncRNAs) has opened up massive new prospects in understanding the regulation of gene expression. Not only are there seemingly almost infinite numbers of lncRNAs in the mammalian cell, but they have highly diverse mechanisms of action. In the nucleus, some are chromatin-associated, transcribed from transcriptional enhancers (eRNAs) and/or direct changes in the epigenetic landscape with profound effects on gene expression. The pituitary gonadotrope is responsible for activation of reproduction through production and secretion of appropriate levels of the gonadotropic hormones. As such, it exemplifies a cell whose function is defined through changes in developmental and temporal patterns of gene expression, including those that are hormonally-induced. Roles for diverse distal regulatory elements and eRNAs in gonadotrope biology have only just begun to emerge. Here, we will present an overview of the different kinds of lncRNAs that alter gene expression, and what is known about their roles in regulating some of the key gonadotrope genes. We will also review various screens that have detected differentially expressed pituitary lncRNAs associated with changes in reproductive state, and those whose expression is found to play a role in gonadotrope-derived non-functioning pituitary adenomas. We hope to shed light on this exciting new field, emphasize the open questions, and encourage research to illuminate the roles of lncRNAs in various endocrine systems.

scholarly journals Transcriptional Enhancers in Drosophila

Genetics ◽  
2020 ◽  
Vol 216 (1) ◽  
pp. 1-26 ◽  
Author(s):  
Stephen Small ◽  
David N. Arnosti
Keyword(s):  
Gene Expression ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Comprehensive Analysis ◽  
Special Focus ◽  
Transcriptional Enhancers ◽  
Quantitative Understanding ◽  
Developmental Role

Key discoveries in Drosophila have shaped our understanding of cellular “enhancers.” With a special focus on the fly, this chapter surveys properties of these adaptable cis-regulatory elements, whose actions are critical for the complex spatial/temporal transcriptional regulation of gene expression in metazoa. The powerful combination of genetics, molecular biology, and genomics available in Drosophila has provided an arena in which the developmental role of enhancers can be explored. Enhancers are characterized by diverse low- or high-throughput assays, which are challenging to interpret, as not all of these methods of identifying enhancers produce concordant results. As a model metazoan, the fly offers important advantages to comprehensive analysis of the central functions that enhancers play in gene expression, and their critical role in mediating the production of phenotypes from genotype and environmental inputs. A major challenge moving forward will be obtaining a quantitative understanding of how these cis-regulatory elements operate in development and disease.

scholarly journals Long Non-Coding RNAs in the Regulation of Gene Expression: Physiology and Disease

2019 ◽  
Vol 5 (1) ◽  
pp. 17 ◽  
Author(s):  
Juliane Fernandes ◽  
Stephanie Acuña ◽  
Juliana Aoki ◽  
Lucile Floeter-Winter ◽  
Sandra Muxel
Keyword(s):  
Gene Expression ◽  
Messenger Rna ◽  
Functional Characterization ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Response Modulation ◽  
Physiological Processes ◽  
Interaction Domains ◽  
Non Coding Rnas ◽  
New Generation

The identification of RNAs that are not translated into proteins was an important breakthrough, defining the diversity of molecules involved in eukaryotic regulation of gene expression. These non-coding RNAs can be divided into two main classes according to their length: short non-coding RNAs, such as microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). The lncRNAs in association with other molecules can coordinate several physiological processes and their dysfunction may impact in several pathologies, including cancer and infectious diseases. They can control the flux of genetic information, such as chromosome structure modulation, transcription, splicing, messenger RNA (mRNA) stability, mRNA availability, and post-translational modifications. Long non-coding RNAs present interaction domains for DNA, mRNAs, miRNAs, and proteins, depending on both sequence and secondary structure. The advent of new generation sequencing has provided evidences of putative lncRNAs existence; however, the analysis of transcriptomes for their functional characterization remains a challenge. Here, we review some important aspects of lncRNA biology, focusing on their role as regulatory elements in gene expression modulation during physiological and disease processes, with implications in host and pathogens physiology, and their role in immune response modulation.

scholarly journals Graph-based data integration predicts long-range regulatory interactions across the human genome

2014 ◽  
Author(s):  
Sofie Demeyer ◽  
Tom Michoel
Keyword(s):  
Gene Expression ◽  
Long Range ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Exon Array ◽  
Regulatory Elements ◽  
Computational Method ◽  
Open Chromatin ◽  
Transcription Start Sites ◽  
Distal Regulatory Elements

Transcriptional regulation of gene expression is one of the main processes that affect cell diversification from a single set of genes. Regulatory proteins often interact with DNA regions located distally from the transcription start sites (TSS) of the genes. We developed a computational method that combines open chromatin and gene expression information for a large number of cell types to identify these distal regulatory elements. Our method builds correlation graphs for publicly available DNase-seq and exon array datasets with matching samples and uses graph-based methods to filter findings supported by multiple datasets and remove indirect interactions. The resulting set of interactions was validated with both anecdotal information of known long-range interactions and unbiased experimental data deduced from Hi-C and CAGE experiments. Our results provide a novel set of high-confidence candidate open chromatin regions involved in gene regulation, often located several Mb away from the TSS of their target gene.

scholarly journals Long non-coding RNAs in brain tumors

NAR Cancer ◽  
2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Keisuke Katsushima ◽  
George Jallo ◽  
Charles G Eberhart ◽  
Ranjan J Perera
Keyword(s):  
Gene Expression ◽  
Brain Tumors ◽  
Brain Cancer ◽  
Regulation Of Gene Expression ◽  
Therapeutic Targets ◽  
Diagnostic Biomarkers ◽  
Cancer Pathogenesis ◽  
Current State ◽  
Non Coding Rnas ◽  
Post Transcriptional Regulation

Abstract Long non-coding RNAs (lncRNAs) have been found to be central players in the epigenetic, transcriptional and post-transcriptional regulation of gene expression. There is an accumulation of evidence on newly discovered lncRNAs, their molecular interactions and their roles in the development and progression of human brain tumors. LncRNAs can have either tumor suppressive or oncogenic functions in different brain cancers, making them attractive therapeutic targets and biomarkers for personalized therapy and precision diagnostics. Here, we summarize the current state of knowledge of the lncRNAs that have been implicated in brain cancer pathogenesis, particularly in gliomas and medulloblastomas. We discuss their epigenetic regulation as well as the prospects of using lncRNAs as diagnostic biomarkers and therapeutic targets in patients with brain tumors.

scholarly journals Epigenomics of Plant’s Responses to Environmental Stress

2017 ◽  
Author(s):  
Suresh Kumar
Keyword(s):  
Gene Expression ◽  
Nuclear Dna ◽  
Environmental Stresses ◽  
Transcriptional Level ◽  
Epigenetic Changes ◽  
Post Translational Modifications ◽  
Genome Wide ◽  
A Cell ◽  
Non Coding Rnas ◽  
Function Activity

Genome-wide epigenetic changes in plants are being reported during the development and environmental stresses, which are often correlated with gene expression at the transcriptional level. Sum total of the biochemical changes in nuclear DNA, post-translational modifications in histone proteins and variations in the biogenesis of non-coding RNAs in a cell is known as epigenome. These changes are often responsible for variation in expression of the gene without any change in the underlying nucleotide sequence. The changes might also cause variation in chromatin structure resulting into the changes in function/activity of the genome. The epigenomic changes are dynamic with respect to the endogenous and/or environmental stimuli which affect phenotypic plasticity of the organism. Both, the epigenetic changes and variation in gene expression might return to the pre-stress state soon after withdrawal of the stress. However, a part of the epigenetic changes may be retained which is reported to play role in acclimatization, adaptation as well as in the evolutionary processes. Understanding epigenome-engineering for improved stress tolerance in plants has become essential for better utilization of the genetic factors. This review delineates the importance of epigenomics towards possible improvement of plant’s responses to environmental stresses for climate resilient agriculture.

scholarly journals BET bromodomain proteins regulate enhancer function during adipogenesis

2018 ◽  
Vol 115 (9) ◽  
pp. 2144-2149 ◽  
Author(s):  
Jonathan D. Brown ◽  
Zachary B. Feldman ◽  
Sean P. Doherty ◽  
Jaime M. Reyes ◽  
Peter B. Rahl ◽  
...  
Keyword(s):  
Gene Expression ◽  
De Novo ◽  
Critical Role ◽  
Regulatory Elements ◽  
Developmental Transitions ◽  
Adipocyte Cell ◽  
Bromodomain Proteins ◽  
Enhancer Function ◽  
Distal Regulatory Elements ◽  
Expression Program

Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/EBPα expression are less well characterized. Here, we show the bromodomain-containing protein, BRD4, regulates transcription of PPARγ and C/EBPα. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation. Inhibition of the bromodomain and extraterminal domain (BET) family of bromodomain-containing proteins impedes BRD4 occupancy at these de novo enhancers and disrupts transcription of Pparg and Cebpa, thereby blocking adipogenesis. Furthermore, silencing of these BRD4-occupied distal regulatory elements at the Pparg locus by CRISPRi demonstrates a critical role for these enhancers in the control of Pparg gene expression and adipogenesis in 3T3L1s. Together, these data establish BET bromodomain proteins as time- and context-dependent coactivators of the adipocyte cell state transition.

scholarly journals Inducible cell-specific mouse models for paired epigenetic and transcriptomic studies of microglia and astroglia

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Ana J. Chucair-Elliott ◽  
Sarah R. Ocañas ◽  
David R. Stanford ◽  
Victor A. Ansere ◽  
Kyla B. Buettner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Affinity Purification ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Tissue Level ◽  
Cell Phenotype ◽  
Specific Gene ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific

AbstractEpigenetic regulation of gene expression occurs in a cell type-specific manner. Current cell-type specific neuroepigenetic studies rely on cell sorting methods that can alter cell phenotype and introduce potential confounds. Here we demonstrate and validate a Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) approach for temporally controlled labeling and isolation of ribosomes and nuclei, and thus RNA and DNA, from specific central nervous system cell types. Analysis of gene expression and DNA modifications in astrocytes or microglia from the same animal demonstrates differential usage of DNA methylation and hydroxymethylation in CpG and non-CpG contexts that corresponds to cell type-specific gene expression. Application of this approach in LPS treated mice uncovers microglia-specific transcriptome and epigenome changes in inflammatory pathways that cannot be detected with tissue-level analysis. The NuTRAP model and the validation approaches presented can be applied to any brain cell type for which a cell type-specific cre is available.

The Role of miR-210 in the Biological System: A Current Overview

2019 ◽  
Vol 84 (6) ◽  
pp. 233-239
Author(s):  
Xu Hui ◽  
Hisham Al-Ward ◽  
Fahmi Shaher ◽  
Chun-Yang Liu ◽  
Ning Liu
Keyword(s):  
Gene Expression ◽  
Regulation Of Gene Expression ◽  
Low Oxygen ◽  
Cellular Functions ◽  
Regulate Gene Expression ◽  
System A ◽  
Non Coding Rnas ◽  
Post Transcriptional Regulation ◽  
A Current

<b><i>Background:</i></b> MicroRNAs (miRNAs) represent a group of non-coding RNAs measuring 19–23 nucleotides in length and are recognized as powerful molecules that regulate gene expression in eukaryotic cells. miRNAs stimulate the post-transcriptional regulation of gene expression via direct or indirect mechanisms. <b><i>Summary:</i></b> miR-210 is highly upregulated in cells under hypoxia, thereby revealing its significance to cell endurance. Induction of this mRNA expression is an important feature of the cellular low-oxygen response and the most consistent and vigorous target of HIF. <b><i>Key Message:</i></b> miR-210 is involved in many cellular functions under the effect of HIF-1α, including the cell cycle, DNA repair, immunity and inflammation, angiogenesis, metabolism, and macrophage regulation. It also plays an important regulatory role in T-cell differentiation and stimulation.

scholarly journals STAT5 regulation of sex-dependent hepatic CpG methylation at distal regulatory elements mapping to sex-biased genes

2020 ◽  
Author(s):  
Pengying Hao ◽  
David J. Waxman
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Mouse Liver ◽  
Regulatory Elements ◽  
Cpg Methylation ◽  
Sex Bias ◽  
Liver Chromatin ◽  
Differential Gene ◽  
Genomic Regions ◽  
Distal Regulatory Elements

Growth hormone-activated STAT5b is an essential regulator of sex-differential gene expression in mouse liver, however, its impact on hepatic gene expression and epigenetic responses is poorly understood. Here, we found a substantial, albeit incomplete loss of liver sex bias in hepatocyte-specific STAT5a/STAT5b (collectively, STAT5)-deficient mouse liver. In male liver, many male-biased genes were down regulated in direct association with the loss of STAT5 binding; many female-biased genes, which show low STAT5 binding, were de-repressed, indicating an indirect mechanism for repression by STAT5. Extensive changes in CpG-methylation were seen in STAT5-deficient liver, where sex differences were abolished at 88% of ∼1,500 sex-differentially methylated regions, largely due to increased DNA methylation upon STAT5 loss. STAT5-dependent CpG-hypomethylation was rarely found at proximal promoters of STAT5-dependent genes. Rather, STAT5 primarily regulated the methylation of distal enhancers, where STAT5 deficiency induced widespread hypermethylation at genomic regions enriched for accessible chromatin, enhancer histone marks (H3K4me1, H3K27ac), STAT5 binding, and DNA motifs for STAT5 and other transcription factors implicated in liver sex differences. Thus, the sex-dependent binding of STAT5 to liver chromatin is closely linked to the sex-dependent demethylation of distal regulatory elements linked to STAT5-dependent genes important for liver sex bias.

Identification of a Gain-of-Function SNP Causing a New Model of α-Thalassaemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 523-523
Author(s):  
Marco De Gobbi ◽  
Vip Viprakasit ◽  
Pieter J. de Jong ◽  
Yuko Yoshinaga ◽  
Jan-Fang Cheng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Site ◽  
Globin Gene ◽  
Regulation Of Gene Expression ◽  
Histone H3 ◽  
Regulatory Elements ◽  
Causative Mutation ◽  
Regulatory Sequences ◽  
Chromosome 16 ◽  
Upstream Regulatory Sequences

Abstract The human α globin cluster includes an embryonic gene ζ and 2 fetal/adult genes (α2 and α1) arranged along the chromosome in the order in which they are expressed in development (5′-ζ-pseudoζ- αD- α2-α1-𝛉-3′). Fully activated expression of these genes in erythroid cells depends on upstream regulatory elements of which HS-40, located 40kb upstream of the cluster, appears to exert the greatest effect. We have recently shown that during terminal differentiation, key transcription factors (GATA-2, GATA-1, NF-E2, SCL complex) sequentially bind the α promoters and their regulatory elements and a domain of histone acetylation develops which eventually encompasses the entire α globin cluster including the upstream regulatory sequences. α-thalassemia most frequently results from deletions or point mutations affecting the structural α globin genes, but may also result from rare sporadic deletions which remove the upstream regulatory sequences. In a single family α globin expression was silenced by a mutation which drives an anti-sense RNA through the α gene. Alpha thalassemia may also result from inherited and acquired mutations in a trans-acting factor called ATRX. Over the past few years we have continued to screen for new mechanisms which lead to α thalassemia and thereby elucidate new principles underlying the regulation of gene expression in hemopoiesis. Here we describe a new mechanism of α thalassemia occurring in Pacific Islanders in whom we could detect no mutations or rearrangements in the α globin gene locus. Despite this, extensive genetic analysis showed unequivocally that the causative mutation is linked to the terminal 169kb of chromosome 16 (Viprakasit et al accompanying abstract). Analysis of globin synthesis, steady state RNA levels and detection of RNA in situ demonstrated that the mutation downregulates α globin transcription. To identify the mutation, we constructed a new BAC library from an affected homozygote, isolated and re-sequenced the candidate region and focussed further analysis on 8 SNPS within the α globin cluster, one of which creates a new GATA-1 binding site (GACA>GATA). Using primary erythroblasts from normal individuals and patients with this form of thalassemia, together with interspecific hybrids containing either the normal or abnormal copy of chromosome 16, we have shown that this SNP creates a new binding site in vivo for GATA-1 and the SCL complex. Furthermore, the chromatin at this site becomes activated as judged by acetylation of histone H3 and H4 (H3ac2 and H4ac4) and methylation of histone H3 (H3K4me2). Based on these data we postulate that an active transcriptional complex binding this new GATA site created by the SNP-mutation, could distract the upstream regulatory regions, which normally interact with the α globin promoter, and silence α globin gene expression. This model thus represents a new example of α globin gene down-regulation and a new mechanism by which gene expression can be perturbed during hemopoiesis.

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