scholarly journals Three-Dimensional Genome Organization in Breast and Gynecological Cancers: How Chromatin Folding Influences Tumorigenic Transcriptional Programs

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 75
Author(s):  
Stephanie I. Nuñez-Olvera ◽  
Jonathan Puente-Rivera ◽  
Rosalio Ramos-Payán ◽  
Carlos Pérez-Plasencia ◽  
Yarely M. Salinas-Vera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Function ◽  
Three Dimensional ◽  
Gene Mutations ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Gene Promoters ◽  
Nucleotide Polymorphisms ◽  
Non Coding Rnas ◽  
Insulator Elements

A growing body of research on the transcriptome and cancer genome has demonstrated that many gynecological tumor-specific gene mutations are located in cis-regulatory elements. Through chromosomal looping, cis-regulatory elements interact which each other to control gene expression by bringing distant regulatory elements, such as enhancers and insulators, into close proximity with promoters. It is well known that chromatin connections may be disrupted in cancer cells, promoting transcriptional dysregulation and the expression of abnormal tumor suppressor genes and oncogenes. In this review, we examine the roles of alterations in 3D chromatin interactions. This includes changes in CTCF protein function, cancer-risk single nucleotide polymorphisms, viral integration, and hormonal response as part of the mechanisms that lead to the acquisition of enhancers or super-enhancers. The translocation of existing enhancers, as well as enhancer loss or acquisition of insulator elements that interact with gene promoters, is also revised. Remarkably, similar processes that modify 3D chromatin contacts in gene promoters may also influence the expression of non-coding RNAs, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), which have emerged as key regulators of gene expression in a variety of cancers, including gynecological malignancies.

scholarly journals Concepts of Osteoblast Growth and Differentiation: Basis for Modulation of Bone Cell Development and Tissue Formation

1992 ◽  
Vol 3 (3) ◽  
pp. 269-305 ◽  
Author(s):  
Jane B. Lian ◽  
Gary S. Stein
Keyword(s):  
Gene Expression ◽  
Cell Growth ◽  
Three Dimensional ◽  
Bone Cell ◽  
Cell Phenotype ◽  
Specific Gene ◽  
Gene Promoters ◽  
Developmental Sequence ◽  
Combined Application ◽  
Bone Cell Differentiation

The combined application of molecular, biochemical, histochemical, and ultrastructural approaches has defined a temporal sequence of gene expression associated with development of the bone cell phenotype in primary osteoblast cultures. The peak levels of expressed genes reflect a developmental sequence of bone cell differentiation characterized by three principal periods: proliferation, extracellular matrix maturation and mineralization, and two restriction points to which the cells can progress but cannot pass without further signals. The regulation of cell growth and bone-specific gene expression has been examined during this developmental sequence and is discussed within the context of several unique concepts. These are (1) that oncogene expression in proliferating osteoblasts contributes to the suppression of genes expressed postproliferatively, (2) that hormone modulation of a gene is dependent upon the maturational state of the osteoblast, and (3) that chromatin structure and the presence of nucleosomes contribute to three-dimensional organization of gene promoters that support synergistic and/or antagonistic activities of physiologic mediators of bone cell growth and differentiation.

scholarly journals Analysing structural diversity of seed storage protein gene promoters: Buckwheat a case study

Fagopyrum ◽  
2018 ◽  
Vol 35 (1) ◽  
pp. 5-17 ◽  
Author(s):  
Upasna Chettry ◽  
Lashaihun Dohtdong ◽  
N. K. Chrungoo
Keyword(s):  
Gene Expression ◽  
Binding Sites ◽  
Regulatory Elements ◽  
Fine Tuning ◽  
Tata Box ◽  
Proximal Promoter ◽  
Specific Gene ◽  
Gene Promoters ◽  
Seed Storage Protein Gene ◽  
Nucleosome Binding

Multiple sequence alignment of 5’UTR of SSP genes from accessions of Fagopyrum esculentumrevealed the invariant nature of sequences with the transcription start site at P761and TATA box located -30bp upstream the TSS. Other cis-elements identified in the sequences included the legumin box (-581, -524, -184, -135, -91), the -131 prolamin box, DOF element (-718, -649, -540,-432, -272,-225, -128) and CAAT box (-692, -530, -475, -411, -282, -168, -54). Other elements identified included those involved in abscisic acid signallingviz., ABI3 at P-470,-95,-68,RAV1 at P-694and -543and AGL15 at P-671. A comparative analysis of regulatory elements of SSP gene promoters of distantly related species the presence of five cis-regulatory elements viz. TATA BOX, E-BOX, RY- element, CAAT box and the Endosperm box, which interplay in seed specific SSP gene expression. Other modulators influencing seed specific gene expression detected in the sequences included the  ABA-responsive elements ABI3, RAV1 and AGL15 which play an integral role in seed maturation. Identification of potential nucleosome binding sites in SSP gene promoters of Cicer arietinum, Brassica napus, B. campestris, Vicia faba, and Pisum sativumat positions 78, 635, 195, 112 and 152 respectively surmises the spatial fine tuning of SSP gene transcriptional regulation in these species. On the other hand, absence of nucleosome binding sites in the promoters of Fagopyrum esculentum, Zea mays, Avena sativa, Triticum aestivum and Oryza sativamay indicate relatively easier access of transcription factors to the proximal promoter, thereby providing higher level of gene expression.

scholarly journals Loop Interrupted: Dysfunctional Chromatin Relations in Neurological Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Marthe Behrends ◽  
Olivia Engmann
Keyword(s):  
Gene Expression ◽  
Psychiatric Disorders ◽  
Long Range ◽  
Brain Research ◽  
Neurological Diseases ◽  
Three Dimensional ◽  
Regulatory Elements ◽  
Causal Link ◽  
Future Research ◽  
Gene Promoters

The majority of genetic variants for psychiatric disorders have been found within non-coding genomic regions. Physical interactions of gene promoters with distant regulatory elements carrying risk alleles may explain how the latter affect gene expression. Recently, whole genome maps of long-range chromosomal contacts from human postmortem brains have been integrated with gene sequence and chromatin accessibility data to decipher disease-specific alterations in chromatin architecture. Cell culture and rodent models provide a causal link between chromatin conformation, long-range chromosomal contacts, gene expression, and disease phenotype. Here, we give an overview of the techniques used to study chromatin contacts and their limitations in brain research. We present evidence for three-dimensional genome changes in physiological brain function and assess how its disturbance contributes to psychiatric disorders. Lastly, we discuss remaining questions and future research directions with a focus on clinical applications.

scholarly journals The regulatory genome of the malaria vector Anopheles gambiae: integrating chromatin accessibility and gene expression

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
José L Ruiz ◽  
Lisa C Ranford-Cartwright ◽  
Elena Gómez-Díaz
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Anopheles Gambiae ◽  
Mosquito Control ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Malaria Vectors ◽  
Specific Gene ◽  
Mosquito Vector ◽  
Human Malaria

Abstract Anopheles gambiae mosquitoes are primary human malaria vectors, but we know very little about their mechanisms of transcriptional regulation. We profiled chromatin accessibility by the assay for transposase-accessible chromatin by sequencing (ATAC-seq) in laboratory-reared A. gambiae mosquitoes experimentally infected with the human malaria parasite Plasmodium falciparum. By integrating ATAC-seq, RNA-seq and ChIP-seq data, we showed a positive correlation between accessibility at promoters and introns, gene expression and active histone marks. By comparing expression and chromatin structure patterns in different tissues, we were able to infer cis-regulatory elements controlling tissue-specific gene expression and to predict the in vivo binding sites of relevant transcription factors. The ATAC-seq assay also allowed the precise mapping of active regulatory regions, including novel transcription start sites and enhancers that were annotated to mosquito immune-related genes. Not only is this study important for advancing our understanding of mechanisms of transcriptional regulation in the mosquito vector of human malaria, but the information we produced also has great potential for developing new mosquito-control and anti-malaria strategies.

A Global Vista of the Epigenomic State of the Mouse Submandibular Gland

2021 ◽  
pp. 002203452110120
Author(s):  
C. Gluck ◽  
S. Min ◽  
A. Oyelakin ◽  
M. Che ◽  
E. Horeth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Control ◽  
Expression Patterns ◽  
Global Gene Expression ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Submandibular Salivary Gland ◽  
Data Sets ◽  
Control Mechanisms ◽  
Chromatin Immunoprecipitation Sequencing

The parotid, submandibular, and sublingual glands represent a trio of oral secretory glands whose primary function is to produce saliva, facilitate digestion of food, provide protection against microbes, and maintain oral health. While recent studies have begun to shed light on the global gene expression patterns and profiles of salivary glands, particularly those of mice, relatively little is known about the location and identity of transcriptional control elements. Here we have established the epigenomic landscape of the mouse submandibular salivary gland (SMG) by performing chromatin immunoprecipitation sequencing experiments for 4 key histone marks. Our analysis of the comprehensive SMG data sets and comparisons with those from other adult organs have identified critical enhancers and super-enhancers of the mouse SMG. By further integrating these findings with complementary RNA-sequencing based gene expression data, we have unearthed a number of molecular regulators such as members of the Fox family of transcription factors that are enriched and likely to be functionally relevant for SMG biology. Overall, our studies provide a powerful atlas of cis-regulatory elements that can be leveraged for better understanding the transcriptional control mechanisms of the mouse SMG, discovery of novel genetic switches, and modulating tissue-specific gene expression in a targeted fashion.

Androgen receptor: acting in the three-dimensional chromatin landscape of prostate cancer cells

2011 ◽  
Vol 5 (1) ◽  
Author(s):  
Harri Makkonen ◽  
Jorma J. Palvimo
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Binding Sites ◽  
Target Genes ◽  
Three Dimensional ◽  
Regulatory Elements ◽  
Gene Promoters ◽  
Loop Formation ◽  
Prostate Cancer Cells

AbstractAndrogen receptor (AR) acts as a hormone-controlled transcription factor that conveys the messages of both natural and synthetic androgens to the level of genes and gene programs. Defective AR signaling leads to a wide array of androgen insensitivity disorders, and deregulated AR function, in particular overexpression of AR, is involved in the growth and progression of prostate cancer. Classic models of AR action view AR-binding sites as upstream regulatory elements in gene promoters or their proximity. However, recent wider genomic screens indicate that AR target genes are commonly activated through very distal chromatin-binding sites. This highlights the importance of long-range chromatin regulation of transcription by the AR, shifting the focus from the linear gene models to three-dimensional models of AR target genes and gene programs. The capability of AR to regulate promoters from long distances in the chromatin is particularly important when evaluating the role of AR in the regulation of genes in malignant prostate cells that frequently show striking genomic aberrations, especially gene fusions. Therefore, in addition to the mechanisms of DNA loop formation between the enhancer bound ARs and the transcription apparatus at the target core promoter, the mechanisms insulating distally bound ARs from promiscuously making contacts and activating other than their normal target gene promoters are critical for proper physiological regulation and thus currently under intense investigation. This review discusses the current knowledge about the AR action in the context of gene aberrations and the three-dimensional chromatin landscape of prostate cancer cells.

Gene-regulatory elements may change the amount, timing, or location of gene expression, cis-Regulation therapy platforms might become a gene therapy to treat many genetic diseases

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Expression ◽  
Genetic Diseases ◽  
Regulatory Elements ◽  
Tissue Type ◽  
Gene Promoters ◽  
Expression Levels ◽  
Cis Regulation ◽  
Gene Regulatory Elements ◽  
Gene Regulatory ◽  
Gene Expression Levels

Changes in gene expression levels above or below a particular threshold may have a dramatic impact on phenotypes, leading to a wide spectrum of human illnesses. Gene-regulatory elements, also known as cis-regulatory elements (CREs), may change the amount, timing, or location (cell/tissue type) of gene expression, whereas mutations in a gene's coding sequence may result in lower or higher gene expression levels resulting in protein loss or gain. Loss-of-function mutations in both genes produce recessive human illness, while haploinsufficient mutations in 65 genes are also known to be deleterious due to function gain, according to the ClinVar1 and ClinGen3 databases. CREs are promoters living near to a gene's transcription start site and switching it on at predefined times, places, and levels. Other distal CREs, like enhancers and silencers, are temporal and tissue-specific control promoters. Enhancers activate promoters, commonly referred to as "promoters," whereas silencers turn them off. Insulators also restrict promiscuous interactions between enhancers and gene promoters. Systematic genomic approaches can help understand the cis-regulatory circuitry of gene expression by highly detecting and functionally defining these CREs. This includes the new use of CRISPR–CRISPR-associated protein 9 (CRISPR–Cas9) and other editing approaches to discover CREs. Cis-Regulation therapy (CRT) provides many promises to heal human ailments. CRT may be used to upregulate or downregulate disease-causing genes due to lower or higher levels of expression, and it may also be used to precisely adjust the expression of genes that assist in alleviating disease features. CRT may employ proteins that generate epigenetic modifications like methylation, histone modification, or gene expression regulation looping. Weighing CRT's advantages and downsides against alternative treatment methods is crucial. CRT platforms might become a practical technique to treat many genetic diseases that now lack treatment alternatives if academics, patient communities, clinicians, regulators and industry work together.

Abstract 12905: Gene Expression and Expression Quantifying Trait Loci Analysis of Left Atrium of Patients With Post-operative Atrial Fibrillation

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Martin I Sigurdsson ◽  
Mahyar Heydarpour ◽  
Louis Saddic ◽  
Tzuu-Wang Chang ◽  
Stanton K Shernan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Atrial Fibrillation ◽  
Left Atrium ◽  
High Throughput ◽  
Specific Gene ◽  
Eqtl Analysis ◽  
Gene Variants ◽  
Nucleotide Polymorphisms ◽  
Novel Genes ◽  
Trait Loci

Introduction: The majority of information on the genetic background of atrial fibrillation (AF) results from genomic DNA variant analysis without consideration of tissue expression. Hypothesis: Analysis of tissue-specific gene expression in left atrium (LA) can further understanding of the molecular mechanism of identified AF risk variants, and identify novel genes and gene variants associated with AF. Methods: We isolated mRNA from samples of the LA free wall taken during mitral valve surgery in 62 Caucasian individuals. Gene expression in the LA was compared between patients who did and did not have post-operative AF (poAF) using high-throughput RNA expression. Using genotypes of 1.4 million single nucleotide polymorphisms (SNP) we performed cis expression quantifying trait loci (eQTL) analysis, correlating gene expression of each gene with the genotypes of adjacent (<1Mbp) SNPs. Results: We identified 23 differentially expressed genes in the LA of patients with poAF, including three potassium channel genes (KCNA7, KCNH8 and KCNK17). The largest expression difference was in LOC645323, a long non-coding RNA. The expression of PITX2, ZFHX3 and KCNN3, previously shown to be associated with AF, did not differ between patients with and without poAF. We identified 12,476 cis eQTL relationships in the LA, several of those included genetic regions and genes previously associated with AF. We confirmed an eQTL relationship between rs3744029 genotype and the expression of MYOZ1. Furthermore we describe a novel eQTL relationship between rs6795970 genotype and the expression of the SCN10A gene. Conclusions: We have analysed the human LA expression via high-throughput RNA sequencing, and identified novel genes and gene variants likely involved in the molecular pathophysiology of AF.

scholarly journals Genetic influences on cell type specific gene expression and splicing during neurogenesis elucidate regulatory mechanisms of brain traits

2020 ◽  
Author(s):  
Nil Aygün ◽  
Angela L. Elwell ◽  
Dan Liang ◽  
Michael J. Lafferty ◽  
Kerry E. Cheek ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulatory Elements ◽  
Regulatory Mechanisms ◽  
Specific Gene ◽  
Cell Type ◽  
Specific Expression ◽  
Risk Variants ◽  
Allele Specific ◽  
Cell Type Specific ◽  
Regulatory Effects

SummaryInterpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing is mainly performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements of cells present during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs and allele specific expression in primary human neural progenitors (n=85) and their sorted neuronal progeny (n=74). Using colocalization and TWAS, we uncover cell-type specific regulatory mechanisms underlying risk for these traits.

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