17 research outputs found
Minor Loops in Major Folds: Enhancer-Promoter Looping, Chromatin Restructuring, and Their Association with Transcriptional Regulation and Disease.
The organization and folding of chromatin within the nucleus can determine the outcome of gene expression. Recent technological advancements have enabled us to study chromatin interactions in a genome-wide manner at high resolution. These studies have increased our understanding of the hierarchy and dynamics of chromatin domains that facilitate cognate enhancer-promoter looping, defining the transcriptional program of different cell types. In this review, we focus on vertebrate chromatin long-range interactions as they relate to transcriptional regulation. In addition, we describe how the alteration of boundaries that mark discrete regions in the genome with high interaction frequencies within them, called topological associated domains (TADs), could lead to various phenotypes, including human diseases, which we term as "TADopathies.
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Genomic and epigenomic mapping of leptin-responsive neuronal populations involved in body weight regulation.
Genome wide association studies (GWAS) in obesity have identified a large number of noncoding loci located near genes expressed in the central nervous system. However, due to the difficulties in isolating and characterizing specific neuronal subpopulations, few obesity-associated SNPs have been functionally characterized. Leptin responsive neurons in the hypothalamus are essential in controlling energy homeostasis and body weight. Here, we combine FACS-sorting of leptin-responsive hypothalamic neuron nuclei with genomic and epigenomic approaches (RNA-seq, ChIP-seq, ATAC-seq) to generate a comprehensive map of leptin-response specific regulatory elements, several of which overlap obesity-associated GWAS variants. We demonstrate the usefulness of our leptin-response neuron regulome, by functionally characterizing a novel enhancer near Socs3, a leptin response-associated transcription factor. We envision our data to serve as a useful resource and a blueprint for functionally characterizing obesity-associated SNPs in the hypothalamus
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Genetic variation in the SIM1 locus is associated with erectile dysfunction.
Erectile dysfunction affects millions of men worldwide. Twin studies support the role of genetic risk factors underlying erectile dysfunction, but no specific genetic variants have been identified. We conducted a large-scale genome-wide association study of erectile dysfunction in 36,649 men in the multiethnic Kaiser Permanente Northern California Genetic Epidemiology Research in Adult Health and Aging cohort. We also undertook replication analyses in 222,358 men from the UK Biobank. In the discovery cohort, we identified a single locus (rs17185536-T) on chromosome 6 near the single-minded family basic helix-loop-helix transcription factor 1 (SIM1) gene that was significantly associated with the risk of erectile dysfunction (odds ratio = 1.26, P = 3.4 × 10-25). The association replicated in the UK Biobank sample (odds ratio = 1.25, P = 6.8 × 10-14), and the effect is independent of known erectile dysfunction risk factors, including body mass index (BMI). The risk locus resides on the same topologically associating domain as SIM1 and interacts with the SIM1 promoter, and the rs17185536-T risk allele showed differential enhancer activity. SIM1 is part of the leptin-melanocortin system, which has an established role in body weight homeostasis and sexual function. Because the variants associated with erectile dysfunction are not associated with differences in BMI, our findings suggest a mechanism that is specific to sexual function
Minor Loops in Major Folds: Enhancer-Promoter Looping, Chromatin Restructuring, and Their Association with Transcriptional Regulation and Disease.
The organization and folding of chromatin within the nucleus can determine the outcome of gene expression. Recent technological advancements have enabled us to study chromatin interactions in a genome-wide manner at high resolution. These studies have increased our understanding of the hierarchy and dynamics of chromatin domains that facilitate cognate enhancer-promoter looping, defining the transcriptional program of different cell types. In this review, we focus on vertebrate chromatin long-range interactions as they relate to transcriptional regulation. In addition, we describe how the alteration of boundaries that mark discrete regions in the genome with high interaction frequencies within them, called topological associated domains (TADs), could lead to various phenotypes, including human diseases, which we term as "TADopathies.
Chromatin insulators and topological domains: adding new dimensions to 3D genome architecture
The spatial organization of metazoan genomes has a direct influence on fundamental nuclear processes that include transcription, replication, and DNA repair. It is imperative to understand the mechanisms that shape the 3D organization of the eukaryotic genomes. Chromatin insulators have emerged as one of the central components of the genome organization tool-kit across species. Recent advancements in chromatin conformation capture technologies have provided important insights into the architectural role of insulators in genomic structuring. Insulators are involved in 3D genome organization at multiple spatial scales and are important for dynamic reorganization of chromatin structure during reprogramming and differentiation. In this review, we will discuss the classical view and our renewed understanding of insulators as global genome organizers. We will also discuss the plasticity of chromatin structure and its re-organization during pluripotency and differentiation and in situations of cellular stress
Mechanisms defining enhancer–promoter recognition.
<p>(A) TAD boundaries pose spatial constraint, allowing for specific enhancer–promoter interactions. (B) Enhancer activity could be obscured by its localization to repressive chromatin compartments. (C) Enhancer–promoter targeting can depend upon the binding compatibility of the transcription factors bound to two interacting loci, termed biochemical compatibility. (D) Insulator elements bound by insulator factors facilitate specific enhancer interaction and eliminate nonspecific enhancer–promoter crosstalk. (E) Noncoding RNA or enhancer RNA (eRNA) transcribed from the enhancer can define its interaction with the target promoter.</p
Enhancer–promoter interactions and human disease.
<p>(A) An inversion between GATA binding protein 2 (<i>GATA2</i>) and ecotopic viral integration site 1 (<i>EVI1</i>) repositions a <i>GATA2</i> enhancer (green oval) near <i>EVI1</i>, leading to its ectopic expression while reducing <i>GATA2</i> expression [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005640#pgen.1005640.ref065" target="_blank">65</a>]. Inversion breakpoints are depicted by magenta and yellow dots. (B) The T-allele of rs12913832, which resides within an enhancer (green oval) of the oculocutaneous albinism II (<i>OCA2</i>) gene, leads to a stronger enhancer–promoter looping interaction versus the C allele, as observed by 3C [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005640#pgen.1005640.ref066" target="_blank">66</a>]. (C) A 660 kb deletion that removes a TAD boundary and enhancer-A (Enh-A) leads to enhancer B (Enh-B) adoption by lamin B1 gene (<i>LMNB1</i>), leading to its misexpression and, subsequently, autosomal dominant adult-onset leukodystrophy (ADLD) [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005640#pgen.1005640.ref067" target="_blank">67</a>]. Deletion breakpoints are depicted by magenta and yellow dots.</p
Structural organization of chromatin.
<p>(A) Chromosomes within an interphase diploid eukaryotic nucleus are found to occupy specific nuclear spaces, termed chromosomal territories [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005640#pgen.1005640.ref025" target="_blank">25</a>]. (B) Each chromosome is subdivided into topological associated domains (TAD) as found in Hi-C studies. TADs with repressed transcriptional activity tend to be associated with the nuclear lamina (dashed inner nuclear membrane and its associated structures), while active TADs tend to reside more in the nuclear interior [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005640#pgen.1005640.ref032" target="_blank">32</a>,<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005640#pgen.1005640.ref033" target="_blank">33</a>]. Each TAD is flanked by regions having low interaction frequencies, as determined by Hi-C, that are called TAD boundaries (purple hexagon) [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005640#pgen.1005640.ref029" target="_blank">29</a>]. (C) An example of an active TAD with several interactions between distal regulatory elements and genes within it.</p