Network analysis of promoter interactions reveals the hierarchical differences in genome organisation between human pluripotent states

SUMMARYA complex and poorly understood interplay between 3D genome organisation, transcription factors and chromatin state underpins cell identity. To gain a systems-level understanding of this interplay, we generated a high-resolution atlas of annotated chromatin interactions in naïve and primed human pluripotent stem cells and developed a network-graph approach to examine the atlas at multiple spatial scales. Investigating chromatin interactions as a network uncovered highly connected hubs that changed substantially in interaction frequency and in transcriptional co-regulation between pluripotent states. Small hubs frequently merged to form larger networks in primed cells, often linked by newly-formed Polycomb-associated interactions. Importantly, we identified state-specific differences in enhancer activity and interactivity that corresponded with widespread reconfiguration of transcription factor binding and target gene expression. These findings provide multilayered insights into the gene regulatory control of human pluripotency and our systems-based network approach could be applied broadly to uncover new principles of 3D genome organisation.

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Widespread reorganisation of pluripotent factor binding and gene regulatory interactions between human pluripotent states

Nature Communications ◽

10.1038/s41467-021-22201-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Peter Chovanec ◽

Amanda J. Collier ◽

Christel Krueger ◽

Csilla Várnai ◽

Claudia I. Semprich ◽

...

Keyword(s):

Spatial Scales ◽

Three Dimensional ◽

Regulatory Control ◽

Network Graph ◽

Enhancer Activity ◽

Regulatory Interactions ◽

Transcriptional Enhancers ◽

Chromatin Organisation ◽

Gene Regulatory

AbstractThe transition from naive to primed pluripotency is accompanied by an extensive reorganisation of transcriptional and epigenetic programmes. However, the role of transcriptional enhancers and three-dimensional chromatin organisation in coordinating these developmental programmes remains incompletely understood. Here, we generate a high-resolution atlas of gene regulatory interactions, chromatin profiles and transcription factor occupancy in naive and primed human pluripotent stem cells, and develop a network-graph approach to examine the atlas at multiple spatial scales. We uncover highly connected promoter hubs that change substantially in interaction frequency and in transcriptional co-regulation between pluripotent states. Small hubs frequently merge to form larger networks in primed cells, often linked by newly-formed Polycomb-associated interactions. We identify widespread state-specific differences in enhancer activity and interactivity that correspond with an extensive reconfiguration of OCT4, SOX2 and NANOG binding and target gene expression. These findings provide multilayered insights into the chromatin-based gene regulatory control of human pluripotent states.

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A functional genomics pipeline identifies pleiotropy and cross-tissue effects within obesity-associated GWAS loci

Nature Communications ◽

10.1038/s41467-021-25614-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Amelia C. Joslin ◽

Débora R. Sobreira ◽

Grace T. Hansen ◽

Noboru J. Sakabe ◽

Ivy Aneas ◽

...

Keyword(s):

Association Studies ◽

Complex Model ◽

Genome Wide Association Studies ◽

Enhancer Activity ◽

Chromatin Interactions ◽

Genome Wide ◽

Causal Variants ◽

Cell Type Specific ◽

Gene Regulatory ◽

Massively Parallel Reporter Assay

AbstractGenome-wide association studies (GWAS) have identified many disease-associated variants, yet mechanisms underlying these associations remain unclear. To understand obesity-associated variants, we generate gene regulatory annotations in adipocytes and hypothalamic neurons across cellular differentiation stages. We then test variants in 97 obesity-associated loci using a massively parallel reporter assay and identify putatively causal variants that display cell type specific or cross-tissue enhancer-modulating properties. Integrating these variants with gene regulatory information suggests genes that underlie obesity GWAS associations. We also investigate a complex genomic interval on 16p11.2 where two independent loci exhibit megabase-range, cross-locus chromatin interactions. We demonstrate that variants within these two loci regulate a shared gene set. Together, our data support a model where GWAS loci contain variants that alter enhancer activity across tissues, potentially with temporally restricted effects, to impact the expression of multiple genes. This complex model has broad implications for ongoing efforts to understand GWAS.

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Inhibition of coral settlement at multiple spatial scales by a pervasive algal competitor

Marine Ecology Progress Series ◽

10.3354/meps12879 ◽

2019 ◽

Vol 612 ◽

pp. 29-42 ◽

Cited By ~ 4

Author(s):

NR Evensen ◽

C Doropoulos ◽

KM Morrow ◽

CA Motti ◽

PJ Mumby

Keyword(s):

Spatial Scales ◽

Coral Settlement ◽

Multiple Spatial Scales

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Glucocorticoid receptor wields chromatin interactions to tune transcription for cytoskeleton stabilization in podocytes

Communications Biology ◽

10.1038/s42003-021-02209-8 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Hong Wang ◽

Aiping Duan ◽

Jing Zhang ◽

Qi Wang ◽

Yuexian Xing ◽

...

Keyword(s):

Transcription Factor ◽

Glucocorticoid Receptor ◽

Protective Effect ◽

Histone Modification ◽

Regulatory Networks ◽

Target Gene ◽

Regulatory Elements ◽

Chromatin Interactions ◽

Super Enhancer

AbstractElucidating transcription mediated by the glucocorticoid receptor (GR) is crucial for understanding the role of glucocorticoids (GCs) in the treatment of diseases. Podocyte is a useful model for studying GR regulation because GCs are the primary medication for podocytopathy. In this study, we integrated data from transcriptome, transcription factor binding, histone modification, and genome topology. Our data reveals that the GR binds and activates selective regulatory elements in podocyte. The 3D interactome captured by HiChIP facilitates the identification of remote targets of GR. We found that GR in podocyte is enriched at transcriptional interaction hubs and super-enhancers. We further demonstrate that the target gene of the top GR-associated super-enhancer is indispensable to the effective functioning of GC in podocyte. Our findings provided insights into the mechanisms underlying the protective effect of GCs on podocyte, and demonstrate the importance of considering transcriptional interactions in order to fine-map regulatory networks of GR.

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Assessment of clogging in constructed wetlands by saturated hydraulic conductivity measurements

Water Science & Technology ◽

10.2166/wst.2019.045 ◽

2019 ◽

Vol 79 (2) ◽

pp. 314-322 ◽

Cited By ~ 6

Author(s):

F. Licciardello ◽

R. Aiello ◽

V. Alagna ◽

M. Iovino ◽

D. Ventura ◽

...

Keyword(s):

Sensitivity Analysis ◽

Hydraulic Conductivity ◽

Constructed Wetlands ◽

Spatial Scales ◽

Pilot Scale ◽

Laboratory Scale ◽

Test Method ◽

Conductivity Measurements ◽

Multiple Spatial Scales ◽

Ks Values

Abstract This study aims at defining a methodology to evaluate Ks reductions of gravel material constituting constructed wetland (CW) bed matrices. Several schemes and equations for the Lefranc's test were compared by using different gravel sizes and at multiple spatial scales. The falling-head test method was implemented by using two steel permeameters: one impervious (IMP) and one pervious (P) on one side. At laboratory scale, mean K values for a small size gravel (8–15 × 10−2 m) measured by the IMP and the P permeameters were equal to 19,466 m/d and 30,662 m/d, respectively. Mean Ks values for a big size gravel (10–25 × 10−2 m) measured by the IMP and the P permeameters were equal to 12,135 m/d and 20,866 m/d, respectively. Comparison of Ks values obtained by the two permeameters at laboratory scale as well as a sensitivity analysis and a calibration, lead to the modification of the standpipe equation, to evaluate also the temporal variation of the horizontal Ks. In particular, both permeameters allow the evaluation of the Ks decreasing after 4 years-operation and 1–1.5 years' operation of the plants at full scale (filled with the small size gravel) and at pilot scale (filled with the big size gravel), respectively.

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FORMULATION OF THE HEAT CONDUCTION EQUATION FOR HETEROGENEOUS MEDIA WITH MULTIPLE SPATIAL SCALES USING REITERATED HOMOGENIZATION

Revista de Engenharia Térmica ◽

10.5380/reterm.v15i1.62165 ◽

2016 ◽

Vol 15 (1) ◽

pp. 96

Author(s):

E. Iglesias-Rodríguez ◽

M. E. Cruz ◽

J. Bravo-Castillero ◽

R. Guinovart-Díaz ◽

R. Rodríguez-Ramos ◽

...

Keyword(s):

Heat Conduction ◽

Small Parameter ◽

Heat Conduction Equation ◽

Heterogeneous Media ◽

Spatial Scales ◽

Conduction Equation ◽

Small Scale ◽

Multiple Spatial Scales ◽

Effective Coefficients ◽

Reiterated Homogenization

Heterogeneous media with multiple spatial scales are finding increased importance in engineering. An example might be a large scale, otherwise homogeneous medium filled with dispersed small-scale particles that form aggregate structures at an intermediate scale. The objective in this paper is to formulate the strong-form Fourier heat conduction equation for such media using the method of reiterated homogenization. The phases are assumed to have a perfect thermal contact at the interface. The ratio of two successive length scales of the medium is a constant small parameter ε. The method is an up-scaling procedure that writes the temperature field as an asymptotic multiple-scale expansion in powers of the small parameter ε . The technique leads to two pairs of local and homogenized equations, linked by effective coefficients. In this manner the medium behavior at the smallest scales is seen to affect the macroscale behavior, which is the main interest in engineering. To facilitate the physical understanding of the formulation, an analytical solution is obtained for the heat conduction equation in a functionally graded material (FGM). The approach presented here may serve as a basis for future efforts to numerically compute effective properties of heterogeneous media with multiple spatial scales.

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