Temporal analysis suggests a reciprocal relationship between 3D chromatin structure and transcription

Reed, Kathleen Shaindel Metz; Davis, Eric S.; Bond, Marielle L.; Cabrera, Alan; Thulson, Eliza; Quiroga, Ivana Yoseli; Cassel, S Florence; Woolery, Kamisha T.; Hilton, Isaac B.; Won, Hyejung; Love, Michael I.; Phanstiel, Douglas H.

doi:10.1016/j.celrep.2022.111567

Cited by 32 publications

(34 citation statements)

References 80 publications

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“…To investigate more rapid dynamics, we examined Hi-C data from human macrophages stimulated with lipopolysaccharide (LPS) and interferon (IFN-) (Fig. 4B) (Reed et al, 2022). Regions that gained H3K27ac upon stimulation also gained ULIs and regions losing H3K27ac, although relatively lowly enriched to begin with, lost ULIs over the time course.…”

Section: Interaction Dynamics and Dna Methylationmentioning

confidence: 99%

“…TSSs were defined as the first TSS for all genes in refGene (O' Leary et al, 2016). Processed H3K27ac values from stimulated THP-1 derived macrophages (Reed et al, 2022) were split into quartiles based on the m0000_VST and m1440_VST columns and regions with adjusted p-values < 0.5 and going from quartiles 1 or 2 to 4 or (up-regulated) or 4 to 1 or 2 (down-regulated) were used. For Supp.…”

Section: Peak and Coverage Filesmentioning

confidence: 99%

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Ultra-long-range interactions between active regulatory elements

Friman

Flyamer

Boyle

et al. 2022

Preprint

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Contacts between enhancers and promoters are thought to relate to their ability to activate transcription. Investigating mechanisms that drive such chromatin interactions is therefore important for understanding gene regulation. Here, we have determined contact frequencies between millions of pairs of cis-regulatory elements from chromosome conformation capture datasets and analysed a collection of hundreds of DNA-binding factors for binding at regions of enriched contacts. This analysis revealed enriched contacts at sites bound by many factors associated with active transcription. We show that active regulatory elements, independent of cohesin and polycomb, interact with each other across distances of 10s of megabases in vertebrate and invertebrate genomes and that interactions correlate and change with activity. However, these ultra-long-range interactions are not dependent on RNA polymerase II transcription or several transcription cofactors. We propose that long-range interactions between cis-regulatory elements are driven by three distinct mechanisms - cohesin-mediated loop extrusion, polycomb contacts, and association between active regions.

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Section: Interaction Dynamics and Dna Methylationmentioning

confidence: 99%

Section: Peak and Coverage Filesmentioning

confidence: 99%

Ultra-long-range interactions between active regulatory elements

Friman

Flyamer

Boyle

et al. 2022

Preprint

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“…Additionally, GWAS SNPs are typically assigned to the nearest gene in the locus, but because of chromatin looping enhancers may actually be in closer three-dimensional proximity with promoters of genes farther away in linear distance. 32–35 A further complication is linkage disequilibrium (LD) which makes causal variant identification difficult, especially in non-coding regions where additional information on conservation and predicted deleteriousness is not available or as informative. Importantly, MAPT falls within the largest LD block known in the human genome, spanning over 1 Mb.…”

Section: Introductionmentioning

confidence: 99%

MAPTexpression is mediated by long-range interactions withcis-regulatory elements

Rogers

Anderson

Lauzon

et al. 2023

Preprint

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Tau is encoded byMAPTand abnormal aggregates of tau are a hallmark of a group of neurodegenerative diseases called tauopathies.MAPTis lowly expressed in neural progenitor cells (NPCs), but it is more highly expressed in oligodendrocytes, astrocytes, and neurons that derive from NPCs. This expression switch at differentiation suggests thatMAPTexpression is controlled by transcription factors andcis-regulatory elements specific to these differentiated cell types, including neurons. Using three-dimensional chromatin conformation capture (Capture-C), single-nucleus multiomics (RNA-seq and ATAC-seq), and chromatin marks (H3K27ac, H3K4me1, and chromatin accessibility (DNase hypersensitivity and ATAC-seq)), we nominated 94 unique regions as candidatecis-regulatory elements forMAPTin human NPCs, NPCs differentiated to neurons, and pure inhibitory or excitatory neuron cultures. We then functionally assessed nominated regions using luciferase assays to test sufficiency for regulatory activity as well as with CRISPR inhibition experiments to assess the effect of nominated regions onMAPTexpression. We identified both proximal and distal regulatory elements forMAPTand confirmed the function for several regions, including three regions centromeric toMAPTbeyond the well-described H1/H2 haplotype inversion breakpoint.

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“…3D chromatin structure is thought to play a critical role in the regulation of gene expression, particularly during development and in response to external stimuli [1][2][3] . Abnormalities in this organization have been implicated in a number of human diseases and developmental disorders 4 .…”

Section: Introductionmentioning

confidence: 99%

“…Computational analysis of Hi-C data can be used to both identify chromatin loops and quantify the interaction frequencies between pairs of loop anchors. The application of Hi-C to investigate differential looping, or changes in looping across samples or biological conditions, has provided valuable insights into the function of the human genome, the role of enhancers in regulating gene expression, and the genetic basis of human disease 2,10 .…”

Section: Introductionmentioning

confidence: 99%

Guiding the design of well-powered Hi-C experiments to detect differential loops

Parker

Davis

Phanstiel

2023

Preprint

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3D chromatin structure plays an important role in gene regulation by connecting regulatory regions and gene promoters. The ability to detect the formation and loss of these loops in various cell types and conditions provides valuable information on the mechanisms driving these cell states and is critical for understanding how long-range gene regulation works. Hi-C is a powerful technique used to characterize three-dimensional chromatin structure; however, Hi-C can quickly become a costly and labor-intensive endeavor, and proper planning is required to determine how to best use time and resources while maintaining experimental rigor and well-powered results. To facilitate better planning and interpretation of Hi-C experiments, we have conducted a detailed evaluation of statistical power using publicly available Hi-C datasets paying particular attention to the impact of loop size on Hi-C contacts and fold change compression. In addition, we have developed Hi-C Poweraid, a publicly-hosted web application to investigate these findings (http://phanstiel-lab.med.unc.edu/poweraid/). For experiments involving well-replicated cell lines, we recommend a total sequencing depth of at least 6 billion contacts per condition, split between at least 2 replicates in order to achieve the power to detect the majority of differential loops. For experiments with higher variation, more replicates and deeper sequencing depths are required. Exact values and recommendations for specific cases can be determined through the use of Hi-C Poweraid. This tool simplifies the complexities behind calculating power for Hi-C data and will provide useful information on the amount of well-powered loops an experiment will be able to detect given a specific set of experimental parameters, such as sequencing depth, replicates, and the sizes of the loops of interest. This will allow for more efficient use of time and resources and more accurate interpretation of experimental results.

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Temporal analysis suggests a reciprocal relationship between 3D chromatin structure and transcription

Cited by 32 publications

References 80 publications

Ultra-long-range interactions between active regulatory elements

Ultra-long-range interactions between active regulatory elements

MAPTexpression is mediated by long-range interactions withcis-regulatory elements

Guiding the design of well-powered Hi-C experiments to detect differential loops

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