The role of loop extrusion in enhancer-mediated gene activation

Karpinska, Magdalena A; Oudelaar, Aukje Marieke

doi:10.1016/j.gde.2023.102022

Cited by 28 publications

(19 citation statements)

References 56 publications

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“…Previously, methodologic limitations prevented systematic detection of spatio-functional discordance between the location of functional enhancers and promoter-contacting structural loop anchors, though this arrangement has been theorized. 34,35 We surmise that chromatin looping facilitated by these spatially-resolved loop anchors could draw functional enhancers close enough to promoters for short-range diffusion of activating factors that facilitate transcription in a loopingthen-diffusion model of transcription factor activation. 36,37 Alternatively, but not mutually exclusively, strong loops provided by structural elements may suffice to draw spatially separated functional enhancers close enough to promoters to permit "bridging" or "direct extension" of transcription factors and activators in large complexes.…”

Section: Functional Enhancer Componentsmentioning

confidence: 98%

IntegrativePTENEnhancer Discovery Reveals a New Model of Enhancer Organization

Cerda-Smith,

Hutchinson,

Liu

et al. 2023

Preprint

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Enhancers possess both structural elements mediating promoter looping and functional elements mediating gene expression. Traditional models of enhancer-mediated gene regulation imply genomic overlap or immediate adjacency of these elements. We test this model by combining densely-tiled CRISPRa screening with nucleosome-resolution Region Capture Micro-C topology analysis. Using this integrated approach, we comprehensively define the cis-regulatory landscape for the tumor suppressor PTEN, identifying and validating 10 distinct enhancers and defining their 3D spatial organization. Unexpectedly, we identify several long-range functional enhancers whose promoter proximity is facilitated by chromatin loop anchors several kilobases away, and demonstrate that accounting for this spatial separation improves the computational prediction of validated enhancers. Thus, we propose a new model of enhancer organization incorporating spatial separation of essential functional and structural components.

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Section: Functional Enhancer Componentsmentioning

confidence: 98%

IntegrativePTENEnhancer Discovery Reveals a New Model of Enhancer Organization

Cerda-Smith,

Hutchinson,

Liu

et al. 2023

Preprint

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“…Besides facilitating double-strand break repair during G 2 ( 2 , 3 ), SCC is necessary for the traction by microtubules of kinetochore pairs in opposite directions, a process essential for chromosome segregation during both meiosis and mitosis ( 4 ). In addition to SCC, cohesin mediates loop extrusion (LE) ( 4 – 6 ), which is important for bringing together certain enhancers and their cognate promoters ( 7 ).…”

mentioning

confidence: 99%

Sister chromatid cohesion is mediated by individual cohesin complexes

Ochs,

Green,

Szczurek

et al. 2024

Science

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Eukaryotic genomes are organized by loop extrusion and sister chromatid cohesion, both mediated by the multimeric cohesin protein complex. Understanding how cohesin holds sister DNAs together, and how loss of cohesion causes age-related infertility in females, requires knowledge as to cohesin’s stoichiometry in vivo. Using quantitative super-resolution imaging, we identified two discrete populations of chromatin-bound cohesin in postreplicative human cells. Whereas most complexes appear dimeric, cohesin that localized to sites of sister chromatid cohesion and associated with sororin was exclusively monomeric. The monomeric stoichiometry of sororin:cohesin complexes demonstrates that sister chromatid cohesion is conferred by individual cohesin rings, a key prediction of the proposal that cohesion arises from the co-entrapment of sister DNAs.

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“…For example, the CCC-technique in T cells, B cells, natural killer cells, and fibroblasts has shown that GATA3 and STAT3 proteins bring promoters of T H 2 cytokine genes, located far away from each other in the linear genome, together through looping (Spilianakis and Flavell 2004). Loops also facilitate enhancer-promoter contact in the eukaryotic genome (Doyle et al 2014, Weintraub et al 2017, Karpinska andOudelaar 2023). The widely spaced enhancer and promoter regions of the rat prolactin gene have been shown to be juxtaposed through looping in a nuclear ligation experiment (Cullen et al 1993).…”

Section: Loopsmentioning

confidence: 99%

Fundamental insights into the correlation between chromosome configuration and transcription

et al. 2023

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Eukaryotic chromosomes exhibit a hierarchical organization that spans a spectrum of length scales, ranging from sub-regions known as loops, which typically comprise hundreds of base pairs, to much larger chromosome territories that can encompass a few mega base pairs. Chromosome conformation capture experiments that involve high-throughput sequencing methods combined with microscopy techniques have enabled a new understanding of inter- and intra-chromosomal interactions with unprecedented details. This information also provides mechanistic insights on the relationship between genome architecture and gene expression. In this article, we review the recent findings on three-dimensional interactions among chromosomes at the compartment, topologically associating domain (TAD), and loop levels and the impact of these interactions on the transcription process. We also discuss current understanding of various biophysical processes involved in multi-layer structural organization of chromosomes. Then, we discuss the relationships between gene expression and genome structure from perturbative genome-wide association studies. Furthermore, for a better understanding of how chromosome architecture and function are linked, we emphasize the role of epigenetic modifications in the regulation of gene expression. Such an understanding of the relationship between genome architecture and gene expression can provide a new perspective on the range of potential future discoveries and therapeutic research.

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The role of loop extrusion in enhancer-mediated gene activation

Cited by 28 publications

References 56 publications

IntegrativePTENEnhancer Discovery Reveals a New Model of Enhancer Organization

IntegrativePTENEnhancer Discovery Reveals a New Model of Enhancer Organization

Sister chromatid cohesion is mediated by individual cohesin complexes

Fundamental insights into the correlation between chromosome configuration and transcription

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