PARP mediated chromatin unfolding is coupled to long-range enhancer activation

Benabdallah, Nezha S.; Williamson, Iain; Illingworth, Robert S.; Boyle, S; Gr, Grimes; Therizols, Pierre; Bickmore, Wendy A.

doi:10.1101/155325

Cited by 28 publications

(20 citation statements)

References 78 publications

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“…Our results seem incompatible with alternative mechanisms of gene regulation that do not necessarily depend on promoter-enhancer interactions 55,56 nor its extension in time 57 . In such an alternative scenario, promoter-enhancer contacts are short-lived but continue to maintain a transcriptionally-competent chromatin environment at promoters to ensure their activity even if long-range interactions are lost.…”

Section: Taddyn Simulations Have Provided New Insights Into Mechanismcontrasting

confidence: 87%

Dynamic simulations of transcriptional control during cell reprogramming reveal spatial chromatin caging

Stefano

Stadhouders

Farabella

et al. 2019

Preprint

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Chromosome structure is a crucial regulatory factor for a wide range of nuclear processes. Chromosome Conformation Capture (3C)-based experiments combined with computational modelling are pivotal for unveiling 3D chromosome structure. Here, we introduce TADdyn, a new tool that integrates time-course 3C data, restraint-based modelling, and molecular dynamics to simulate the structural rearrangements of genomic loci in a completely data-driven way. We applied TADdyn on in-situ Hi-C time-course experiments studying the reprogramming of murine B cells to pluripotent cells, and characterized the structural rearrangements that take place upon changes in the transcriptional state of 11 genomic loci. TADdyn simulations show that structural cages form around the transcription starting site of active loci to stabilize their dynamics, by initiating (hit) and maintaining (stick) interactions with regulatory regions. Consistent findings with TADdyn for all loci under study suggest that this hit-and-stick mechanism may represent a general mechanism to trigger and stabilize transcription.

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Section: Taddyn Simulations Have Provided New Insights Into Mechanismcontrasting

confidence: 87%

Dynamic simulations of transcriptional control during cell reprogramming reveal spatial chromatin caging

Stefano

Stadhouders

Farabella

et al. 2019

Preprint

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“…TAL effectors (TALEs) are a class of proteins that have been used to modulate transcription, epigenetic states (40,41) and nuclear organization (42,43). As regulatory elements are landing pads for transcription factor binding, which transfer signals and factors onto gene promoter sequences, we reasoned that targeting a regulatory element with a transactivator could be a useful approach to understand its specificity and behaviour.…”

Section: Resultsmentioning

confidence: 99%

Functional characteristics of novel pancreatic Pax6 regulatory elements

Buckle

Nozawa

Kleinjan

et al. 2018

Human Molecular Genetics

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Complex diseases, such as diabetes, are influenced by comprehensive transcriptional networks. Genome-wide association studies have revealed that variants located in regulatory elements for pancreatic transcription factors are linked to diabetes, including those functionally linked to the paired box transcription factor Pax6. Pax6 deletions in adult mice cause rapid onset of classic diabetes, but the full spectrum of pancreatic Pax6 regulators is unknown. Using a regulatory element discovery approach, we identified two novel Pax6 pancreatic cis-regulatory elements in a poorly characterized regulatory desert. Both new elements, Pax6 pancreas cis-regulatory element 3 (PE3) and PE4, are located 50 and 100 kb upstream and interact with different parts of the Pax6 promoter and nearby non-coding RNAs. They drive expression in the developing pancreas and brain and code for multiple pancreas-related transcription factor-binding sites. PE3 binds CCCTC-binding factor (CTCF) and is marked by stem cell identity markers in embryonic stem cells, whilst a common variant located in the PE4 element affects binding of Pax4, a known pancreatic regulator, altering Pax6 gene expression. To determine the ability of these elements to regulate gene expression, synthetic transcriptional activators and repressors were targeted to PE3 and PE4, modulating Pax6 gene expression, as well as influencing neighbouring genes and long non-coding RNAs, implicating the Pax6 locus in pancreas function and diabetes.

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“…Hence, within the domain, chromatin decompaction is uncoupled from transcriptional upregulation of the α-globin genes, indicating a response to earlier events at the locus. Decompaction of chromatin has also been uncoupled from enhancer-promoter interaction at the Shh locus in mice 21 .…”

mentioning

confidence: 99%

A tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions

Brown

Roberts

Graham

et al. 2017

Preprint

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A variety of self-interacting domains, defined at different levels of resolution, have been described in mammalian genomes. These include Chromatin Compartments (A and B)1, Topologically Associated Domains (TADs)2,3, contact domains4,5, sub-TADs6, insulated neighbourhoods7 and frequently interacting regions (FIREs)8. Whereas many studies have found the organisation of self-interacting domains to be conserved across cell types389, some do form in a lineage-specific manner6710. However, it is not clear to what degree such tissue-specific structures result from processes related to gene activity such as enhancer-promoter interactions or whether they form earlier during lineage commitment and are therefore likely to be prerequisite for promoting gene expression. To examine these models of genome organisation in detail, we used a combination of high-resolution chromosome conformation capture, a newly-developed form of quantitative fluorescence in-situ hybridisation and super-resolution imaging to study a 70 kb self-interacting domain containing the mouse α-globin locus. To understand how this self-interacting domain is established, we studied the region when the genes are inactive and during erythroid differentiation when the genes are progressively switched on. In contrast to many current models of long-range gene regulation, we show that an erythroid-specific, decompacted self-interacting domain, delimited by convergent CTCF/cohesin binding sites, forms prior to the onset of robust gene expression. Using previously established mouse models we show that formation of the self-interacting domain does not rely on interactions between the α-globin genes and their enhancers. As there are also no tissue-specific changes in CTCF binding, then formation of the domain may simply depend on the presence of activated lineage-specific cis-elements driving a transcription-independent mechanism for opening chromatin throughout the 70 kb region to create a permissive environment for gene expression. These findings are consistent with a model of loop-extrusion in which all segments of chromatin, within a region delimited by CTCF boundary elements, can contact each other. Our findings suggest that activation of tissue-specific element(s)within such a self-interacting region is sufficient to influence all chromatin within the domain.

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PARP mediated chromatin unfolding is coupled to long-range enhancer activation

Cited by 28 publications

References 78 publications

Dynamic simulations of transcriptional control during cell reprogramming reveal spatial chromatin caging

Dynamic simulations of transcriptional control during cell reprogramming reveal spatial chromatin caging

Functional characteristics of novel pancreatic Pax6 regulatory elements

A tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions

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