Decreased Enhancer-Promoter Proximity Accompanying Enhancer Activation

Benabdallah, Nezha S.; Williamson, Iain; Illingworth, Robert S.; Kane, Lauren; Boyle, Shelagh; Sengupta, Dipta; Grimes, Graeme R.; Therizols, Pierre; Bickmore, Wendy A.

doi:10.1016/j.molcel.2019.07.038

Cited by 243 publications

(257 citation statements)

References 77 publications

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“…Here, we integrate caQTL and eQTL studies as an additional method to both identify the genes regulated by REs and to propose causal variants altering the function of these REs. This is complementary to chromatin interaction assays, such as Hi-C, which demonstrate physical interaction with a promoter region, but are not always indicative of regulation (Alexander et al, 2019;Benabdallah et al, 2019) . caQTL and eQTL studies require genetic variation to be present in a population in order to detect their impact.…”

Section: Discussionmentioning

confidence: 97%

Cell-type specific effects of genetic variation on chromatin accessibility during human neuronal differentiation

Liang

Elwell

Aygün

et al. 2020

Preprint

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Common genetic risk for neuropsychiatric disorders is enriched in regulatory elements active during cortical neurogenesis. However, the mechanisms mediating the effects of genetic variants on gene regulation are poorly understood. To determine the functional impact of common genetic variation on the non-coding genome longitudinally during human cortical development, we performed a chromatin accessibility quantitative trait loci (caQTL) analysis in neural progenitor cells and their differentiated neuronal progeny from 92 donors. We identified 8,111 caQTLs in progenitors and 3,676 caQTLs in neurons, with highly temporal, cell-type specific effects. A subset (~20%) of caQTLs were also associated with changes in gene expression. Motif-disrupting alleles of transcriptional activators generally led to decreases in chromatin accessibility, whereas motif-disrupting alleles of repressors led to increases in chromatin accessibility. By integrating cell-type specific caQTLs and brain-relevant genome-wide association data, we were able to fine-map loci and identify regulatory mechanisms underlying non-coding neuropsychiatric disorder risk variants.

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Section: Discussionmentioning

confidence: 97%

Cell-type specific effects of genetic variation on chromatin accessibility during human neuronal differentiation

Liang

Elwell

Aygün

et al. 2020

Preprint

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“…Maintenance of enhancer-promoter looping is thought to be crucial for gene activation, but emerging evidence and the data presented here suggest that enhancer-promoter contact and gene activation may be partially separable events. Importantly, physical interaction with the promoter may not be necessary for all enhancers 5,6 , although it appears to be a requisite for most. At the same time, enhancer-promoter looping alone is not sufficient for activation, as enhancer-promoter contacts have been observed in the absence of transcription 57,58 .…”

Section: Discussionmentioning

confidence: 99%

“…Enhancers can be situated far away from the genes they regulate 1,4 . Although not always the case 5,6 , at many gene loci proximity between enhancers and promoters is thought to be essential for enhancer function and gene activation 7,8 . How these enhancer-promoter interactions are initiated and maintained is not clearly understood.…”

Section: Introductionmentioning

confidence: 99%

BET inhibition disrupts transcription but retains enhancer-promoter contact

Crump

Ballabio

Godfrey

et al. 2019

Preprint

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In higher eukaryotes, enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. The formation of phase condensates is thought to be an essential component of enhancer function. Here, we show that pharmacological targeting of cells with inhibitors of BET (Bromodomain and Extra-Terminal domain) proteins can have a strong impact on transcription but very little impact on enhancer-promoter interactions. Treatment with 1,6-hexanediol, which dissolves phase condensate structures and reduces BET and Mediator protein binding at enhancers, can also have a strong effect on gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancerpromoter interactions are separable events. Our findings further suggest that enhancer-promoter interactions are not dependent on high levels of BRD4 (Bromodomain-containing protein 4) and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and loop extrusion by CTCF/cohesin.

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“…Furthermore, advances in live cell imaging will complement the continually improving structural and mechanistic models of Pol II transcription. Despite recent progress (Liu and Tjian 2018), many basic questions remain unanswered, such as (1) how genomes are organized in the three-dimensional space of the nucleus (Furlong and Levine 2018), (2) how transcriptional bursting occurs (Donovan et al 2019;Rodriguez et al 2019;Stavreva et al 2019), (3) how enhancer-promoter interactions are controlled (Lim et al 2018;Li et al 2019), (4) how enhancers actually work to activate gene expression (Benabdallah et al 2019;Heist et al 2019), (5) how gene expression patterns are maintained (i.e., active vs. repressed) through mitosis (Teves et al 2018), and so on. Also, what set of cofactors are essential for these processes, and which are redundant, context-specific, or cell type-specific?…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Structure and mechanism of the RNA polymerase II transcription machinery

2020

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RNA polymerase II (Pol II) transcribes all protein-coding genes and many noncoding RNAs in eukaryotic genomes. Although Pol II is a complex, 12-subunit enzyme, it lacks the ability to initiate transcription and cannot consistently transcribe through long DNA sequences. To execute these essential functions, an array of proteins and protein complexes interact with Pol II to regulate its activity. In this review, we detail the structure and mechanism of over a dozen factors that govern Pol II initiation (e.g., TFIID, TFIIH, and Mediator), pausing, and elongation (e.g., DSIF, NELF, PAF, and P-TEFb). The structural basis for Pol II transcription regulation has advanced rapidly in the past decade, largely due to technological innovations in cryoelectron microscopy. Here, we summarize a wealth of structural and functional data that have enabled a deeper understanding of Pol II transcription mechanisms; we also highlight mechanistic questions that remain unanswered or controversial.

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Decreased Enhancer-Promoter Proximity Accompanying Enhancer Activation

Abstract: Highlights d Super-resolution microscopy reveals increased enhancerpromoter separation upon activation d Synthetic enhancer activation supports decreased enhancerpromoter proximity d Enhancer-promoter separation can be driven by poly(ADPribose) polymerase 1

Cited by 243 publications

References 77 publications

Cell-type specific effects of genetic variation on chromatin accessibility during human neuronal differentiation

Cell-type specific effects of genetic variation on chromatin accessibility during human neuronal differentiation

BET inhibition disrupts transcription but retains enhancer-promoter contact

Structure and mechanism of the RNA polymerase II transcription machinery

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