Systematic analysis of intrinsic enhancer-promoter compatibility in the mouse genome

Martinez-Ara, Miguel; Comoglio, Federico; Arensbergen, Joris van; Steensel, Bas van

doi:10.1101/2021.10.21.465269

Cited by 9 publications

(29 citation statements)

References 69 publications

(96 reference statements)

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“…To test these candidate elements in promoter-reporter gene assay, we first constructed a Luciferase plasmid that contained a 444 bp Trappc9 promoter fragment upstream of and including noncoding exon 1 (Figure 1C). The size of this promoter fragment is in line with standards from high-throughput testing of promoterenhancer interactions in the mouse genome (Martinez-Ara et al, 2022). We positioned the candidate regulatory elements downstream or upstream of the promoter-reporter gene cassette, depending on their relative locations within the Trappc9 locus (Figures 6A,B).…”

Section: Analysis Of Potential Gene Regulatory Regions Indicates Seve...mentioning

confidence: 65%

“…However, there is currently no widely accepted consensus for a silencer chromatin signature and many silencer elements might be bifunctional elements acting through various mechanisms (Segert et al, 2021). Furthermore, a recent functional study of ENCODE3 candidate cis-regulatory elements (cCREs) found that the majority of annotated cCREs had no effect on transcription, while similar numbers of the remaining elements had enhancer or repressor activity, respectively, which was surprising given that cCREs are predicted to be enhancers (Martinez-Ara et al, 2022). Further experiments will be required to determine whether the silencer elements we identified within the Trappc9 locus might function in an allele-specific way and contribute to the brain-specific imprinted expression bias of this gene.…”

Section: Discussionmentioning

confidence: 99%

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Variable allelic expression of imprinted genes at the Peg13, Trappc9, Ago2 cluster in single neural cells

Claxton

Pulix

Seah

et al. 2022

Front. Cell Dev. Biol.

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Genomic imprinting is an epigenetic process through which genes are expressed in a parent-of-origin specific manner resulting in mono-allelic or strongly biased expression of one allele. For some genes, imprinted expression may be tissue-specific and reliant on CTCF-influenced enhancer-promoter interactions. The Peg13 imprinting cluster is associated with neurodevelopmental disorders and comprises canonical imprinted genes, which are conserved between mouse and human, as well as brain-specific imprinted genes in mouse. The latter consist of Trappc9, Chrac1 and Ago2, which have a maternal allelic expression bias of ∼75% in brain. Findings of such allelic expression biases on the tissue level raise the question of how they are reflected in individual cells and whether there is variability and mosaicism in allelic expression between individual cells of the tissue. Here we show that Trappc9 and Ago2 are not imprinted in hippocampus-derived neural stem cells (neurospheres), while Peg13 retains its strong bias of paternal allele expression. Upon analysis of single neural stem cells and in vitro differentiated neurons, we find not uniform, but variable states of allelic expression, especially for Trappc9 and Ago2. These ranged from mono-allelic paternal to equal bi-allelic to mono-allelic maternal, including biased bi-allelic transcriptional states. Even Peg13 expression deviated from its expected paternal allele bias in a small number of cells. Although the cell populations consisted of a mosaic of cells with different allelic expression states, as a whole they reflected bulk tissue data. Furthermore, in an attempt to identify potential brain-specific regulatory elements across the Trappc9 locus, we demonstrate tissue-specific and general silencer activities, which might contribute to the regulation of its imprinted expression bias.

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Section: Analysis Of Potential Gene Regulatory Regions Indicates Seve...mentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Variable allelic expression of imprinted genes at the Peg13, Trappc9, Ago2 cluster in single neural cells

Claxton

Pulix

Seah

et al. 2022

Front. Cell Dev. Biol.

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“…How the cell can make the correct decision to upregulate the correct gene is an important question for the future. One possibility is for instance promoter enhancer compatibility (Martinez-Ara et al, 2022), which is something that we cannot easily explore in our system.…”

Section: Open Chromatin Sites Are Highly Predictive For Gene Expressi...mentioning

confidence: 99%

“…This would mean that the distal downstream element drives 85% of expression and the proximal element a much smaller part of expression. Massively parallel reporter assays show that the both elements drive expression in roughly equal measure in an episomal context (Martinez-Ara et al, 2022). An alternative is the super-additive model in which multiple weak enhancers synergistically activate gene expression to a higher level than would be predicted from the sum of all enhancer activities.…”

Section: Open Chromatin Sites Are Highly Predictive For Gene Expressi...mentioning

confidence: 99%

Pioneer activity distinguishes activating from non-activating pluripotency transcription factor binding sites

Maresca

Brand

et al. 2022

Preprint

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Genome-wide transcriptional activity involves the binding of many transcription factors to thousands of sites in the genome. Determining which sites are directly driving transcription remains a challenge. Here we use acute protein depletion of the pioneer transcription factors OCT4 and SOX2 to establish their functionality in maintaining chromatin accessibility. We show that thousands of accessible sites are lost within an hour of protein depletion, indicating rapid turnover of these sites in the absence of pioneer factors. To understand the relationship with transcription we performed nascent transcription analysis and found that open chromatin sites that are maintained by SOX2 are highly predictive of gene expression, in contrast to SOX2 binding sites that do not maintain accessibility. We use CRISPR-Cas9 genome editing in the Klf2 locus to functionally validate a predicted regulatory element. We conclude that the regulatory activity of SOX2 is exerted largely at sites where it maintains accessibility and that other binding sites are largely dispensable for gene regulation.

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“…Work in the Drosophila system suggested that many enhancers display high functional specificity for promoters with optimum expression requiring paired elements from either the developmental or housekeeping gene classes 22 . In contrast, recent work in human and mouse systems suggests that most enhancers can activate a wide range of core promoters and therefore display low specificity 23,24 . These later studies found that selectivity in enhancer activity at various core promoters is subtle and largely corresponds to matched enhancers and promoters from the same regulatory class.…”

Section: Introductionmentioning

confidence: 91%

Broad compatibility between yeast UAS elements and core promoters and identification of promoter elements that determine cofactor specificity

Schofield

Hahn

2022

Preprint

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Three general classes of yeast protein-coding genes are distinguished by their dependence on the transcription cofactors TFIID, SAGA and Mediator (MED) Tail, but little is known about whether this dependence is determined by the core promoter, Upstream activation sites (UASs), or other gene features. It is also unclear whether UASs can broadly activate transcription from the different promoter classes or whether efficient transcription requires matching UASs and promoters of similar gene class. Here we measure transcription and cofactor specificity for tens of thousands of UAS-core promoter combinations. We find that <5% of UASs display strong core promoter specificity while most UASs can broadly activate promoters regardless of regulatory class. However, we find that matching UASs and promoters from the same gene class is generally important for optimal expression. From examining the cofactor dependence of this large UAS-promoter set, we find that sensitivity to rapid depletion of MED Tail or SAGA is dependent on the identity of both UAS and promoter while dependence on TFIID localizes to only the core promoter. Our results explain why transcription factor-mediated MED recruitment to the UAS does not always result in Tail-dependent transcription and highlight the role of TATA and TATA-like promoter sequences in MED Tail function.

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Systematic analysis of intrinsic enhancer-promoter compatibility in the mouse genome

Cited by 9 publications

References 69 publications

Variable allelic expression of imprinted genes at the Peg13, Trappc9, Ago2 cluster in single neural cells

Variable allelic expression of imprinted genes at the Peg13, Trappc9, Ago2 cluster in single neural cells

Pioneer activity distinguishes activating from non-activating pluripotency transcription factor binding sites

Broad compatibility between yeast UAS elements and core promoters and identification of promoter elements that determine cofactor specificity

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