The Evf2 Ultraconserved Enhancer lncRNA Functionally and Spatially Organizes Megabase Distant Genes in the Developing Forebrain

Cajigas, Ivelisse; Chakraborty, Abhijit; Swyter, Kelsey R.; Luo, Hao; Bastidas, Monique; Nigro, Maximilliano; Morris, Elizabeth R.; Chen, Sean; VanGompel, Michael J.W.; Leib, David E.; Kohtz, Sara J.; Martina, Marco; Koh, Sooky; Ay, Ferhat; Kohtz, Jhumku D.

doi:10.1016/j.molcel.2018.07.024

Cited by 65 publications

(76 citation statements)

References 74 publications

(103 reference statements)

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“…There may also be a role for noncoding RNA in enhancer-promoter interactions 25,26,[78][79][80] . Notably, whilst mRNA has been shown to direct the formation of phase condensate compartments in the cytoplasm 81 and eRNAs have been proposed to play a similar role in the formation of enhancer-promoter complexes 25,26 our results following dissolution of phase condensates with hexanediol treatment argue that these interactions are not sufficient for maintaining contact at many genes.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

BET inhibition disrupts transcription but retains enhancer-promoter contact

Crump

Ballabio

Godfrey

et al. 2019

Preprint

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“…In addition to primary structure heterogeneity, eRNAs demonstrate diverse secondary structures that model those seen in tRNAs, miRNAs, snRNAs, and lncRNAs (Cheng et al, 2015;Ren et al, 2017). Some eRNA molecules contain different domains with unique functions (Cajigas et al, 2018;Cichewicz et al, 2018;Tsai et al, 2018). Post-transcriptional modifications have also been observed, such as cytosine methylation by NSun7, which may promote stability of eRNAs (Aguilo et al, 2016).…”

Section: Structure and Heterogeneity Of Ernamentioning

confidence: 99%

“…Thus, RNA is a key contributor to the biology of biomolecular condensates. For an extensive review on phase-separation and biomolecular condensates, please see Banani et al (2017). positioning to direct long-range UCE interactions (Cajigas et al, 2018). Additionally, the 5 UCE-containing region of Evrf2 was sufficient for localizing cohesin to target genes, while the 3 end was necessary for target gene activation.…”

Section: Enhancer-promoter Interactionmentioning

confidence: 99%

Diversity and Emerging Roles of Enhancer RNA in Regulation of Gene Expression and Cell Fate

Arnold

Wells

2020

Front. Cell Dev. Biol.

173

157

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Enhancers are cis-regulatory elements in the genome that cooperate with promoters to control target gene transcription. Unlike promoters, enhancers are not necessarily adjacent to target genes and can exert their functions regardless of enhancer orientations, positions and spatial segregations from target genes. Thus, for a long time, the question as to how enhancers act in a temporal and spatial manner attracted considerable attention. The recent discovery that enhancers are also abundantly transcribed raises interesting questions about the exact roles of enhancer RNA (eRNA) in gene regulation. In this review, we highlight the process of enhancer transcription and the diverse features of eRNA. We review eRNA functions, which include enhancer-promoter looping, chromatin modifying, and transcription regulating. As eRNA are transcribed from active enhancers, they exhibit tissue and lineage specificity, and serve as markers of cell state and function. Finally, we discuss the unique relationship between eRNA and super enhancers in phase separation wherein eRNA may contribute significantly to cell fate decisions.

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“…Functionally, Sox2ot, like other lncRNAs, may act either in cis (Clark & Blackshaw, 2014;Joung et al, 2017) or in trans (Briggs et al, 2015) to regulate Sox2 expression, and currently there is some evidence of both types of mechanism (Askarian-Amiri et al, 2014;Messemaker at al, 2018). The recently identified cis-level mechanism in mouse embryonic stem cells (Messemaker at al, 2018) involves an interaction of Sox2ot with a Sox2 enhancer, in accordance with a widespread recognition of enhancer-lncRNA interactions (Vucicevic et al, 2015;Cajigas et al, 2018). Therefore, in view of this large body of data, there is clearly a need to conduct an integrated analysis of the multiple potential Sox2 regulatory sequences that are likely to be involved in permitting adult neuronal expression of this gene.…”

Section: Introductionmentioning

confidence: 99%

Integrated analysis of different non-coding features across the Sox2 locus implicates a diencephalic enhancer in adult brain expression

Carter

2019

Preprint

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SOX2 is a prominent member of the SOX family of transcription factors that has many different functional roles. This pleiotropy is made possible by multiple regulatory mechanisms that direct appropriate spatial and temporal patterns of expression, and therefore action. The current study concerns the mechanisms that determine Sox2 gene expression in the adult mammalian brain, where SOX2 protein is absent in general, but is selectively and abundantly expressed in a majority of neurons within a ventral diencephalic brain structure, the suprachiasmatic nucleus (SCN). In this study, a comparative bioinformatic and biochemical analysis of different adult rat brain regions was conducted in order to identify SCN-selective (immaturity-related) regulatory mechanisms. The approach incorporated an integrated analysis of Sox2 enhancers, CTCF binding sites, and also expression of the Sox2-overlapping, long non-coding (lnc)RNA, Sox2ot. Initial experiments revealed brain region-specific Sox2ot expression (including region-specific novel transcripts), indicating a significant diversity of Sox2ot expression across the adult brain. However, the pattern and abundance of Sox2ot expression in the SCN, relative to selected control areas of the brain, did not indicate an overt relationship to Sox2 gene expression. Furthermore, although multiple individual Sox2ot exon sequences were shown to overlap annotated Sox2 gene enhancers at different sites across the Sox2 locus, again there was no indication of a SCN-specific functional correlation. Further integration with an analysis of selectively-active CTCF sites within the Sox2 locus directed attention to one site with both a prominent peak of activity in immature brain, and proximity to a functionally-characterized, ventral diencephalic, Sox2 enhancer termed U6 (upstream enhancer 6). Ex vivo analysis of the U6-associated CTCF site revealed SCN-selective CTCF binding, and these sequences were both localized within a known (brain region-selective) super-enhancer. Bioinformatic analysis of the U6 enhancer sequence revealed an abundance of consensus sites for the SCN-selective transcription factor LHX1, and over-expression of this factor enhanced the activity of cloned U6 sequence in transfected cells. However, despite this compelling evidence for a molecular mechanism that underlies adult brain expression of SOX2, further analysis of LHX1-SOX2 co-expression in the SCN confounded this view, indicating the presence of other concurrent mechanisms in the different cell populations of the SCN.

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The Evf2 Ultraconserved Enhancer lncRNA Functionally and Spatially Organizes Megabase Distant Genes in the Developing Forebrain

Cited by 65 publications

References 74 publications

BET inhibition disrupts transcription but retains enhancer-promoter contact

BET inhibition disrupts transcription but retains enhancer-promoter contact

Diversity and Emerging Roles of Enhancer RNA in Regulation of Gene Expression and Cell Fate

Integrated analysis of different non-coding features across the Sox2 locus implicates a diencephalic enhancer in adult brain expression

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