Gene regulation at a distance: From remote enhancers to 3D regulatory ensembles

Spitz, François

doi:10.1016/j.semcdb.2016.06.017

Cited by 83 publications

(63 citation statements)

References 160 publications

(212 reference statements)

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“…While proximal epigenetic modifications are the most likely cause for a given gene's altered transcription, DMCs that modulate transcription have been reported as distant as 1Mbp[37], which our data further supports. Just as a few critical DMCs may be more influential than an abundance of trivial DMCs to modulate expression, methylation of key sites located more than 3kb away from the TSS may be as imperative as changes closer to the TSS.…”

Section: Discussionsupporting

confidence: 84%

Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72-associated and sporadic ALS, and implicates SERPINA1 in disease

et al. 2017

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We previously found C9orf72-associated (c9ALS) and sporadic amyotrophic lateral sclerosis (sALS) brain transcriptomes comprise thousands of defects, among which, some are likely key contributors to ALS pathogenesis. We have now generated complementary methylome data and combine these two data sets to perform a comprehensive “multi-omic” analysis to clarify the molecular mechanisms initiating RNA misregulation in ALS. We found that c9ALS and sALS patients have generally distinct but overlapping methylome profiles, and that the c9ALS- and sALS-affected genes and pathways have similar biological functions, indicating conserved pathobiology in disease. Our results strongly implicate SERPINA1 in both C9orf72 repeat expansion carriers and non-carriers, where expression levels are greatly increased in both patient groups across the frontal cortex and cerebellum. SERPINA1 expression is particularly pronounced in C9orf72 repeat expansion carriers for both brain regions, where SERPINA1 levels are strictly down regulated across most human tissues, including the brain, except liver and blood, and are not measurable in E18 mouse brain. The altered biological networks we identified contain critical molecular players known to contribute to ALS pathology, which also interact with SERPINA1. Our comprehensive combined methylation and transcription study identifies new genes and highlights that direct genetic and epigenetic changes contribute to c9ALS and sALS pathogenesis.

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Section: Discussionsupporting

confidence: 84%

Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72-associated and sporadic ALS, and implicates SERPINA1 in disease

et al. 2017

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“…In eukaryotes, similar strategies are acting at the level of enhancer-promoter modules where the action at “distance” of the enhancer sequences are conditioned to their physical contacts with the promoter: as for the lac system, distal enhancer sequences might actually act as secondary recruitment sequences for TFs that, by associating with mediator and other architectural proteins, can promote recruitment and stabilization of the transcriptional machinery at promoters via long-range looping and clustering (Spitz 2016; Liu et al 2014). …”

Section: From 3d To 1d: Spatial Chromatin Compartments and The Nanorementioning

confidence: 99%

Perspectives: using polymer modeling to understand the formation and function of nuclear compartments

2017

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Compartmentalization is a ubiquitous feature of cellular function. In the nucleus, early observations revealed a non-random spatial organization of the genome with a large-scale segregation between transcriptionally active—euchromatin—and silenced—heterochromatin—parts of the genome. Recent advances in genome-wide mapping and imaging techniques have strikingly improved the resolution at which nuclear genome folding can be analyzed and have revealed a multiscale spatial compartmentalization with increasing evidences that such compartment may indeed result from and participate to genome function. Understanding the underlying mechanisms of genome folding and in particular the link to gene regulation requires a cross-disciplinary approach that combines the new high-resolution techniques with computational modeling of chromatin and chromosomes. In this perspective article, we first present how the copolymer theoretical framework can account for the genome compartmentalization. We then suggest, in a second part, that compartments may act as a “nanoreactor,” increasing the robustness of either activation or repression by enhancing the local concentration of regulators. We conclude with the need to develop a new framework, namely the “living chromatin” model that will allow to explicitly investigate the coupling between spatial compartmentalization and gene regulation.

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“…Transcription factors (TFs) bind these enhancer elements and regulate transcription from the promoters of nearby or distant genes through physical contacts that involve looping of DNA between enhancers and promoters (Bonev and Cavalli, 2016; Fraser et al, 2015; Heard and Bickmore, 2007; de Laat and Duboule, 2013; Pombo and Dillon, 2015; Spitz, 2016). Despite the fundamental importance of proper gene control to cell identity and development, the proteins that contribute to structural interactions between enhancers and promoters are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

YY1 Is a Structural Regulator of Enhancer-Promoter Loops

Weintraub

Zamudio

et al. 2017

Cell

834

808

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SUMMARY There is considerable evidence that chromosome structure plays important roles in gene control, but we have limited understanding of the proteins that contribute to structural interactions between gene promoters and their enhancer elements. Large DNA loops that encompass genes and their regulatory elements depend on CTCF-CTCF interactions, but most enhancer-promoter interactions do not employ this structural protein. Here, we show that the ubiquitously expressed transcription factor Yin Yang 1 (YY1) contributes to enhancer-promoter structural interactions in a manner analogous to DNA interactions mediated by CTCF. YY1 binds to active enhancers and promoter-proximal elements and forms dimers that facilitate the interaction of these DNA elements. Deletion of YY1 binding sites or depletion of YY1 protein disrupts enhancer-promoter looping and gene expression. We propose that YY1-mediated enhancer-promoter interactions are a general feature of mammalian gene control.

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Gene regulation at a distance: From remote enhancers to 3D regulatory ensembles

Cited by 83 publications

References 160 publications

Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72-associated and sporadic ALS, and implicates SERPINA1 in disease

Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72-associated and sporadic ALS, and implicates SERPINA1 in disease

Perspectives: using polymer modeling to understand the formation and function of nuclear compartments

YY1 Is a Structural Regulator of Enhancer-Promoter Loops

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