scholarly journals A complex regulatory landscape involved in the development of mammalian external genitals

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ana Rita Amândio ◽  
Lucille Lopez-Delisle ◽  
Christopher Chase Bolt ◽  
Bénédicte Mascrez ◽  
Denis Duboule
Keyword(s):  
Transcriptional Response ◽  
Regulatory Sequences ◽  
Conventional View ◽  
Hoxd Cluster ◽  
Specific Factors ◽  
Enhancer Function ◽  
And Inversion ◽  
Regulatory Landscape ◽  
Regulatory Landscapes ◽  
Ctcf Site

Developmental genes are often controlled by large regulatory landscapes matching topologically associating domains (TADs). In various contexts, the associated chromatin backbone is modified by specific enhancer–enhancer and enhancer–promoter interactions. We used a TAD flanking the mouse HoxD cluster to study how these regulatory architectures are formed and deconstructed once their function achieved. We describe this TAD as a functional unit, with several regulatory sequences acting together to elicit a transcriptional response. With one exception, deletion of these sequences didn’t modify the transcriptional outcome, a result at odds with a conventional view of enhancer function. The deletion and inversion of a CTCF site located near these regulatory sequences did not affect transcription of the target gene. Slight modifications were nevertheless observed, in agreement with the loop extrusion model. We discuss these unexpected results considering both conventional and alternative explanations relying on the accumulation of poorly specific factors within the TAD backbone.

scholarly journals A Complex Regulatory Landscape Involved In The Development Of External Genitals

2019 ◽  
Author(s):  
Ana Rita Amândio ◽  
Lucille Lopez-Delisle ◽  
Christopher Chase Bolt ◽  
Bénédicte Mascrez ◽  
Denis Duboule
Keyword(s):  
Transcriptional Response ◽  
Regulatory Sequences ◽  
Conventional View ◽  
System A ◽  
Functional Consequences ◽  
Enhancer Function ◽  
And Inversion ◽  
Ctcf Site ◽  
Promoter Interaction

ABSTRACTIn vertebrates, developmental genes are often controlled by large regulatory landscapes matching the dimensions of topologically associating domains (TADs). In various ontogenic contexts, the associated constitutive chromatin backbone is modified by fine-tuned specific variations in enhancer-enhancer and enhancer-promoter interaction profiles. In this work, we take one of the TADs flanking the HoxD gene cluster as a paradigm to address the question of how these complex regulatory architectures are formed and how they are de-constructed once their function has been achieved. We suggest that this TAD can be considered as a coherent functional unit in itself, with several regulatory sequences acting together to elicit a transcriptional response. With one notable exception, the deletion of each of these sequences in isolation did not produce any substantial modification in the global transcriptional outcome of the system, a result at odds with a conventional view of long-range enhancer function. Likewise, both the deletion and inversion of a supposedly critical CTCF site located in a region rich in such sequences did not affect transcription of the target gene. In the latter case, however, slight modifications were observed in interaction profiles in vivo in agreement with the loop extrusion model, despite no apparent functional consequences. We discuss these unexpected results by considering both conventional explanations and an alternative possibility whereby a rather unspecific accumulation of particular factors within the TAD backbone may have a global impact upon transcription.

scholarly journals A regulatory ‘landscape effect’ over the HoxD cluster

2011 ◽  
Vol 351 (2) ◽  
pp. 288-296 ◽  
Author(s):  
Patrick Tschopp ◽  
Denis Duboule
Keyword(s):  
Hoxd Cluster ◽  
Regulatory Landscape

scholarly journals Temporal transcriptional response to latency reversing agents identifies specific factors regulating HIV-1 viral transcriptional switch

Retrovirology ◽  
2015 ◽  
Vol 12 (1) ◽  
Author(s):  
Narasimhan J. Venkatachari ◽  
Jennifer M. Zerbato ◽  
Siddhartha Jain ◽  
Allison E. Mancini ◽  
Ansuman Chattopadhyay ◽  
...  
Keyword(s):  
Transcriptional Response ◽  
Transcriptional Switch ◽  
Specific Factors ◽  
Hiv 1 ◽  
Reversing Agents

scholarly journals Transcriptional Heat Shock Response in the Smallest Known Self-Replicating Cell, Mycoplasma genitalium

2006 ◽  
Vol 188 (8) ◽  
pp. 2845-2855 ◽  
Author(s):  
Oxana Musatovova ◽  
Subramanian Dhandayuthapani ◽  
Joel B. Baseman
Keyword(s):  
Heat Shock ◽  
Elevated Temperatures ◽  
Regulation Of Gene Expression ◽  
Bacterial Pathogen ◽  
Transcriptional Response ◽  
Mycoplasma Genitalium ◽  
Regulatory Sequence ◽  
Regulatory Sequences ◽  
Promoter Regions ◽  
Transient Nature

ABSTRACT Mycoplasma genitalium is a human bacterial pathogen linked to urethritis and other sexually transmitted diseases as well as respiratory and joint pathologies. Though its complete genome sequence is available, little is understood about the regulation of gene expression in this smallest known, self-replicating cell, as its genome lacks orthologues for most of the conventional bacterial regulators. Still, the transcriptional repressor HrcA (heat regulation at CIRCE [controlling inverted repeat of chaperone expression]) is predicted in the M. genitalium genome as well as three copies of its corresponding regulatory sequence CIRCE. We investigated the transcriptional response of M. genitalium to elevated temperatures and detected the differential induction of four hsp genes. Three of the up-regulated genes, which encode DnaK, ClpB, and Lon, possess CIRCE within their promoter regions, suggesting that the HrcA-CIRCE regulatory mechanism is functional. Additionally, one of three DnaJ-encoding genes was up-regulated, even though no known regulatory sequences were found in the promoter region. Transcript levels returned to control values after 1 h of incubation at 37°C, reinforcing the transient nature of the heat shock transcriptional response. Interestingly, neither of the groESL operon genes, which encode the GroEL chaperone and its cochaperone GroES, responded to heat shock. These data suggest that M. genitalium selectively regulates a limited number of genes in response to heat shock.

scholarly journals A Global Control Region Defines a Chromosomal Regulatory Landscape Containing the HoxD Cluster

Cell ◽  
2003 ◽  
Vol 113 (3) ◽  
pp. 405-417 ◽  
Author(s):  
François Spitz ◽  
Federico Gonzalez ◽  
Denis Duboule
Keyword(s):  
Control Region ◽  
Global Control ◽  
Hoxd Cluster ◽  
Regulatory Landscape

Transcriptional enhancers: from prediction to functional assessment on a genome-wide scale

Genome ◽  
2020 ◽  
pp. 1-23
Author(s):  
Ian C. Tobias ◽  
Luis E. Abatti ◽  
Sakthi D. Moorthy ◽  
Shanelle Mullany ◽  
Tiegh Taylor ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Target Genes ◽  
Regulatory Sequences ◽  
Enhancer Activity ◽  
Reading Frame ◽  
Enhancer Prediction ◽  
Genome Wide ◽  
A Genome ◽  
Enhancer Function

Enhancers are cis-regulatory sequences located distally to target genes. These sequences consolidate developmental and environmental cues to coordinate gene expression in a tissue-specific manner. Enhancer function and tissue specificity depend on the expressed set of transcription factors, which recognize binding sites and recruit cofactors that regulate local chromatin organization and gene transcription. Unlike other genomic elements, enhancers are challenging to identify because they function independently of orientation, are often distant from their promoters, have poorly defined boundaries, and display no reading frame. In addition, there are no defined genetic or epigenetic features that are unambiguously associated with enhancer activity. Over recent years there have been developments in both empirical assays and computational methods for enhancer prediction. We review genome-wide tools, CRISPR advancements, and high-throughput screening approaches that have improved our ability to both observe and manipulate enhancers in vitro at the level of primary genetic sequences, chromatin states, and spatial interactions. We also highlight contemporary animal models and their importance to enhancer validation. Together, these experimental systems and techniques complement one another and broaden our understanding of enhancer function in development, evolution, and disease.

scholarly journals Impact of Genome Architecture Upon the Functional Activation and Repression of Hox Regulatory Landscapes

2019 ◽  
Author(s):  
Eddie Rodríguez-Carballo ◽  
Lucille Lopez-Delisle ◽  
Nayuta Yakushiji-Kaminatsui ◽  
Asier Ullate-Agote ◽  
Denis Duboule
Keyword(s):  
Gene Cluster ◽  
Spatial Organization ◽  
Target Genes ◽  
Polycomb Group ◽  
Chromatin Domain ◽  
Regulatory Sequences ◽  
Distal Limb ◽  
Polycomb Repressive Complex 2 ◽  
Enhancer Sequences ◽  
Regulatory Landscapes

BackgroundThe spatial organization of the mammalian genome relies upon the formation of chromatin domains of various scales. At the level of gene regulation in cis, collections of enhancer sequences define large regulatory landscapes that usually match with the presence of topologically associating domains (TADs). These domains are largely determined by bound CTCF molecules and often contain ranges of enhancers displaying similar or related tissue specificity, suggesting that in some cases such domains may act as coherent regulatory units, with a global on or off state.ResultsBy using the HoxD gene cluster as a paradigm, we investigated the effect of large genomic rearrangements affecting the two TADs flanking this locus, including their fusion into a single chromatin domain. We show that, within a single hybrid TAD, the activation of both proximal and distal limb enhancers initially positioned in either TADs globally occurred as when both TADs are intact. We also show that the timely implementation of distal limb enhancers depends on whether or not target genes had previously responded to proximal enhancers, due to the presence or absence of H3K27me3 marks.ConclusionsFrom this work, we conclude that antagonistic limb proximal and distal enhancers can exert their specificities when positioned into the same TAD and in the absence of their genuine target genes. We also conclude that removing these target genes reduced the coverage of a regulatory landscape by chromatin marks associated with silencing and thus prolonged its activity in time. Since Polycomb group proteins are mainly recruited at the Hox gene cluster, our results suggest that Polycomb Repressive Complex 2 (PRC2) can extend its coverage to far-cis regulatory sequences as long as confined to the neighboring TAD structure.

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