2019
DOI: 10.1073/pnas.1900672116
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Preformed chromatin topology assists transcriptional robustness ofShhduring limb development

Abstract: Long-range gene regulation involves physical proximity between enhancers and promoters to generate precise patterns of gene expression in space and time. However, in some cases, proximity coincides with gene activation, whereas, in others, preformed topologies already exist before activation. In this study, we investigate the preformed configuration underlying the regulation of the Shh gene by its unique limb enhancer, the ZRS, in vivo during mouse development. Abrogating the constitutive transcription coverin… Show more

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Cited by 153 publications
(159 citation statements)
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“…Moreover, sufficient Shh expression was maintained for compound heterozygote embryos carrying either ΔCTCF1 or the 35 kb deletion opposite a Shh null allele to have no abnormal phenotype. A contemporaneous study on the same genomic territory has largely recapitulated these resultsdeletions of Lmbr1 CTCF sites and the gene promoter caused perturbations to local chromatin conformation but Shh expression, although reported to be reduced, was enough to drive normal limb development (Paliou et al, 2019). The Shh regulatory landscape is set up to ensure optimal activation of the gene and here, we have shown that this is robust to perturbations of TAD integrity and structure.…”
Section: Ectopic Expression Across Disrupted Tad Boundaries Is Not Cosupporting
confidence: 57%
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“…Moreover, sufficient Shh expression was maintained for compound heterozygote embryos carrying either ΔCTCF1 or the 35 kb deletion opposite a Shh null allele to have no abnormal phenotype. A contemporaneous study on the same genomic territory has largely recapitulated these resultsdeletions of Lmbr1 CTCF sites and the gene promoter caused perturbations to local chromatin conformation but Shh expression, although reported to be reduced, was enough to drive normal limb development (Paliou et al, 2019). The Shh regulatory landscape is set up to ensure optimal activation of the gene and here, we have shown that this is robust to perturbations of TAD integrity and structure.…”
Section: Ectopic Expression Across Disrupted Tad Boundaries Is Not Cosupporting
confidence: 57%
“…Shh expression in the limb bud driven by ZRS lasts only 48 h from initiation to downregulation. qRT-PCR performed from limb buds at E10.5 can detect changes in expression in response to deletions within the Shh TAD (Paliou et al, 2019). However, we detected no differences in the percentage of expressing Shh alleles on E11.5 developing limb buds using RNA FISH (Fig.…”
Section: Shh Expression Patterns and Development Are Unaffected In Ctmentioning
confidence: 73%
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“…This behavior is similar to that observed in a Mediator mutant cell line 21 , suggesting that it may be a genuine consequence of Mediator loss. It is possible that these structural changes are an indirect effect of the transcriptional disruption following BRD4/Mediator loss, as has been observed before 70,71 , although there was no correlation with transcriptional response.…”
Section: Discussionmentioning
confidence: 86%
“…Despite severe changes in loop and TAD structure, the effects of 3D genome changes on transcription are either mild or difficult to explain genome-wide (Hyle et al, 2019;Nora et al, 2017;Rao et al, 2017). Despite the existence of specific examples where CTCF assists in bringing promoters and enhancers together to activate gene expression (Hadjur et al, 2009;Paliou et al, 2019), these results cannot be generalized. Although, the role of architectural proteins in genome organization is becoming clearer, the detailed molecular mechanisms of how these proteins contribute to gene regulation is still poorly understood.…”
Section: Introductionmentioning
confidence: 92%