Ultraconserved enhancer function does not require perfect sequence conservation

Snetkova, Valentina; Ypsilanti, Athéna R.; Akiyama, Jennifer A.; Mannion, Brandon J.; Plajzer-Frick, Ingrid; Novak, Catherine S.; Harrington, Anne; Pham, Quan; Kato, Momoe; Zhu, Yiwen; Godoy, Janeth; Meky, Eman M; Hunter, Riana D; Shi, Marie; Kvon, Evgeny Z.; Afzal, Veena; Tran, Susan H; Rubenstein, John L.R.; Visel, Axel; Pennacchio, L; Dickel, Diane E.

doi:10.1038/s41588-021-00812-3

Cited by 52 publications

(53 citation statements)

References 39 publications

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“…In fact, a large fraction of H3K27ac-positive sequences detected either in the mouse or in the chicken PT cells were not conserved between the two species, suggesting that they evolved in a species-specific manner. In contrast, the high proportion of chicken promoters that display similar H3K27ac enrichments in mice, together with the similar expression patterns observed for mouse and chicken Hoxd genes in embryonic trunk cells, demonstrate that conserved gene expression can occur despite a high evolutionary plasticity in the cis -regulatory code usage, in agreement with previous reports (Berthelot et al, 2018; Snetkova et al, 2021). This may point to a regulatory strategy where multiple enhancers act coordinately to regulate the same target gene(s) thus creating a quantitive effect in a way similar to the reported action of super-enhancers (Sabari et al, 2018), yet where various subsets of CREs may display distinct tissue-specificities.…”

Section: Discussionsupporting

confidence: 92%

Developmental and Evolutionary Comparative Analysis of a Regulatory Landscape in Mammals and Birds

Hintermann

Guerreiro

Bolt

et al. 2021

Preprint

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Modifications in gene regulation during development are considered to be a driving force in the evolution of organisms. Part of these changes involve rapidly evolving cis-regulatory elements (CREs), which interact with their target genes through higher-order 3D chromatin structures. How such 3D architectures and variations in CREs contribute to transcriptional evolvability nevertheless remains elusive. During vertebrate evolution, Hox genes were redeployed in different organs in a class-specific manner, while maintaining the same basic function in organizing the primary body axis. Since a large part of the relevant enhancers are located in a conserved regulatory landscape, this gene cluster represents an interesting paradigm to study the emergence of regulatory innovations. In this work, we analyzed Hoxd gene regulation in both murine vibrissae and chicken feather primordia, two mammalian- and avian-specific skin appendages which express different subsets of Hoxd genes, and compared their regulatory modalities with the regulations at work during the elongation of the posterior trunk, a mechanism highly conserved in amniotes. We show that in the former two structures, distinct subsets of Hoxd genes are contacted by different lineage-specific enhancers, likely as a result of using an ancestral chromatin topology as an evolutionary playground, whereas the regulations implemented in the mouse and chicken embryonic trunk rely more on conserved CREs. Nevertheless, a high proportion of these non-coding sequences active in the trunk appear to have functionally diverged between the two species, suggesting that transcriptional robustness is maintained despite a considerable divergence in CRE sequences, an observation supported by a genome-wide comparative approach.

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Section: Discussionsupporting

confidence: 92%

Developmental and Evolutionary Comparative Analysis of a Regulatory Landscape in Mammals and Birds

Hintermann

Guerreiro

Bolt

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…Based on phastCons scores, it indicates that these functionally conserved SEs do not necessarily exhibit higher scores than non-conserved ones. Consistently, a recent study suggests that the function of enhancer activities does not necessarily require the perfect sequence conservation (Snetkova et al, 2021). In fact, a previous study has also indicated that rarely conserved enhancers have overlapping functions even in phylogenetically distant species (Clarke et al, 2012;Villar et al, 2015).…”

Section: Discussionsupporting

confidence: 64%

A Comparative Analysis of Super-Enhancers and Broad H3K4me3 Domains in Pig, Human, and Mouse Tissues

et al. 2021

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Super-enhancers (SEs) and broad H3K4me3 domains (BDs) are crucial regulators in the control of tissue identity in human and mouse. However, their features in pig remain largely unknown. In this study, by integrative computational analyses of epigenomic and transcriptomic data, we have characterized SEs and BDs in six pig tissues and analyzed their conservation in comparison with human and mouse tissues. Similar to human and mouse, pig SEs and BDs display higher tissue specificity than their typical counterparts. Genes proximal to SEs and BDs are associated with tissue identity in most tissues. About 55–182 SEs (5–17% in total) and 99–309 BDs (8–16% in total) across pig tissues are considered as functionally conserved elements because they have orthologous SEs and BDs in human and mouse. However, these elements do not necessarily exhibit sequence conservation. The functionally conserved SEs are correlated to tissue identity in majority of pig tissues, while those conserved BDs are linked to tissue identity in a few tissues. Our study provides resources for future gene regulatory studies in pig. It highlights that SEs are more effective in defining tissue identity than BDs, which is contrasting to a previous study. It also provides novel insights on understanding the sequence features of functionally conserved elements.

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“…In contrast, our analyses show that only a small fraction of candidate CREs in Vitis leaf tissue are under sequence constraint, while the majority permit an average nucleotide diversity similar to random intergenic regions. These results are consistent with the rapid enhancer evolution recently documented in another plant species, cotton ( Gossypium hirsutum ; Wang et al., 2017 ), and multiple studies that suggest mutations drive beneficial variation and evolution in enhancers (Odom et al., 2007 ; Villar et al., 2015 ) and that, while enhancer function is conserved, enhancer sequence conservation is not required (Blow et al., 2010 ; Hare et al., 2008 ; Plessy et al., 2005 ; Snetkova et al., 2021 ). This apparent paradox in CRE maintenance likely reflects the coexistence of multiple enhancer types as previously described (Li et al., 2019 ), whose characteristics are obscured with ensemble analyses.…”

Section: Discussionmentioning

confidence: 97%

Open chromatin in grapevine marks candidate CREs and with other chromatin features correlates with gene expression

et al. 2021

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Vitis vinifera is an economically important crop and a useful model in which to study chromatin dynamics. In contrast to the small and relatively simple genome of Arabidopsis thaliana, grapevine contains a complex genome of 487 Mb that exhibits extensive colonization by transposable elements. We used Hi-C, ChIP-seq and ATAC-seq to measure how chromatin features correlate to the expression of 31 845 grapevine genes. ATAC-seq revealed the presence of more than 16 000 open chromatin regions, of which we characterize nearly 5000 as possible distal enhancer candidates that occur in intergenic space > 2 kb from the nearest transcription start site (TSS). A motif search identified more than 480 transcription factor (TF) binding sites in these regions, with those for TCP family proteins in greatest abundance. These open chromatin regions are typically within 15 kb from their nearest promoter, and a gene ontology analysis indicated that their nearest genes are significantly enriched for TF activity. The presence of a candidate cis-regulatory element (cCRE) > 2 kb upstream of the TSS, location in the active nuclear compartment as determined by Hi-C, and the enrichment of H3K4me3, H3K4me1 and H3K27ac at the gene are correlated with gene expression. Taken together, these results suggest that regions of intergenic open chromatin identified by ATAC-seq can be considered potential candidates for cis-regulatory regions in V. vinifera. Our findings enhance the characterization of a valuable agricultural crop, and help to clarify the understanding of unique plant biology.

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Ultraconserved enhancer function does not require perfect sequence conservation

Abstract: in ultraconserved enhancers result in very subtle but still selectively disadvantageous effects on gene expression, or additional, yet-to-be-identified, regulatory or nonregulatory functions of these sequences contribute to their extreme conservation in evolution.

Cited by 52 publications

References 39 publications

Developmental and Evolutionary Comparative Analysis of a Regulatory Landscape in Mammals and Birds

Developmental and Evolutionary Comparative Analysis of a Regulatory Landscape in Mammals and Birds

A Comparative Analysis of Super-Enhancers and Broad H3K4me3 Domains in Pig, Human, and Mouse Tissues

Open chromatin in grapevine marks candidate CREs and with other chromatin features correlates with gene expression

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