Evolution of 3D chromatin organization at different scales

ElsevierVolume 78, February 2023, 102019Current Opinion in Genetics & DevelopmentAuthor links open overlay panel

Most animal genomes fold in 3D chromatin domains called topologically associated domains (TADs) that facilitate interactions between cis-regulatory elements (CREs) and promoters. Owing to their critical role in the control of developmental gene expression, we explore how TADs have shaped animal evolution. In the light of recent studies that profile TADs in disparate animal lineages, we discuss their phylogenetic distribution and the mechanisms that underlie their formation. We present evidence indicating that TADs are plastic entities composed of genomic strata of different ages: ancient cores are combined with newer regions and brought into extant TADs through genomic rearrangements. We highlight that newly incorporated TAD strata enable the establishment of new CRE-promoter interactions and in turn new expression patterns that can drive phenotypical innovation. We further highlight how subtle changes in chromatin folding may fine-tune the expression levels of developmental genes and hold a potential for evolutionary significance.

Introduction

In metazoans, transcription is controlled by cis-regulatory elements (CREs), such as enhancers, that communicate with their genes to produce coherent expression outputs. While some CRE-promoter pairs are in close proximity in the genome from a linear perspective, many are separated by large distances and require precise chromatin folding to interact [1]. Chromatin Conformation Capture (3C) techniques unveiled that most metazoan chromosomes fold into arrays of 3D domains termed Topologically Associated Domains (TADs), separated by boundary regions with an insulator function. Such organization contributes to CRE-gene specificity by favoring functional interactions within TADs and hindering those across boundaries 1, 2. Consequently, TAD disruption can lead to diseases, through alterations in the regulation of developmental genes [3]. Importantly, analogous changes in transcriptional regulation have been proposed to contribute to the evolution of traits. 4, 5. In this review, we summarize recent evidence supporting the role of modifications in 3D chromatin folding as an evolutionary driver.

Section snippetsThe rise of topologically associated domains as modulators of enhancer–promoter communication

To understand how TADs may influence the evolution of gene regulation, it is crucial to determine when these domains emerged and to infer their presence or absence across taxa. The term TAD was first coined to describe self-insulated domains in mammals 6, 7 although a similar phenomenon was previously reported in Drosophila [8]. Later, similar domains were also described across the tree of life (Figure 1) from prokaryotes [9] to animals 10••, 11••, 12••, 13••, 14••, 15••, including plants 16•,

The ancient origins of extant topologically associated domain structures

The degree of evolutionary conservation of individual TADs remains a source of controversy [45]. TADs span hundreds of kilobases of noncoding, hardly alignable DNA between distant species. Moreover, the identification of consensus TADs is highly influenced by the algorithm and parameters used [46]. A recent study comparing Hi-C data between humans and chimpanzees reported 43% of conserved TADs [47••], conflicting with previous notions of deep TAD conservation across mammals [48]. Crucially, the

Topologically associated domain rearrangements contribute to novel adaptations

Structural variants spanning TAD boundaries can potentially rewire CREs to alternative genes, thus generating novel expression patterns. Nevertheless, such mutations appear to be generally counterselected, as breakpoints of synteny rearrangements are enriched at TAD boundaries both in vertebrates 10••, 56• and Drosophila lineages [37••]. This is consistent with boundaries being hotspots for breakpoints, due to topological stress that results in double-strand breaks [57]. Nevertheless, small

Evolution through subtle changes in 3D chromatin folding

While TAD rearrangements can lead to drastic alterations in gene expression patterns, quantitative transcriptional changes might also have important and overlooked roles in evolution. Recently, a comparison of ultra-deep-sequenced Hi-C from human and macaque fetal brains revealed the existence of divergent loops and the disappearance of weak boundaries in the human lineage [66••] For instance, a 316-bp insertion causes the loss of a tissue-specific boundary that allows the neighboring gene

Concluding remarks

Accumulating evidence is supporting an important role for 3D chromatin organization during evolution. Yet, our knowledge on how these mechanisms lead to the emergence of new traits is still limited. While it is likely that TADs perform analogous tasks across metazoans, their mechanisms of formation are unclear. Gaining such knowledge represents a critical step to interpret the functional effects that genomic mutations might exert in gene regulation, in particular on how different genomic strata

Conflict of interest statement

Nothing declared.

Acknowledgements

We apologize to those researchers whose work could not be discussed due to space limitations. We thank N. Maeso, I. Almudí, C. Paliou, M. Franke, J.J. Tena, Francisca Martínez Real, C. Anania, and members of the Lupiañez laboratory for their valuable input and comments on the paper. This research was supported by a grant from the Deutsche Forschungsgemeinschaft (grant no. LU 2426/2-1). R.D.A. was supported by an EMBO Postdoctoral Fellowship (grant no. EMBO ALTF 537-2020).

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