An evolutionary perspective of regulatory landscape dynamics in development and disease

Abstract

The organization of animal genomes into topologically associating domains (TADs) provides a structural scaffold in which cis-regulatory elements (CREs) operate on their target genes. Determining the position of CREs and genes relative to TADs has become instrumental to trace gene expression changes during evolution and in diseases. Here we will review recent studies and discuss TADs as structural units with respect to their conservation and stability during genome reorganization. Furthermore, we describe how TAD restructuring contributed to morphological novelties during evolution but also their deleterious effects associated with disease. Despite considering TADs as structural units, the nested and dynamic scaffold within TADs contributes to tissue-specific gene expression, implying that such changes can also account for gene expression differences during evolution.

The impact of chromosomal fusions on 3D genome folding and recombination in the germ line

“…Thus, disturbances of domain architecture due to genome reshuffling (i.e., inversions, fusions, or indels) represent a nongradual change in gene regulation because shifting of domain boundaries exposes genes to novel regulatory environments 4 . Models 5 , 6 and growing experimental evidence 7 , 8 suggest that indels and inversions can alter interactions between contiguous topological associated domains (TADs), which can lead to oncogene activation, morphological alterations, and novel gene functions. However, the impact of balanced chromosomal rearrangements, such as Robertsonian (Rb) fusions 9 , on genome architecture and its heritability are less explored.…”

Genome Biology: Unconventional DNA Repair in an Extreme Genome

“…A prerequisite for this must have been that this ancestor's genome was presumably already 'primed' to be scrambled without fatally disrupting gene regulation at high frequency. Thus, the precursor to the appendicularian ancestor must already have evolved to a state in which its gene regulatory mechanisms were presumably focused on short-range gene-specific processes rather than the long-range multigenic mechanisms involving topologically associated domains and genomic regulatory blocks more typical of many other animal genomes [15,16]. Why this should be the case still remains an evolutionary mystery, which may be resolved by the burgeoning work on urochordates.…”

A (3D-Nuclear) Space Odyssey: Making Sense of Hi-C Maps

“…Furthermore, the capacity of chromatin to mediate long-range interactions has been proposed to underlie the regulatory expansion of vertebrate genomes and the exponential increase of pleiotropic gene functions that are central to develop complex organisms [3]. Compelling evidence accumulates, supporting the important role of spatial organization in development and delineating its alterations as prominent causes of human diseases, such as congenital malformation and cancer [4,5], or evolutionary adaptation [6]. Therefore, the elucidation of the molecular mechanisms controlling 3D-chromatin organization represents one of the cornerstones of modern biology.…”