Order and disorder: abnormal 3D chromatin organization in human disease

Abstract

A precise three-dimensional (3D) organization of chromatin is central to achieve the intricate transcriptional patterns that are required to form complex organisms. Growing evidence supports an important role of 3D chromatin architecture in development and delineates its alterations as prominent causes of disease. In this review, we discuss emerging concepts on the fundamental forces shaping genomes in space and on how their disruption can lead to pathogenic phenotypes. We describe the molecular mechanisms underlying a wide range of diseases, from the systemic effects of coding mutations on 3D architectural factors, to the more tissue-specific phenotypes resulting from genetic and epigenetic modifications at specific loci. Understanding the connection between the 3D organization of the genome and its underlying biological function will allow a better interpretation of human pathogenesis.

Keywords: 3D chromatin organization; disease; epigenetics; long-range gene regulation.

Figure 1

Factors organizing chromatin in the 3D space and effects of associated mutations. Within the nucleus, chromatin segregates into transcriptionally active, A compartments (red) or inactive, B compartments (blue), that also associate to specialized locations such as the NL, nuclear speckles or the nucleolus. Chromatin is further subdivided into TADs, mainly formed by loop extrusion and delimited by boundaries that are frequently associated to CTCF and the cohesin complex. The disruption of individual components of the loop extrusion machinery (CTCF or the cohesin complex) can induce gene misexpression by a global loss of TAD organization. In contrast, compartments are largely preserved. The disruption of nuclear compartments, like the NL can induce gene misexpression by compartment switching. In this case, TAD organization is overall preserved.

Figure 2

Effects of locus-specific 3D chromatin misfolding. In a wild-type situation, the correct segregation of TADs ensures proper gene activation. Structural variants can affect TAD organization and cause gene miexpression and disease. Left: deletions affecting TAD boundaries can lead to gene misexpression through TAD fusion. Center: duplications including TAD boundaries can form neo-TADs, which pathogenicity is determined by the regulatory elements and genes contained within. Right: inversions involving TAD boundaries can alter the relative position of regulatory elements causing phenotypes by either gene misexpression through novel enhancer-promoter associations (gene A), or by loss-of-function through the disconnection of enhancers from their cognate genes (gene B). TAD boundary function can be affected by epigenetic mechanisms. In the example, a trinucleotide expansion causes hypermethylation of a CTCF element and relocates the boundary to a more telomeric position, originating the disconnection of gene B from its endogenous enhancers and causing loss-of-function. De novo insertions of mobile elements can cause disease by altering the 3D chromatin landscape. In the example, a CTCF-associated retrovirus integrates and creates a new boundary element that partitions a TAD and disconnects gene B from its endogenous enhancers, thus causing loss-of-function.