Enhancer-adoption as a mechanism of human developmental disease

Abstract

Disruption of the long-range cis-regulation of developmental gene expression is increasingly recognized as a cause of human disease. Here, we report a novel type of long-range cis-regulatory mutation, in which ectopic expression of a gene is driven by an enhancer that is not its own. We have termed this gain of regulatory information as "enhancer adoption." We mapped the breakpoints of a de novo 7q inversion in a child with features of a holoprosencephaly spectrum (HPES) disorder and severe upper limb syndactyly with lower limb synpolydactyly. The HPES plausibly results from the 7q36.3 breakpoint dislocating the sonic hedgehog (SHH) gene from enhancers that are known to drive expression in the early forebrain. However, the limb phenotype cannot be explained by loss of known SHH enhancers. The SHH transcription unit is relocated to 7q22.1, ∼190 kb 3 of a highly conserved noncoding element (HCNE2) within an intron of EMID2. We show that HCNE2 functions as a limb bud enhancer in mouse embryos and drives ectopic expression of Shh in vivo recapitulating the limb phenotype in the child. This developmental genetic mechanism may explain a proportion of the novel or unexplained phenotypes associated with balanced chromosome rearrangements.

Twenty-First Century Glucocorticoid Receptor Molecular Biology

“…Moreover, CTCF depletion disrupts TAD boundaries [52] and impacts gene expression [53]. Dysregulation of CTCF is associated with improper gene regulation during development and oncogenesis [54,55].…”

Examining Topological Domain Influence on Enhancer Function

“…In addition, sequence variants that remove or rearrange TAD boundaries can lead to enhancer hijacking, where genes that are normally in an adjacent TAD become regulated by inappropriate enhancers (Franke et al, 2016;Lettice et al, 2011;Lupiáñez et al, 2015;Northcott et al, 2014), arguing that TAD boundaries can act as insulators, restricting enhancer activity to only those genes within the same TAD. One unresolved question is how enhancers achieve specificity: can they act pervasively on any gene within a given TAD or are their target genes selected on some other basis?…”

Alterations to the remote control ofShhgene expression cause congenital abnormalities

“…These SHH chromosomal lesions usually result in holoprosencephaly; however, we recently reported a patient with additional malformations displaying severe syndactyly (fusion of the digits) of the hands and feet. An intrachromosomal inversion was identified which interrupts the normal regulatory landscape of the SHH gene [13]. However, the limb defects were not owing to the loss of SHH regulatory information, but rather the influence of newly juxtaposed enhancers.…”

“…Syndactyly, however, is more difficult to explain. Recent analysis that led to mis-expression of Shh in the distal mesenchyme of the limb at later stages of limb bud development (at stages when wild-type expression has turned-off) led to syndactyly in the mouse [13]. In these analyses, the interdigital tissue that normally undergoes programmed cell death persisted.…”