A misplaced lncRNA causes brachydactyly in humans

Abstract

Translocations are chromosomal rearrangements that are frequently associated with a variety of disease states and developmental disorders. We identified 2 families with brachydactyly type E (BDE) resulting from different translocations affecting chromosome 12p. Both translocations caused downregulation of the parathyroid hormone-like hormone (PTHLH) gene by disrupting the cis-regulatory landscape. Using chromosome conformation capturing, we identified a regulator on chromosome 12q that interacts in cis with PTHLH over a 24.4-megabase distance and in trans with the sex-determining region Y-box 9 (SOX9) gene on chromosome 17q. The element also harbored a long noncoding RNA (lncRNA). Silencing of the lncRNA, PTHLH, or SOX9 revealed a feedback mechanism involving an expression-dependent network in humans. In the BDE patients, the human lncRNA was upregulated by the disrupted chromosomal association. Moreover, the lncRNA occupancy at the PTHLH locus was reduced. Our results document what we believe to be a novel in cis-and in trans-acting DNA and lncRNA regulatory feedback element that is reciprocally regulated by coding genes. Furthermore, our findings provide a systematic and combinatorial view of how enhancers encoding lncRNAs may affect gene expression in normal development.

MUNC, a Long Noncoding RNA That Facilitates the Function of MyoD in Skeletal Myogenesis

“…Our genomes undergo widespread transcription (3), and lncRNA genes are in comparable abundance to protein-coding genes (4). While lncRNAs are not as well conserved between species as protein-coding genes (5), there have been a number of examples of lncRNAs that confer marked cellular and developmental phenotypes when their expression is altered by experiment or disease (6)(7)(8)(9). Recently, a large class of lncRNAs named e-RNAs, for enhancer RNAs, has been described that are produced from known DNA enhancer elements and that activate transcription of neighboring genes by facilitating enhancer-promoter contacts and/or recruiting core transcription factors such as the mediator complex (reviewed in references 10 and 11).…”

Long non-coding RNA in health and disease

“…translocations physically disrupted CISTR-ACT from the major chondrogenic morphogene, PTHLH, and caused dysregulation of the coding gene and lncRNA [39]. These data underscore the important interface between genome conformation and gene-lncRNA-regulation.…”

“…Some lncRNAs seem to translate higher spatial chromosome structures and processes such as looping into defined chromatin modifications and domains to control gene expression. The same mechanism could be subject to CISTR-ACT and other enhancer-encoded lncRNAs [39,37], (Fig. 2 c) Fig.…”

Preparation for hypertension specialists:

“…But the effort has led us to discover other genetic findings, including a long noncoding RNA that leads to brachydactyly. 19 One difficult question to answer is: why have the GWAS studies not identified the gene loci of Mendelian syndromes, since the genes responsible for these conditions are clearly highly related to hypertension? The effects of alleles in many genes contribute to common complex diseases such as hypertension.…”