ZFIN ID: ZDB-PUB-120830-4
Functional characterization of tissue-specific enhancers in the DLX5/6 locus
Birnbaum, R.Y., Everman, D.B., Murphy, K., Gurrieri, F., Schwartz, C.E., and Ahituv, N.
Date: 2012
Source: Human molecular genetics   21(22): 4930-4938 (Journal)
Registered Authors: Ahituv, Nadav, Murphy, Karl
Keywords: none
MeSH Terms:
  • Animals
  • Comparative Genomic Hybridization
  • Enhancer Elements, Genetic*
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Gene Order
  • Genetic Loci*
  • Homeodomain Proteins/genetics*
  • Humans
  • Mice
  • Organ Specificity/genetics
  • Proteasome Endopeptidase Complex/genetics
  • Transcription Factors/genetics*
  • Zebrafish/genetics
PubMed: 22914741 Full text @ Hum. Mol. Genet.

Disruption of distaless homeobox 5 and 6 (Dlx5/6) in mice results in brain, craniofacial, genital, ear and limb defects. In humans, chromosomal aberrations in the DLX5/6 region, some of which do not encompass DLX5/6, are associated with split hand and foot malformation 1 (SHFM1) as well as intellectual disability, craniofacial anomalies and hearing loss, suggesting that disruption of DLX5/6 regulatory elements could lead to these abnormalities. Here, we characterized enhancers in the DLX5/6 locus whose tissue-specific expression and genomic location along with previously characterized enhancers correlate with phenotypes observed in individuals with chromosomal abnormalities. By analyzing chromosomal aberrations at 7q21, we refined the minimal SHFM1 critical region and used comparative genomics to select twenty-six evolutionary conserved noncoding sequences in this critical region for zebrafish enhancer assays. Eight of these sequences were shown to function as brain, olfactory bulb, branchial arch, otic vesicle and fin enhancers, recapitulating dlx5a/6a expression. Using a mouse enhancer assay, several of these zebrafish enhancers showed comparable expression patterns in the branchial arch, otic vesicle, forebrain and/or limb at embryonic day 11.5. Examination of the coordinates of various chromosomal rearrangements in conjunction with the genomic location of these tissue-specific enhancers showed a correlation with the observed clinical abnormalities. Our findings suggest that chromosomal abnormalities that disrupt the function of these tissue-specific enhancers could be the cause of SHFM1 and its associated phenotypes. In addition, they highlight specific enhancers in which mutations could lead to non-syndromic hearing loss, craniofacial defects, or limb malformations.