16 research outputs found
HLA-DRB1-DQB1 Haplotypes Confer Susceptibility and Resistance to Multiple Sclerosis in Sardinia
Introduction: Genetic predisposition to multiple sclerosis (MS) in Sardinia (Italy) has been associated with five DRB1*-DQB1* haplotypes of the human leukocyte antigen (HLA). Given the complexity of these associations, an in-depth re-analysis was performed with the specific aims of confirming the haplotype associations; establishing the independence of the associated haplotypes; and assessing patients ’ genotypic risk of developing MS. Methods and Results: A transmission disequilibrium test (TDT) of the DRB1*-DQB1 * haplotypes in 943 trio families
Mouse Transgenesis Identifies Conserved Functional Enhancers and cis-Regulatory Motif in the Vertebrate LIM Homeobox Gene Lhx2 Locus
The vertebrate Lhx2 is a member of the LIM homeobox family of
transcription factors. It is essential for the normal development of the
forebrain, eye, olfactory system and liver as well for the differentiation of
lymphoid cells. However, despite the highly restricted spatio-temporal
expression pattern of Lhx2, nothing is known about its
transcriptional regulation. In mammals and chicken, Crb2,
Dennd1a and Lhx2 constitute a conserved
linkage block, while the intervening Dennd1a is lost in the
fugu Lhx2 locus. To identify functional enhancers of
Lhx2, we predicted conserved noncoding elements (CNEs) in
the human, mouse and fugu Crb2-Lhx2 loci and
assayed their function in transgenic mouse at E11.5. Four of the eight CNE
constructs tested functioned as tissue-specific enhancers in specific regions of
the central nervous system and the dorsal root ganglia (DRG), recapitulating
partial and overlapping expression patterns of Lhx2 and
Crb2 genes. There was considerable overlap in the
expression domains of the CNEs, which suggests that the CNEs are either
redundant enhancers or regulating different genes in the locus. Using a large
set of CNEs (810 CNEs) associated with transcription factor-encoding genes that
express predominantly in the central nervous system, we predicted four
over-represented 8-mer motifs that are likely to be associated with expression
in the central nervous system. Mutation of one of them in a CNE that drove
reporter expression in the neural tube and DRG abolished expression in both
domains indicating that this motif is essential for expression in these domains.
The failure of the four functional enhancers to recapitulate the complete
expression pattern of Lhx2 at E11.5 indicates that there must
be other Lhx2 enhancers that are either located outside the
region investigated or divergent in mammals and fishes. Other approaches such as
sequence comparison between multiple mammals are required to identify and
characterize such enhancers