6 research outputs found
The centromeric/nucleolar chromatin protein ZFP-37 may function to specify neuronal nuclear domains
Murine ZFP-37 is a member of the large family of C2H2 type zinc finger
proteins. It is characterized by a truncated NH2-terminal
Kruppel-associated box and is thought to play a role in transcriptional
regulation. During development Zfp-37 mRNA is most abundant in the
developing central nervous system, and in the adult mouse expression is
restricted largely to testis and brain. Here we show that at the protein
level ZFP-37 is detected readily in neurons of the adult central nervous
system but hardly in testis. In brain ZFP-37 is associated with nucleoli
and appears to contact heterochromatin. Mouse and human ZFP-37 have a
basic histone H1-like linker domain, located between KRAB and zinc finger
regions, which binds double-stranded DNA. Thus we suggest that ZFP-37 is a
structural protein of the neuronal nucleus which plays a role in the
maintenance of specialized chromatin domains
Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection
Background: chronic sputum production impacts on quality of life and is a feature of many respiratory diseases. Identification of the genetic variants associated with chronic sputum production in a disease agnostic sample could improve understanding of its causes and identify new molecular targets for treatment.Methods: we conducted a genome-wide association study (GWAS) of chronic sputum production in UK Biobank. Signals meeting genome-wide significance (p<5×10−8) were investigated in additional independent studies, were fine-mapped and putative causal genes identified by gene expression analysis. GWASs of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease among the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWASs).Results: from a GWAS of 9714 cases and 48 471 controls, we identified six novel genome-wide significant signals for chronic sputum production including signals in the human leukocyte antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B) and FUT2 locus. The four common variant associations were supported by independent studies with a combined sample size of up to 2203 cases and 17 627 controls. The mucin locus signal had previously been reported for association with moderate-to-severe asthma. The HLA signal was fine-mapped to an amino acid change of threonine to arginine (frequency 36.8%) in HLA-DRB1 (HLA-DRB1*03:147). The signal near FUT2 was associated with expression of several genes including FUT2, for which the direction of effect was tissue dependent. Our PheWAS identified a wide range of associations including blood cell traits, liver biomarkers, infections, gastrointestinal and thyroid-associated diseases, and respiratory disease.Conclusions: novel signals at the FUT2 and mucin loci suggest that mucin fucosylation may be a driver of chronic sputum production even in the absence of diagnosed respiratory disease and provide genetic support for this pathway as a target for therapeutic intervention
Zfp-37 is a member of the KRAB zinc finger gene family and is expressed in neurons of the developing and adult CNS.
The murine Zfp-37 gene encodes a protein with 12 zinc fingers at its C-terminus (Nelki et al., 1990, Nucleic Acids Res. 18: 3655; Burke and Wolgemuth, 1992, Nucleic Acids Res. 20: 2827-2834). Contrary to the published data, our Northern blot analysis demonstrates not only that the Zfp-37 gene is expressed as 2.3, 2.6, and 4.2 kb mRNAs in testis, but also that there is a 3.7-kb message in the adult mouse brain. Using a partial cDNA as a probe, we have isolated a brain-specific Zfp-37 cDNA clone of 3.3 kb, whose sequence was extended to full length using 5' end RACE. This revealed that the 3.7-kb mRNA is in fact a collection of transcripts with heterogenous 5' ends. Comparison of cDNA and genomic sequences shows that the Zfp-37 gene is spread over a region of approximately 20 kb and consists of six exons, the large 3' end exon containing the complete zinc finger domain, and 3' UTR. Our data show that the Zfp-37 gene utilizes different promoters, alternative splicing, and differential polyadenylation to generate the distinct transcripts of brain and testis. Several protein isoforms are encoded by these mRNAs, some of which contain a truncated form of a conserved domain (Kruppel-associated box) found in other zinc finger genes. In situ hybridization analysis of postnatal brain sections indicates that the Zfp-37 gene is expressed in all neurons of the central nervous system. Together, these results suggest that ZFP-37 is a transcriptional regulator predominantly present in postmitotic cells from two different lineages