|
| Status |
Public on Jul 03, 2024 |
| Title |
Mutations in linker-2 of KLF1 impair expression of membrane transporters and cytoskeletal proteins causing hemolysis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
The SP/KLF family of transcription factors harbour three C-terminal C2H2 zinc fingers interspersed by two linkers which confers DNA-binding to a 9-10bp motif. Mutations in KLF1, the founding member of the family, are common. Missense mutations in linker two result in a mild phenotypes. However, when co-inherited with loss-of-function mutations, they result in severe non-spherocytic hemolytic anemia. We generated a mouse model of this disease by crossing Klf1+/- mice with Klf1H350R/+ mice that harbour a missense mutation in linker-2. Klf1H350R/- mice exhibit severe hemolysis without thalassemia. RNA-seq demonstrated loss of expression of genes encoding transmembrane and cytoskeletal proteins, but not globins. ChIP-seq showed no change in DNA-binding specificity, but a global reduction in affinity, which was confirmed using recombinant proteins and in vitro binding assays. This study provides new insights into how linker mutations in zinc finger transcription factors result in different phenotypes to those caused by loss-of-function mutations.
|
| |
|
| Overall design |
RNAseq and ChIPseq in 14.5DPC fetal livers
---------------------------------
The comparisons in cuffdiff corresponds as follows:
Q1 KLF1 D45/- mRNAseq
Q2 KLF1 -/- mRNAseq
Q3 KLF1 +/- mRNAseq
|
| Web link |
https://www.nature.com/articles/s41467-024-50579-4
|
| |
|
| Contributor(s) |
Huang S, Gillinder KR, Perkins AC, Magor GG |
| Citation(s) |
39147774 |
| |
| Submission date |
Jan 31, 2017 |
| Last update date |
Oct 02, 2024 |
| Contact name |
Stephen Huang |
| Organization name |
University of Queensland
|
| Department |
Mater Research institute
|
| Lab |
Cancer Genomics
|
| Street address |
37 Kent Street Woolloongabba
|
| City |
Brisbane |
| State/province |
Queensland |
| ZIP/Postal code |
4102 |
| Country |
Australia |
| |
|
| Platforms (2) |
| GPL18635 |
Ion Torrent Proton (Mus musculus) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
|
| Samples (13)
|
|
| Relations |
| BioProject |
PRJNA369423 |
| SRA |
SRP098659 |
Less...
More...