|
| Status |
Public on Jul 07, 2020 |
| Title |
Structural basis of epigenetic protection of mouse lymphoid progenitor cells by Dnmt1 (Zebrafish) |
| Organism |
Danio rerio |
| Experiment type |
Methylation profiling by high throughput sequencing
|
| Summary |
DNA methylation is a universal epigenetic mechanism involved in regulation of gene expression and genome stability. The DNA maintenance methylase DNMT1 ensures that DNA methylation patterns are faithfully transmitted to daughter cells during cell division. Because DNMT1 is essential for cell viability, little is known about its tissue-specific function. To overcome this impediment, forward genetic screens were conducted in medaka and zebrafish to identify viable dnmt1 alleles. The recovered recessive missense mutations lead to distorted structures of the catalytic pocket and reduced enzymatic activities, resulting in hypomethylation of genomic DNA that specifically impairs lymphoid development. The insights gleaned from fish dnmt1 alleles enabled the structure-guided generation of a hypomorphic variant of mouse Dnmt1, which also causes cell-autonomous defects of lymphoid development. The similar phenotypes observed in three distinct species suggest that the unique sensitivity of lymphocytes to perturbations of DNA methylation patterns is an evolutionarily conserved feature of all vertebrates.
|
| |
|
| Overall design |
Forward genetic screens in zebrafish and medaka identified missense mutations in maintenance DNA methylase Dnmt1 specifically affecting lymphoid development. To examine the molecular consequences of these hypomorphic mutations, DNA methylatio9n levels were assessed in selceted regions of the genomes. Based on strucrual analyses of fish Dnmt1 mutant proteins, a specific Dnmt1 mutation was also generated in mice. This led to hypomethylation of genomic DNA in lineage-negative cells of the bone marrow; additionally, the transcriptomes of several subtypes of hematopoietic progenitor cells (HSC; MPP1; MPP4) were compared by RNA-seq.
|
| |
|
| Contributor(s) |
Iwanami N, Sikora KO, Boehm T |
| Citation(s) |
32585597 |
| |
| Submission date |
Nov 27, 2019 |
| Last update date |
Jul 07, 2020 |
| Contact name |
Thomas Boehm |
| E-mail(s) |
boehm@ie-freiburg.mpg.de
|
| Organization name |
MPI-IE Freiburg
|
| Department |
Immunology
|
| Street address |
Stübeweg 51
|
| City |
Freiburg im Breisgau |
| ZIP/Postal code |
79108 |
| Country |
Germany |
| |
|
| Platforms (1) |
| GPL18413 |
Illumina HiSeq 2500 (Danio rerio) |
|
| Samples (12)
|
| GSM4195093 |
Zebrafish WT2 (EpiGnome) reanalysis |
| GSM4195094 |
Zebrafish WT3 (TruSeq) reanalysis |
| GSM4195095 |
Zebrafish WT3 (EpiGnome) reanalysis |
| GSM4195096 |
Zebrafish Dnmt1 Mut1 (TruSeq) reanalysis |
| GSM4195097 |
Zebrafish Dnmt1 Mut1 (EpiGnome) reanalysis |
| GSM4195098 |
Zebrafish Dnmt1 Mut2 (TruSeq) reanalysis |
| GSM4195099 |
Zebrafish Dnmt1 Mut2 (EpiGnome) reanalysis |
| GSM4195100 |
Zebrafish Dnmt1 Mut3 (TruSeq) reanalysis |
| GSM4195101 |
Zebrafish Dnmt1 Mut3 (EpiGnome) reanalysis |
|
| This SubSeries is part of SuperSeries: |
| GSE98648 |
Structural basis of epigenetic protection of mouse lymphoid progenitor cells by Dnmt1 |
|
| Relations |
| BioProject |
PRJNA592151 |
| SRA |
SRP233494 |
Less...
More...