 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Jun 23, 2016 |
| Title |
Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene expression program and acute leukemia development |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
Genome binding/occupancy profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
|
| Summary |
DNA methyltransferase 3A (DNMT3A) is frequently mutated in hematological cancers; however, the underlying oncogenic mechanism remains elusive. Here, we report that DNMT3A mutational hotspot at Arg882 (DNMT3A R882H) cooperates with NRAS mutation to transform hematopoietic stem/progenitor cells and induce acute leukemia development. Mechanistically, DNMT3A R882H directly binds to and potentiates transactivation of stemness genes critical for leukemogenicity including Meis1, Mn1 and Hoxa gene cluster. DNMT3A R882H induces focal epigenetic alterations, including CpG hypomethylation and concurrent gain of active histone modifications, at cis-regulatory elements such as enhancers to facilitate gene transcription. CRISPR/Cas9-mediated ablation of a putative Meis1 enhancer carrying DNMT3A R882H-induced DNA hypomethylation impairs Meis1 expression. Importantly, DNMT3A R882H-induced gene expression programs can be repressed through Dot1l inhibition, providing an attractive therapeutic strategy for DNMT3A-mutated leukemias.
This SuperSeries is composed of the SubSeries listed below.
|
| |
|
| Overall design |
Refer to individual Series
|
| |
|
| Citation(s) |
27344947 |
| |
| Submission date |
Jul 29, 2015 |
| Last update date |
May 15, 2019 |
| Contact name |
Rui Lu |
| E-mail(s) |
[email protected]
|
| Organization name |
Univ of Alabama at Birmingham
|
| Street address |
1824 6th Ave S
|
| City |
Birmingham |
| State/province |
AL |
| ZIP/Postal code |
35294 |
| Country |
USA |
| |
|
| Platforms (3) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
| GPL17400 |
[MoGene-2_1-st] Affymetrix Mouse Gene 2.1 ST Array [transcript (gene) version] |
|
| Samples (46)
|
| GSM1834194 |
RH_RAS_day12_2 |
| GSM1834195 |
WT_RAS_day12_1 |
| GSM1834196 |
WT_RAS_day12_2 |
| GSM1834197 |
EV_RAS_day16_1 |
| GSM1834198 |
EV_RAS_day16_2 |
| GSM1834199 |
RH_RAS_day16_1 |
| GSM1834200 |
RH_RAS_day16_2 |
| GSM1834201 |
WT_RAS_day16_1 |
| GSM1834202 |
WT_RAS_day16_2 |
| GSM1834391 |
RH-RAS LSC, line 1 |
| GSM1834392 |
RH-RAS LSC, line 2 |
| GSM1834393 |
RH-RAS LSC, line 3 |
| GSM1834394 |
RH-RAS LSC, line 4 |
| GSM1834395 |
RH-RAS LSC, line 1, treated with Dot1l inhibitor |
| GSM1834396 |
RH-RAS LSC, line 3, treated with Dot1l inhibitor |
| GSM1834397 |
MLL-AF9 LSC |
| GSM1834398 |
NUP98-JARID1A LSC, line 1 |
| GSM1834399 |
NUP98-JARID1A LSC, line 2 |
| GSM1834400 |
NUP98-JARID1A LSC, line 3 |
| GSM1835276 |
HSPC_EVRAS_H3K27ac |
| GSM1835277 |
HSPC_EVRAS_H3K4me1 |
| GSM1835278 |
HSPC_EVRAS_INPUT |
| GSM1835279 |
HSPC_RHRAS_H3K27ac |
| GSM1835280 |
HSPC_RHRAS_H3K4me1 |
| GSM1835281 |
HSPC_RHRAS_INPUT |
| GSM1835282 |
HSPC_WTRAS_H3K27ac |
| GSM1835283 |
HSPC_WTRAS_H3K4me1 |
| GSM1835284 |
HSPC_WTRAS_INPUT |
| GSM1835285 |
HSPC_EVRAS_H3K79me2 |
| GSM1835286 |
HSPC_EVRAS_INPUT_ForH3K79me2 |
| GSM1835287 |
HSPC_RHRAS_H3K79me2 |
| GSM1835288 |
HSPC_RHRAS_INPUT_ForH3K79me2 |
| GSM1835296 |
EV_RAS_eRRBS |
| GSM1835297 |
RH_RAS_eRRBS |
| GSM1835298 |
WT_RAS_eRRBS |
| GSM1835299 |
LSC RH-RAS/ Input |
| GSM1835300 |
LSC RH-RAS/ Myc-DNMT3AR882H (9E10) |
| GSM1835301 |
LSC RH-RAS/ H3K4me1 |
| GSM1835302 |
LSC RH-RAS/ H3K4me3 |
| GSM1835303 |
LSC RH-RAS/ H3K27me3 |
| GSM1835304 |
HOXA9-MEIS1/ Input |
| GSM1835305 |
HOXA9-MEIS1/ H3K4me1 |
| GSM3745013 |
LSC RH-RAS/ Brd4 |
|
| This SuperSeries is composed of the following SubSeries:
|
| GSE71437 |
Effect of DNMT3A R882H mutation or WT on gene expression in hematopoietic stem/progenitor cells with NRAS G12D co-transduction (Microarray) |
| GSE71439 |
Expression profiling of murine leukemia stem cell (LSC) lines established ex vivo by coexpression of R882H-mutated DNMT3A and NRAS-G12D post treatment with Dot1l inhibitor (Microarray) |
| GSE71472 |
Effect of DNMT3A R882H mutation or WT expression on epigenetic landscapes of hematopoietic stem/progenitor cells with NRAS G12D co-transduction (ChIP-seq) |
| GSE71473 |
Effect of DNMT3A R882H mutation or WT expression on global DNA methylation patterns of hematopoietic stem/progenitor cells with NRAS G12D co-transduction (eRRBS) |
| GSE71474 |
Epigenomic profiling studies of murine leukemia stem cell (LSC) lines established ex vivo by coexpression of R882H-mutated DNMT3A and NRAS-G12D (ChIP-seq) |
|
| Relations |
| BioProject |
PRJNA291347 |
|
|
|
|
 |
Less...
More...