Identification of the global miR-130a targetome reveals a role for TBL1XR1 in hematopoietic stem cell self-renewal and t(8;21) AML.
Gabriela Krivdova, Veronique Voisin, Erwin M Schoof, Sajid A Marhon, Alex Murison, Jessica L McLeod, Martino M Gabra, Andy G X Zeng, Stefan Aigner, Brian A Yee, Alexander A Shishkin, Eric L Van Nostrand, Karin G Hermans, Aaron C Trotman-Grant, Nathan Mbong, James A Kennedy, Olga I Gan, Elvin Wagenblast, Daniel D De Carvalho, Leonardo Salmena, Mark D Minden, Gary D Bader, Gene W Yeo, John E Dick, Eric R Lechman
Cell reports · 2022 · Vol. 38 (10) · pp. 110481
Abstract
Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSCs) point to shared core stemness properties. However, discordance between mRNA and protein signatures highlights an important role for post-transcriptional regulation by microRNAs (miRNAs) in governing this critical nexus. Here, we identify miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impairs B lymphoid differentiation and expands long-term HSCs. Integration of protein mass spectrometry and chimeric AGO2 crosslinking and immunoprecipitation (CLIP) identifies TBL1XR1 as a primary miR-130a target, whose loss of function phenocopies miR-130a overexpression. Moreover, we report that miR-130a is highly expressed in t(8;21) acute myeloid leukemia (AML), where it is critical for maintaining the oncogenic molecular program mediated by the AML1-ETO complex. Our study establishes that identification of the comprehensive miRNA targetome within primary cells enables discovery of genes and molecular networks underpinning stemness properties of normal and leukemic cells.
Linked datasets 7
Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML [miR-130a OE]
Homo sapiens
Global Identification of the miR-130a targetome in human HSPC Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML
Homo sapiens
18 data files
| File | Type | Size |
|---|---|---|
| Au13_S13_L001_R1_001.fastq.gz | RIP-Seq | 583.0 MB |
| Au14_S14_L001_R1_001.fastq.gz | RIP-Seq | 759.7 MB |
| Au1_S1_L001_R1_001.fastq.gz | OTHER | 3.8 GB |
| Au2_S2_L001_R1_001.fastq.gz | RIP-Seq | 2.2 GB |
| Au3_S3_L001_R1_001.fastq.gz | RIP-Seq | 2.0 GB |
| Au5_S5_L001_R1_001.fastq.gz | OTHER | 3.1 GB |
| Au6_S6_L001_R1_001.fastq.gz | RIP-Seq | 1.8 GB |
| Au7_S7_L001_R1_001.fastq.gz | RIP-Seq | 1.6 GB |
| Au9_S9_L001_R1_001.fastq.gz | RIP-Seq | 453.8 MB |
| SRR15142308_GSM5453665 | RIP-Seq | 2.2 GB |
| SRR15142309_GSM5453666 | RIP-Seq | 2.0 GB |
| SRR15142310_GSM5453667 | RIP-Seq | 1.8 GB |
| SRR15142311_GSM5453668 | RIP-Seq | 1.6 GB |
| SRR15142312_GSM5453669 | RIP-Seq | 583.0 MB |
| SRR15142313_GSM5453670 | RIP-Seq | 453.0 MB |
| SRR15236468_GSM5470531 | OTHER | 3.8 GB |
| SRR15236469_GSM5470532 | OTHER | 3.1 GB |
| SRR17259466_GSM5733559 | RIP-Seq | 759.0 MB |
Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML [TBL1XR1 KD]
Homo sapiens
Global Identification of the miR-130a targetome in human HSPC Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML [CUT&RUN]
Homo sapiens
Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML [miR130aKD_Kasumi]
Homo sapiens
Potentially related datasets 4
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.
| Accession | Source | Title |
|---|---|---|
| GSE153264 | GSE · GEO GEO ↗ | Definition of a Small Core Transcriptional Circuit Regulated by AML1-ETO [RNA-seq] |
| GSE153279 | GSE · GEO GEO ↗ | Definition of a Small Core Transcriptional Circuit Regulated by AML1-ETO [ChIP-seq, Cut&Run] |
| PXD027331 | PXD · PRIDE | No title in the index |
| GSE181140 | GSE · GEO GEO ↗ | Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML |
Analysis pipelines 9
| Pipeline | Assay | Steps | Dataset |
|---|---|---|---|
| GSE153264 RNA-seq Data Processing geo_data_processing | RNA-seq | 3 | GSE153264 |
| GSE153279 ChIP-seq Data Processing geo_data_processing | ChIP-seq | 13 | GSE153279 |
| GSE180129 eCLIP Data Processing geo_data_processing | eCLIP | 24 | GSE180129 |
| GSE181136 ChIP-seq Data Processing geo_data_processing | ChIP-seq | 15 | GSE181136 |
| GSE181137 Data Processing geo_data_processing | — | 1 | GSE181137 |
| GSE181138 Data Processing geo_data_processing | — | 2 | GSE181138 |
| GSE181139 Data Processing geo_data_processing | — | 1 | GSE181139 |
| GSE181140 eCLIP Data Processing geo_data_processing | eCLIP | 24 | GSE181140 |
| GSE196177 Microarray Data Processing geo_data_processing | Microarray | 4 | GSE196177 |
Funding 5 grants
| Grant | Funder |
|---|---|
| U24 HG009889 | NHGRI NIH HHS (United States) |
| R01 HG004659 | NHGRI NIH HHS (United States) |
| R00 HG009530 | NHGRI NIH HHS (United States) |
| U41 HG009889 | NHGRI NIH HHS (United States) |
| K99 HG009530 | NHGRI NIH HHS (United States) |