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Knockdown of Hnrnpa0, a del(5q) Gene, Alters Myeloid Cell Fate in Murine Cells

ABSTRACT: To understand the effect of loss of Hnrnpa0, an RNA-binding protein shown to regulate transcript stability via binding to the AU-rich elements (AREs) of mRNAs, on myelopoiesis, we used RNAi interference to model Hnrnpa0 loss in an experimental murine cell system, and then used global expression profiling techniques to determine the impact of that knockdown on gene expression, especially ARE-containing genes. The PUER system is a murine myeloid progenitor cell line expressing the tamoxifen (4-OHT) responsive, PU.1-ER fusion gene, allowing controlled myeloid differentiation in cells in which Hnrnpa0 expression has been altered via RNAi technology. By examining perturbations in gene expression both before and during myeloid differentiation, we have shown the Hnrnpa0 loss preferentially alters ARE-containing genes, leading to a shift in myeloid specification away from the monocytic lineage. Gene expression in the PUER cell line expressing the construct of interest, was measured before and 24 hours after 4-OHT induced differentiation. Three independent experiments using unique clones for the control vector and Hnrnpa0 shRNA vector were carried out in parallel.

ORGANISM(S): Mus musculus

SUBMITTER: David Young

PROVIDER: E-GEOD-39934 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Knockdown of Hnrnpa0, a del(5q) Gene, Alters Myeloid Cell Fate in Murine Cells

Project description:To understand the effect of loss of Hnrnpa0, an RNA-binding protein shown to regulate transcript stability via binding to the AU-rich elements (AREs) of mRNAs, on myelopoiesis, we used RNAi interference to model Hnrnpa0 loss in an experimental murine cell system, and then used global expression profiling techniques to determine the impact of that knockdown on gene expression, especially ARE-containing genes. The PUER system is a murine myeloid progenitor cell line expressing the tamoxifen (4-OHT) responsive, PU.1-ER fusion gene, allowing controlled myeloid differentiation in cells in which Hnrnpa0 expression has been altered via RNAi technology. By examining perturbations in gene expression both before and during myeloid differentiation, we have shown the Hnrnpa0 loss preferentially alters ARE-containing genes, leading to a shift in myeloid specification away from the monocytic lineage.

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Knockdown of Hnrnpa0, a del(5q) Gene, Alters Myeloid Cell Fate in Murine Cells through Regulation of AU-rich Transcripts

Project description:The post-transcriptional control of mRNA stability plays a critical role in numerous biological functions, including the immune response, cell cycle regulation and DNA damage response. HNRNPA0, which encodes an RNA-binding protein shown to regulate transcript stability via binding to the AU-rich elements (AREs) of mRNAs, is located within the commonly deleted segment of 5q31.2 in therapy-related myeloid neoplasms (t-MNs) with a del(5q). We hypothesized that loss of HNRNPA0 leads to alterations in hematopoietic differentiation due to changes in the expression of its target AU-rich transcripts. Using RNAi interference to model Hnrnpa0 loss in primary murine cells and an experimental cell system, we found that reduced Hnrnpa0 expression leads to a shift from monocytic towards granulocytic differentiation. Microarray-based global expression profiling revealed that Hnrnpa0 knockdown disproportionally impacts ARE-containing transcripts and alters expression of myeloid specification genes. The biological importance of ARE-containing genes in myeloid neoplasms is further supported by changes in gene expression of ARE-mRNAs in t-MN del(5q) patients, predicted by pathway analysis to activate tumor growth. Together, our findings suggest that alterations in ARE-containing genes can positively regulate the cellular proliferation of del(5q) cells and implicate haploinsufficiency of HNRNPA0 as one of the key initiation mutations in the pathogenesis of t-MN. Gene expression profiling was performed on 38 single t-MN tumor samples. No control or reference samples were included.

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