Dataset Information

hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival.

ABSTRACT: Chronic myeloid leukemia (CML) stem/progenitor cells (SPCs) express a transcriptional program characteristic of proliferation, yet can achieve and maintain quiescence. Understanding the mechanisms by which leukemic SPCs maintain quiescence will help to clarify how they persist during long-term targeted treatment. We have identified a novel BCR-ABL1 protein kinase-dependent pathway mediated by the upregulation of hsa-mir183, the downregulation of its direct target early growth response 1 (EGR1), and, as a consequence, upregulation of E2F1. We show here that inhibition of hsa-mir183 reduced proliferation and impaired colony formation of CML SPCs. Downstream of this, inhibition of E2F1 also reduced proliferation of CML SPCs, leading to p53-mediated apoptosis. In addition, we demonstrate that E2F1 plays a pivotal role in regulating CML SPC proliferation status. Thus, for the first time, we highlight the mechanism of hsa-mir183/EGR1-mediated E2F1 regulation and demonstrate this axis as a novel, critical factor for CML SPC survival, offering new insights into leukemic stem cell eradication.

SUBMITTER: Pellicano F

PROVIDER: S-EPMC6027092 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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<i>hsa-mir183/EGR1</i>-mediated regulation of E2F1 is required for CML stem/progenitor cell survival.

Pellicano Francesca F Park Laura L Hopcroft Lisa E M LEM Shah Mansi M MM Jackson Lorna L Scott Mary T MT Clarke Cassie J CJ Sinclair Amy A Abraham Sheela A SA Hair Alan A Helgason G Vignir GV Aspinall-O'Dea Mark M Bhatia Ravi R Leone Gustavo G Kranc Kamil R KR Whetton Anthony D AD Holyoake Tessa L TL

Blood 20180205 14

Chronic myeloid leukemia (CML) stem/progenitor cells (SPCs) express a transcriptional program characteristic of proliferation, yet can achieve and maintain quiescence. Understanding the mechanisms by which leukemic SPCs maintain quiescence will help to clarify how they persist during long-term targeted treatment. We have identified a novel BCR-ABL1 protein kinase-dependent pathway mediated by the upregulation of <i>hsa-mir183</i>, the downregulation of its direct target early growth response 1 ( ...[more]

PMID: 29437554

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Project description:Self-renewal and differentiation of spermatogonial stem cells (SSCs) are the foundation of spermatogenesis throughout a male's life. SSC transplantation will be a valuable solution for young male patients to preserve their fertility. As SSCs in the collected testis tissue from the patients are very limited, it is necessary to expansion the SSCs in vitro. Previous studies suggested that histone methyltransferase ERG-associated protein with SET domain (ESET) represses gene expression and is essential for the maintenance of the pool of embryonic stem cells and neurons. The objective of this study was to determine the role of ESET in SSCs using in vitro cell culture and germ cell transplantation. Cell transplantation assay showed that knockdown of ESET reduced the number of seminiferous tubules with spermatogenesis when compared with that of the control. Knockdown of ESET also upregulated the expression of apoptosis-associated genes (such as P53, Caspase9, Apaf1), whereas inhibited the expression of apoptosis-suppressing genes (such as Bcl2l1, X-linked inhibitor of apoptosis protein). In addition, suppression of ESET led to increase in expression of Caspase9 and activation of Caspase3 (P17) as well as cleavage of poly (ADP-ribose) polymerase. Among the five ESET-targeting genes (Cox4i2, spermatogenesis and oogenesis Specific Basic Helix-Loop-Helix 2, Nobox, Foxn1 and Dazl) examined by ChIP assay, Cox4i2 was found to regulate SSC apoptosis by the rescue experiment. BSP analyses further showed that DNA methylation in the promoter loci of Cox4i2 was influenced by ESET, indicating that ESET also regulated gene expression through DNA methylation in addition to histone methylation. In conclusion, we found that ESET regulated SSC apoptosis by suppressing of Cox4i2 expression through histone H3 lysine 9 tri-methylation and DNA methylation. The results obtained will provide unique insights that would broaden the research on SSC biology and contribute to the treatment of male infertility.

Dataset Information

hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival.

Publications

<i>hsa-mir183/EGR1</i>-mediated regulation of E2F1 is required for CML stem/progenitor cell survival.

Similar Datasets

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Dataset Information

hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival.

Publications

&lt;i&gt;hsa-mir183/EGR1&lt;/i&gt;-mediated regulation of E2F1 is required for CML stem/progenitor cell survival.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

<i>hsa-mir183/EGR1</i>-mediated regulation of E2F1 is required for CML stem/progenitor cell survival.