Transcriptional control of CBX5 by the RNA-binding proteins RBMX and RBMXL1 maintains chromatin state in myeloid leukemia Journal Article

Authors: Prieto, C.; Nguyen, D. T. T.; Liu, Z.; Wheat, J.; Perez, A.; Gourkanti, S.; Chou, T.; Barin, E.; Velleca, A.; Rohwetter, T.; Chow, A.; Taggart, J.; Savino, A. M.; Hoskova, K.; Dhodapkar, M.; Schurer, A.; Barlowe, T. S.; Vu, L. P.; Leslie, C.; Steidl, U.; Rabadan, R.; Kharas, M. G.
Article Title: Transcriptional control of CBX5 by the RNA-binding proteins RBMX and RBMXL1 maintains chromatin state in myeloid leukemia
Abstract: RNA-binding proteins (RBPs) are key arbiters of post-transcriptional regulation and are found to be dysregulated in hematological malignancies. Here we identify the RBP RNA-binding motif protein, X-linked (RBMX; also known as hnRNPG), and its retrogene RBMXL1 to be required for murine and human myeloid leukemogenesis. RBMX and RBMXL1 were overexpressed in individuals with acute myeloid leukemia (AML) compared to healthy individuals, and RBMX/RBMXL1 loss delayed leukemia development. RBMX/RBMXL1 loss lead to global changes in chromatin accessibility as well as chromosomal breaks and gaps. We found that RBMX and RBMXL1 directly bind to mRNAs, affect transcription of multiple loci, including CBX5 (also known as heterochromatin protein 1 alpha (HP1-α)), and control the nascent transcription of the CBX5 locus. Forced CBX5 expression rescued the RBMX/RBMXL1 depletion effects on cell growth and apoptosis. Overall, we determined that RBMX and RBMXL1 control leukemia cell survival by regulating chromatin state through the downstream target CBX5. These findings identify a mechanism for RBPs directly promoting transcription and suggest RBMX and RBMXL1, as well as CBX5, as potential therapeutic targets in myeloid malignancies. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords: clinical article; controlled study; unclassified drug; human cell; nonhuman; flow cytometry; polymerase chain reaction; animal cell; mouse; cell survival; stem cell factor; apoptosis; cell growth; granulocyte macrophage colony stimulating factor; animal experiment; animal model; gene locus; transcription factor; rna binding protein; fluorescence in situ hybridization; transcription regulation; xenograft; chromatin; leukemogenesis; immunoblotting; interleukin 6; dactinomycin; tamoxifen; chromosomal instability; karyotyping; antibody; reagent; polyacrylamide gel electrophoresis; rna sequence; transcriptional control; thrombopoietin; colony forming unit; myeloid leukemia; colony formation; interleukin 3; cell nucleus transplantation; phosphate buffered saline; puromycin; human; male; female; article; methylcellulose; luciferase assay; chromatin state; crispr cas system; 4',6 diamidino 2 phenylindole; nb4 cell line; hek293t cell line; thp-1 cell line; molm-13 cell line; k-562 cell line; kasumi-1 cell line; illumina sequencing; cbs antibody; cbx5 antibody; chromobox 5; dach1 antibody; flga antibody; gadph antibody; hoxa9 antibody; methocult 3434; myc antibody; pabpc4 antibody; polysorbate 20; rbmx antibody; rbmx like 1; rna binding motif protein x linked; sept11 antibody; c57bl/6n mouse; hl-60 cell line; kcl-22 cell line; kg-1 cell line; nomo-1 cell line; tf-1 cell line; u-937 cell line
Journal Title: Nature Cancer
Volume: 2
Issue: 7
ISSN: 2662-1347
Publisher: Nature Research  
Date Published: 2021-07-01
Start Page: 741
End Page: 757
Language: English
DOI: 10.1038/s43018-021-00220-w
PROVIDER: scopus
PMCID: PMC8388313
PUBMED: 34458856
Notes: Article -- Export Date: 1 September 2021 -- Source: Scopus
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