RFX transcription factors control a miR-150/PDAP1 axis that restrains the proliferation of human T cells

Within the immune system, microRNAs (miRNAs) exert key regulatory functions. However, what are the mRNA targets regulated by miRNAs and how miRNAs are transcriptionally regulated themselves remain for the most part unknown. We found that in primary human memory T helper lymphocytes, miR-150 was the...

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Published in:PLoS biology Vol. 20; no. 2; p. e3001538
Main Authors: Chirichella, Michele, Bianchi, Niccolò, Džafo, Emina, Foli, Elena, Gualdrini, Francesco, Kenyon, Amy, Natoli, Gioacchino, Monticelli, Silvia
Format: Journal Article
Language:English
Published: United States Public Library of Science 10.02.2022
Public Library of Science (PLoS)
Subjects:
Cell growth
Cell proliferation
CRISPR
Gene expression
Genome editing
Genomics
Health aspects
Immune system
Lymphocytes
Lymphocytes T
Measurement
MicroRNA
MicroRNAs
miRNA
Proteins
RNA-binding protein
T cell receptors
T cells
Transcription activation
Transcription factors
Italy
ISSN:1545-7885, 1544-9173, 1545-7885
Online Access:Get full text
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Summary:Within the immune system, microRNAs (miRNAs) exert key regulatory functions. However, what are the mRNA targets regulated by miRNAs and how miRNAs are transcriptionally regulated themselves remain for the most part unknown. We found that in primary human memory T helper lymphocytes, miR-150 was the most abundantly expressed miRNA, and its expression decreased drastically upon activation, suggesting regulatory roles. Constitutive MIR150 gene expression required the RFX family of transcription factors, and its activation-induced down-regulation was linked to their reduced expression. By performing miRNA pull-down and sequencing experiments, we identified PDGFA-associated protein 1 (PDAP1) as one main target of miR-150 in human T lymphocytes. PDAP1 acted as an RNA-binding protein (RBP), and its CRISPR/Cas-9–mediated deletion revealed that it prominently contributed to the regulation of T-cell proliferation. Overall, using an integrated approach involving quantitative analysis, unbiased genomics, and genome editing, we identified RFX factors, miR-150, and the PDAP1 RBP as the components of a regulatory axis that restrains proliferation of primary human T lymphocytes.
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These authors share first authorship on this work.
The authors have declared that no competing interests exist.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.3001538