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Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate
terminal NKT cell differentiation and effector function
#MMPMID25848867
Pobezinsky LA
; Etzensperger R
; Jeurling S
; Alag A
; Kadakia T
; McCaughtry TM
; Kimura MY
; Sharrow SO
; Guinter TI
; Feigenbaum L
; Singer A
Nat Immunol
2015[May]; 16
(5
): 517-24
PMID25848867
show ga
Lethal-7 (let-7) microRNAs (miRNAs) are the most abundant miRNAs in the genome,
but their role in developing thymocytes is unclear. We found that let-7 miRNAs
targeted Zbtb16 mRNA, which encodes the lineage-specific transcription factor
PLZF, to post-transcriptionally regulate PLZF expression and thereby the effector
functions of natural killer T cells (NKT cells). Dynamic upregulation of let-7
miRNAs during the development of NKT thymocytes downregulated PLZF expression and
directed their terminal differentiation into interferon-? (IFN-?)-producing NKT1
cells. Without upregulation of let-7 miRNAs, NKT thymocytes maintained high PLZF
expression and terminally differentiated into interleukin 4 (IL-4)-producing NKT2
cells or IL-17-producing NKT17 cells. Upregulation of let-7 miRNAs in developing
NKT thymocytes was signaled by IL-15, vitamin D and retinoic acid. Such targeting
of a lineage-specific transcription factor by miRNA represents a previously
unknown level of developmental regulation in the thymus.
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