Ground-state pluripotency is a cell state in which pluripotency is established and maintained through efficient repression of endogenous differentiation pathways. Self-renewal and pluripotency of embryonic stem cells (ESCs) are influenced by ESC-associated microRNAs (miRNAs).

Here, researchers from the Royan Institute for Stem Cell Biology and Technology make use of miRNA sequencing and provide a comprehensive assessment of the “miRNome” of ESCs cultured under conditions favoring ground-state pluripotency. They found that ground-state ESCs express a distinct set of miRNAs compared with ESCs grown in serum. Interestingly, most “ground-state miRNAs” are encoded by an imprinted region on chromosome 12 within the Dlk1-Dio3 locus. Functional analysis revealed that ground-state miRNAs embedded in the Dlk1-Dio3 locus (miR-541-5p, miR-410-3p, and miR-381-3p) promoted pluripotency via inhibition of multi-lineage differentiation and stimulation of self-renewal.

Overall, these results demonstrate that ground-state pluripotency is associated with a unique miRNA signature, which supports ground-state self-renewal by suppressing differentiation.

(A) Phase-contrast images of ESCs cultured under serum, 2i, and R2i. Scale bar, 200 μm.

(B) Raw, processed, aligned, and assigned read counts of each ESC sample. Small RNA-sequencing data were obtained for two ESC lines (RB18 and EB20) each time using pools of three independently grown cultures (independent experiments).

(C) Pie chart indicating the proportion of processed reads accounting for miRNAs. Small RNA profiles were obtained for RB18 and EB20 ESC lines using pools of three independently grown cultures (independent experiments).

(D) Pearson heatmap of the ESC samples. Samples are shown as rows and columns. Each square represents the Pearson correlation coefficient between two samples. Each small RNA profile was obtained from three independently grown cultures (independent experiments).

(E) Principal component (PC) analysis of the ESC samples maintained under serum, 2i, and R2i culture conditions. Each small RNA-sequencing data was obtained from three independently grown cultures (independent experiments).

Small RNA Sequencing of ESCs Cultured under Serum, 2i, and R2i Conditions

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Moradi S, Sharifi-Zarchi A, Ahmadi A, Mollamohammadi S, Stubenvoll A, Günther S, Hosseini Salekdeh G, Asgari S, Braun T, Baharvand H. (2017) Small RNA Sequencing Reveals Dlk1-Dio3 Locus-Embedded MicroRNAs as Major Drivers of Ground-State Pluripotency. Stem Cell Reports 9(6):2081–2096. [article]

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