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A MicroRNA with a Large Role in Human Pluripotent Stem Cells

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Review of “A Novel role for miR-1305 in Regulation of Pluripotency-Differentiation Balance, Cell Cycle and Apoptosis in Human Pluripotent Stem Cells” from Stem Cells by Stuart P. Atkinson

Although they have a rather diminutive name, microRNAs (miRNAs) are now appreciated as playing an large role in the maintenance of the pluripotent state. Expression of specific miRNAs can control levels of pluripotency-associated factors [1] and cell cycle regulators [2] leading to the loss of pluripotency and the onset of differentiation in human pluripotent cells (hPSCs)

In a new Stem Cells study, Irina Neganova and Majlinda Lako (Newcastle University, UK) have now identified a new miRNA which regulates early differentiation events, cell survival, and cell cycle progression in hPSCs [3], and in doing so, have revealed more of regulatory mechanisms which regulate pluripotency.

The initial steps in this new study utilized miRNA microarray comparisons and cell cycle specific gene expression analysis to reveal miRNAs with the potential to regulate the cell cycle and pluripotency. Concentrating on miRNAs specific to the S phase of the cell cycle, due to the relative importance of this phase to the pluripotent state [4], the study uncovered miR-1305 as a potentially interesting candidate. Overexpression of miR-1305 enhanced hPSC differentiation and apoptosis and “sped-up” the G1/S transition, while inhibition mediated enhanced hPSC pluripotency and cell survival, so highlighting the relative importance of this new miRNA.

So how is miR-1305 functioning in hPSCs? Targets of miR-1305 included three factors previously linked to the maintenance of pluripotency, cell cycle regulation, or differentiation: LIN28A [5], ZIC2 [6], and the RNA polymerase III subunit POLR3G. POLR3G is a downstream target of OCT4 and NANOG controlled by the ERK1/2 signaling pathway [7] and target analysis by the authors suggested that miR-1305 could directly bind POLR3G mRNA. Further proof of the importance of this interaction derived from the observation that the differentiation-inducing capabilities of miRNA-1305 could be negated following overexpression of POLR3G, while the promotion of the pluripotent state following miR-1305 inhibition was lost following POLR3G inhibition.

Few previous studies have indicated potential roles for miR-1305, and so this link to the pluripotent state and cell cycle of hPSCs adds a welcome new section to the vast sprawl that is extended pluripotency network represents (See attached figure). The authors do however note that this is merely the start of their miRNA journey; much more is left to accomplish in the hope of fully understanding just how this single miRNA can affect pluripotent self-renewal, differentiation, and also survival. However, they have garnered some hints on how to start this journey; miRNA-1305 may also target a plethora of apoptosis, cell cycle, and pluripotency/differentiation regulators. The journey has just begun!

Discussion Points

  • How many other direct targets of miR-1305 are altered during the cell cycle and differentiation?
  • How is miRNA-1305 itself regulated?
  • Do miRNAs control pluripotency/cell cycle regulators during other phases of the cell cycle?

References

  1. Tay Y, Zhang J, Thomson AM, et al. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 2008;455:1124-1128.
  2. Qi J, Yu JY, Shcherbata HR, et al. microRNAs regulate human embryonic stem cell division. Cell Cycle 2009;8:3729-3741.
  3. Jin S, Collin J, Zhu L, et al. A Novel Role for miR-1305 in Regulation of Pluripotency-Differentiation Balance, Cell Cycle, and Apoptosis in Human Pluripotent Stem Cells. Stem Cells 2016;34:2306-2317.
  4. Gonzales KA, Liang H, Lim YS, et al. Deterministic Restriction on Pluripotent State Dissolution by Cell-Cycle Pathways. Cell 2015;162:564-579.
  5. Qiu C, Ma Y, Wang J, et al. Lin28-mediated post-transcriptional regulation of Oct4 expression in human embryonic stem cells. Nucleic Acids Res 2010;38:1240-1248.
  6. Pourebrahim R, Houtmeyers R, Ghogomu S, et al. Transcription factor Zic2 inhibits Wnt/beta-catenin protein signaling. J Biol Chem 2011;286:37732-37740.
  7. Wong RC, Pollan S, Fong H, et al. A novel role for an RNA polymerase III subunit POLR3G in regulating pluripotency in human embryonic stem cells. Stem Cells 2011;29:1517-1527.