The miR-302-Mediated Induction of Pluripotent Stem Cells (iPSC): Multiple Synergistic Reprogramming Mechanisms

Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1733)

Abstract

Pluripotency represents a unique feature of embryonic stem cells (ESCs). To generate ESC-like-induced pluripotent stem cells (iPSCs) derived from somatic cells, the cell genome needs to be reset and reprogrammed to express the ESC-specific transcriptome. Numerous studies have shown that genomic DNA demethylation is required for epigenetic reprogramming of somatic cell nuclei to form iPSCs; yet, the mechanism remains largely unclear. In ESCs, the reprogramming process goes through two critical stages: germline and zygotic demethylation, both of which erase genomic DNA methylation sites and hence allow for different gene expression patterns to be reset into a pluripotent state. Recently, miR-302, an ESC-specific microRNA (miRNA), was found to play an essential role in four aspects of this reprogramming mechanism—(1) initiating global genomic DNA demethylation, (2) activating ESC-specific gene expression, (3) inhibiting developmental signaling, and (4) preventing stem cell tumorigenicity. In this review, we will summarize miR-302 functions in all four reprogramming aspects and further discuss how these findings may improve the efficiency and safety of the current iPSC technology.

Key words

miR-302 MicroRNA Induced pluripotent stem cell Epigenetic reprogramming DNA demethylation Pluripotency 

Abbreviations

3′-UTRs

The 3′-untranslated regions

5hmC

5-Hysroxymethylcytosine

Ago 1–4

Argonaute proteins 1–4

AID

Activation-induced cytidine deaminase

AOF1/2 (LSD1/2 or KMD1/1B)

Flavin-containing amine oxidase domain-containing protein ½

BER

A base excision DNA repair

BMI-1

B Lymphoma mouse Moloney leukemia virus insertion region

BMP

Bone morphogenetic protein

cMyc

c-Myelocytomatosis oncogene

CXCR4

C-X-C Chemokine receptor type 4

DAZAP2

DAZ-associated protein 2

DNMT1

DNA (Cytosine-5-)-methyltransferase 1

EIF2C

Eukaryotic translation initiation factor 2C

ESC

Embryonic stem cells

GCNF or NR6A1

Germ cell nuclear factor

H3K4me2/3

Methylation of histone 3 on lysine 4

HDAC2/4

Histone deacetylase 2 and 4

HDM2

E3 ubiquitin ligase for p53

iPSCs

Induced pluripotent stem cells

Klf4

Kruppel-like factor 4

LARP7 or PIP7S

La ribonucleoprotein domain family member 7 gene

LIN28

RNA-binding protein LIN-28

mdm2

P53 E3 ubiquitin protein ligase

MEPC1/2

Methyl-CpG binding 1 and 2

miR-302

MicroRNA-302

miRNA

MicroRNA

miRNAs

MicroRNAs

mirPS cells

miR-302-mediated pluripotent stem cells

NANOG

A transcription factor critically involved with self-renewal of undifferentiated embryonic stem cells

ncRNAs

Noncoding RNAs

NR2F2

Nuclear receptor subfamily 2, group F, member 2

Oct4

Octamer-binding transcription factor 4; a protein that is critically involved in the self-renewal of undifferentiated embryonic stem cells

PCAF

p300-CBP-associated factor

PGC

Primordial germ cells

pre-miRNA

Hairpin-like miRNA precursors

pri-miRNA

Primary miRNA precursors

RAS-MAPK

Ras-mitogen-activated protein kinase

RISC

RNA-induced silencing complexes

RNA pol II

Type-II RNA polymerases

SCNT

Somatic cell nuclear transfer

SCR

Somatic cell reprogramming

SLAIN1

SLAIN motif family, member 1

Sox2

SRY (sex determining region Y)-box 2

SSEA ¾

3-Mercaptopyruvate sulfurtransferase-3 or 4

Tcf3

Transcription factor 3

Tet

Tet methylcytosine dioxygenase 1 or 2

TGFβ-SMAD

Transforming growth factorβ-mothers against DPP homolog family members

TOB2

Protein Tob2; transducer of erbB-2 2

UTF1

Undifferentiated embryonic cell transcription factor 1

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Copyright information

© Springer Science+Business Media, LLC 2018

Authors and Affiliations

  1. 1.Department of Integrative Anatomical Sciences, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Division of Regenerative MedicineWJWU & LYNN (W&L) Institute for Stem Cell ResearchSanta Fe SpringsUSA

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