PMID- 22140464
OWN - NLM
STAT- MEDLINE
DCOM- 20120409
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 11
DP  - 2011
TI  - Epigenetic modulation of miR-122 facilitates human embryonic stem cell 
      self-renewal and hepatocellular carcinoma proliferation.
PG  - e27740
LID - 10.1371/journal.pone.0027740 [doi]
LID - e27740
AB  - The self-renewal capacity ascribed to hESCs is paralleled in cancer cell 
      proliferation, suggesting that a common network of genes may facilitate the 
      promotion of these traits. However, the molecular mechanisms that are involved in 
      regulating the silencing of these genes as stem cells differentiate into 
      quiescent cellular lineages remain poorly understood. Here, we show that a 
      differentiated cell specific miR-122 exemplifies this regulatory attribute by 
      suppressing the translation of a gene, Pkm2, which is commonly enriched in hESCs 
      and liver cancer cells (HCCs), and facilitates self-renewal and proliferation. 
      Through a series of gene expression analysis, we show that miR-122 expression is 
      highly elevated in quiescent human primary hepatocytes (hPHs) but lost or 
      attenuated in hESCs and HCCs, while an opposing expression pattern is observed 
      for Pkm2. Depleting hESCs and HCCs of Pkm2, or overexpressing miR-122, leads to a 
      common deficiency in self-renewal and proliferation. Likewise, during the 
      differentiation process of hESCs into hepatocytes, a reciprocal expression 
      pattern is observed between miR-122 and Pkm2. An examination of the genomic 
      region upstream of miR-122 uncovered hyper-methylation in hESCs and HCCs, while 
      the same region is de-methylated and occupied by a transcription initiating 
      protein, RNA polymerase II (RNAPII), in hPHs. These findings indicate that one 
      possible mechanism by which hESC self-renewal is modulated in quiescent hepatic 
      derivatives of hESCs is through the regulatory activity of a differentiated 
      cell-specific miR-122, and that a failure to properly turn "on" this miRNA is 
      observed in uncontrollably proliferating HCCs.
FAU - Jung, Christine J
AU  - Jung CJ
AD  - Transplant Research Program, University of California Davis Medical Center, 
      Sacramento, California, United States of America. cjjung@ucdavis.edu
FAU - Iyengar, Sushma
AU  - Iyengar S
FAU - Blahnik, Kimberly R
AU  - Blahnik KR
FAU - Ajuha, Tijess P
AU  - Ajuha TP
FAU - Jiang, Joy X
AU  - Jiang JX
FAU - Farnham, Peggy J
AU  - Farnham PJ
FAU - Zern, Mark
AU  - Zern M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111128
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (3' Untranslated Regions)
RN  - 0 (MIRN122 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (RNA, Messenger)
RN  - EC 2.7.7.- (RNA Polymerase II)
SB  - IM
MH  - 3' Untranslated Regions/genetics
MH  - Animals
MH  - Base Sequence
MH  - Carcinoma, Hepatocellular/*genetics/*pathology
MH  - Cell Differentiation/genetics
MH  - Cell Division
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Chromatin Immunoprecipitation
MH  - DNA Methylation/genetics
MH  - Embryonic Stem Cells/*cytology/*metabolism
MH  - *Epigenesis, Genetic
MH  - Gene Expression Regulation, Neoplastic
MH  - Genome, Human/genetics
MH  - Hepatocytes/metabolism/pathology
MH  - Humans
MH  - Liver Neoplasms/genetics/*pathology
MH  - Mice
MH  - MicroRNAs/*genetics/metabolism
MH  - Molecular Sequence Data
MH  - Promoter Regions, Genetic/genetics
MH  - Protein Binding/genetics
MH  - Protein Biosynthesis
MH  - RNA Polymerase II/metabolism
MH  - RNA, Messenger/genetics/metabolism
MH  - Sequence Analysis, DNA
PMC - PMC3225380
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2011/12/06 06:00
MHDA- 2012/04/10 06:00
PMCR- 2011/11/28
CRDT- 2011/12/06 06:00
PHST- 2011/02/16 00:00 [received]
PHST- 2011/10/24 00:00 [accepted]
PHST- 2011/12/06 06:00 [entrez]
PHST- 2011/12/06 06:00 [pubmed]
PHST- 2012/04/10 06:00 [medline]
PHST- 2011/11/28 00:00 [pmc-release]
AID - PONE-D-11-03488 [pii]
AID - 10.1371/journal.pone.0027740 [doi]
PST - ppublish
SO  - PLoS One. 2011;6(11):e27740. doi: 10.1371/journal.pone.0027740. Epub 2011 Nov 28.