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Regulation of non-coding RNA contributes to the complete cessation of cell proliferation of …
Regulation of non-coding RNA contributes to the complete cessation of cell
proliferation of neuron-like cells  

  The majority of long non-coding RNAs (ncRNAs) in mammals have been thought to
downregulate the expression of the corresponding messenger RNAs (mRNAs) that encode
proteins by forming ncRNA-mRNA duplex structures. However, according to a study published
March 4th in Nucleic Acids Research, comprehensive analysis of bidirectional promoters for the
expression of ncRNA-mRNA pairs have identified a set of gene-activation-associated ncRNAs
that are upregulated or downregulated by cyclic AMP mediating the cell cycle dynamics of
energy metabolism. Subsequent functional assays have revealed that bidirectional
promoter-associated ncRNA (pancRNA) contributes to the epigenetic memory formation for
adaptation of extracellular signal-induced gene decoding system in cells, and functions in the
terminal differentiation.

■Background of this study
Neurons do not proliferate once their fate is determined. This is because if they proliferated, newly
generated neurons might cause electronic noise that would disturb the already existing finely tuned
neuronal cell network (Fig. 1). Similarly, de-regulation of cell cycling mechanisms in cells other
than neurons may increase the risk of tumor formation. In order to avoid such de-regulation,
genomic DNA that defines genes involved in the cell cycling is set appropriately according to given
environmental contexts. In addition to the genes that encode proteins, next generation sequencing
technique allows to find a large group of “non-coding RNAs” transcribed from genomic DNA.

■Achievements of this study
The process of the DNA-level inheritance over cell cycling consists of two major parts: synthesis of
the genomic DNA at S-phase and the equal division of the duplicated DNA at M-phase (Fig. 2). It is
well known that regulations during S-phase are important steps for keeping the neuron
non-proliferating. In this study, Imamura and colleagues have found that regulations at M-phase
are also very important to keeping neuron-like cells non-proliferating. This strongly suggests that
neurons are under double security to stably express their specialized function by prohibiting
entrance into S-phase and M-phase as well.

■Significance of this study and perspectives
In this study, Imamura et al. also found that cell proliferation can be de-regulated by artificially
introducing the corresponding pancRNA. In mammals, including humans, independently from
terminally differentiated neurons, neural stem cells exist for shaping the neuronal networks in
response to metabolic changes. Progress in the field of integrative medical science for tissue repair
advances our understanding of how both neurons and neural stem cells maintain the neuronal
network. Towards the appropriate use of engineered cells in living organisms, discovery of
functional ncRNAs for not only downregulation but also upregulation of gene expression provides a
molecular basis for establishing the ON/OFF switch system that ultimately maintains the cellular

Authors: Naoki Yamamoto, Kiyokazu Agata, Kinichi Nakashima, Takuya Imamura
Title: Bidirectional promoters link cAMP signaling with irreversible differentiation through
promoter-associated noncoding RNA (pancRNA) expression in PC12 cells
Journal: Nucleic Acids Research doi: 10.1093/nar/gkw113

This work was supported by Japan Society for the Promotion of Science; Global COE program A06
to Kyoto University; and Scientific Research on Innovative Areas ‘Genome Science’ grants from the
Ministry of Education, Culture, Sports, Science and Technology (MEXT).



      Author contact  
      Takuya IMAMURA, Kyushu University
      TEL: +81-92-642-6196
      FAX: +81-92-642-6561
      Mail: imamura(at)

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