Transcriptional regulation through noncoding RNAs and epigenetic modifications

The recognition that substantial portions of the “noncoding (nc)” regions of metazoan genomes are transcribed has generated intense interest in the potential biological roles of ncRNAs. Gene silencing has emerged as one of the major functions of short double stranded ncRNAs (22~25 nucleotides, nt) that are generated by specific processing machinery. Transcription is also regulated by other classes of ncRNAs, including long (more than 200 nt), single-stranded, polyadenylated RNA molecules. Here, we review recent studies suggesting that some ncRNAs appear to function by binding to and regulating the activities of transcriptional co-activator or co-repressor complexes. Although the extents to which these mechanisms are used remains to be established, the identification of highly conserved ncRNAs and the presence of RNA binding domains in a large number of transcriptional co-regulators raise the possibility that ncRNA/coregulator interactions play broad roles in the regulation of gene expression.

[1]  P. Puigserver,et al.  A Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis , 1998, Cell.

[2]  A. Durrbach,et al.  Human POMp75 is identified as the pro-oncoprotein TLS/FUS: both POMp75 and POMp100 DNA homologous pairing activities are associated to cell proliferation , 1999, Oncogene.

[3]  Neil J McKenna,et al.  A Steroid Receptor Coactivator, SRA, Functions as an RNA and Is Present in an SRC-1 Complex , 1999, Cell.

[4]  Howard Y. Chang,et al.  Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs , 2007, Cell.

[5]  Brian S. Clark,et al.  The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. , 2006, Genes & development.

[6]  Paul T. Groth,et al.  The ENCODE (ENCyclopedia Of DNA Elements) Project , 2004, Science.

[7]  Thomas E. Royce,et al.  Global Identification of Human Transcribed Sequences with Genome Tiling Arrays , 2004, Science.

[8]  N. Mandahl,et al.  Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma , 1993, Nature.

[9]  C. Glass,et al.  Differential use of CREB binding protein-coactivator complexes. , 1998, Science.

[10]  R. Lyle,et al.  The imprinted antisense RNA at the Igf2r locus overlaps but does not imprint Mas1 , 2000, Nature Genetics.

[11]  C. Glass,et al.  Induced ncRNAs Allosterically Modify RNA Binding Proteins in cis to Inhibit Transcription , 2008, Nature.

[12]  Jennifer A. Mitchell,et al.  The Air Noncoding RNA Epigenetically Silences Transcription by Targeting G9a to Chromatin , 2008, Science.

[13]  M. Itoh,et al.  Involvement of the Pro-oncoprotein TLS (Translocated in Liposarcoma) in Nuclear Factor-κB p65-mediated Transcription as a Coactivator* , 2001, The Journal of Biological Chemistry.

[14]  Jeannie T. Lee,et al.  Polycomb Proteins Targeted by a Short Repeat RNA to the Mouse X Chromosome , 2008, Science.

[15]  D. Immanuel,et al.  TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling. , 1997, Journal of cell science.

[16]  B. O’Malley,et al.  A Subset of Nuclear Receptor Coregulators Act as Coupling Proteins during Synthesis and Maturation of RNA Transcripts , 2005, Molecular and Cellular Biology.

[17]  Gene W. Yeo,et al.  Divergent Transcription from Active Promoters , 2008, Science.

[18]  Bert W O'Malley,et al.  Coordinate Regulation of Transcription and Splicing by Steroid Receptor Coregulators , 2002, Science.

[19]  B. Howard,et al.  The Transcriptional Coactivators p300 and CBP Are Histone Acetyltransferases , 1996, Cell.

[20]  W. Filipowicz,et al.  Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? , 2008, Nature Reviews Genetics.

[21]  D. Ron.  TLS-CHOP and the role of RNA-binding proteins in oncogenic transformation. , 1997, Current topics in microbiology and immunology.

[22]  Masatoshi Hagiwara,et al.  Phosphorylated CREB binds specifically to the nuclear protein CBP , 1993, Nature.

[23]  A. Fire,et al.  Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans , 1998, Nature.

[24]  S. Salzberg,et al.  The Transcriptional Landscape of the Mammalian Genome , 2005, Science.

[25]  P. Puigserver,et al.  Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. , 2003, Endocrine reviews.

[26]  Andrew J. Bannister,et al.  The CBP co-activator is a histone acetyltransferase , 1996, Nature.