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DNA: One man’s trash is another man’s treasure, but there is no JUNK after all

Author: Demet Sag, PhD

One man’s trash is another man’s treasure, but there is no JUNK after all:

The JUNK has a meaning

Long non-coding RNAs recognized after transcriptome sequencing and studied more closely recently thanks to genomic tiling arrays, cDNA sequencing and RNA-Seq, which they have provided initial insights into the extent and depth of transcribed sequence across human and other genomes. How many are there in the genome? What are their mechanisms? How can we use them in molecular diagnostics and targeted therapies?  How do they effect the function in a disease? Is it possible to modulate gene expression at the level of stem cell to redirect the cell differentiation? These are the main questions that we are looking for.

In early 90s actually first lincRNA was described, Xist. The main function was dosage compensation. Then in 2000s FANTOM consortium project changed the perspective on these long transcripts. Then they are called natural antisense transcripts (NATs), because very large number of these transcripts is overlapping with, and is transcribed in the antisense direction, to protein-coding genes.  As a result of this study 11000 lincRNA discovered from full length cDNAs in mice. Later, yet another shift occur since these transcribed units are solely located in the introns or within “junk” DNA of protein-coding genes.  Another independent study quantified that about 40% of protein-coding genes express NATs. Proven that there is nothing junk about DNA. Then, it was found that there are 8000 lincRNAs and among these 4000 are determined since they provide cell identity with multi-exogenic, polyadenylated, capped, ether in the cytoplasm or in the nucleus. However, even more recent studies show that there are about 20,000 lincRNAs.  Furthermore, lincRNAs are classified under three distinct class: 1. Long-non-coding RNAs away from protein-coding genes, 2 NATs transcribed from the opposite strand of protein-coding genes, 3. Intronic lincRNAs expressed from within the introns of protein coding genes.

The human genome, categorized by function of each gene product, given both as number of genes and as percentage of all genes. (Photo credit: Wikipedia)

Their function is under study. However, keep in mind that they are redundant, so deleting or creating null mutations may or may not answer specific development questions. On the other hand, epigenetics, gene imprinting, and pathologies can be the best resource to identify their specific roles in biological functions and interactions.  Distinct gene regulation either as a cis or trans element, gene imprinting, modulating alternative splicing, nuclear organization, determining a chromatin structure are under study.  This will allow us to relate genome structure and function in health and disease better.  Identification of their function during biological responses require a long way to be completed due to complexity since lincRNAs also regulate microRNAs.  Regardless of many obstacles there is a progress.  Disregulation of these lincRNA mainly observed in several cancer types, prostate, breast, hepatocellular carcinoma, colorectal, glioma and melanoma, possibly more. Most of the studies are done in vitro. However, there are many great model organism work as well, such as mice, zebra fish, and worm.

It was also not surprising that their regulation possibly under control of hormones based on circadian clock of our body. So better to sleep eight hour a day is not a cliché.

Next topic will include understanding of lincRNA mechanisms and epigenetics followed by lincRNAs during disease and cellular genesis.

Mechanism, Genome and Genetics:

”Long non-coding RNAs: insights into functions”. Mercer TR, Dinger ME, Mattick JS Nat. Rev. Genet. 2009;10:155–159. http://www.ncbi.nlm.nih.gov/pubmed/19188922

“Long Noncoding RNAs: Past, Present, and Future” Genetics 1 March 2013: 651-669. http://www.genetics.org/content/193/3/651.abstract

“RNA-protein analysis using a conditional CRISPR nuclease” Proc. Natl. Acad. Sci. USA 2 April 2013: 5416-5421. http://www.pnas.org/content/110/14/5416.abstract

“Noncoding RNA and Polycomb recruitment” RNA 1 April 2013: 429-442. http://rnajournal.cshlp.org/content/19/4/429.abstract

“Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs” Nucleic Acids Res 1 August 2012: 6391-6400. http://nar.oxfordjournals.org/content/40/14/6391.abstract

“Long noncoding RNAs regulate adipogenesis” Proc. Natl. Acad. Sci. USA 26 February 2013: 3387-3392. http://www.pnas.org/content/110/9/3387.abstract

“Circadian changes in long noncoding RNAs in the pineal gland” Proc. Natl. Acad. Sci. USA 14 August 2012: 13319-13324. http://www.pnas.org/content/109/33/13319.abstract

Animal and Development:

“Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis” Genome Res 1 March 2012: 577-591. http://genome.cshlp.org/content/22/3/577.abstract

“Genes for embryo development are packaged in blocks of multivalent chromatin in zebrafish sperm” Genome Res 1 April 2011: 578-589. http://genome.cshlp.org/content/21/4/578.abstract

“Long noncoding RNAs in C. elegans” Genome Res 1 December 2012: 2529-2540. http://genome.cshlp.org/content/22/12/2529.abstract

“A spatial and temporal map of C. elegans gene expression” Genome Res 1 February 2011: 325-341. http://genome.cshlp.org/content/21/2/325.abstract

“SFMBT1 functions with LSD1 to regulate expression of canonical histone genes and chromatin-related factors” Genes Dev. 1 April 2013: 749-766. http://genesdev.cshlp.org/content/27/7/749.abstract

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