New Research Helps to Clarify Rules Governing Tissue Sp...

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New Research Helps to Clarify Rules Governing Tissue Specificity

John Rinn

A career scientist focused on studying the human genome, John Rinn serves as the Leslie Orgel Professor of RNA Science at the University of Colorado. John Rinn has a long-standing history of “innovation by integration” that requires collaborations across multiple research disciplines to better understand how the human genome instructs cell fate decisions. One recurring theme in the Rinn lab at CU Boulder’s research is understanding how certain genes are only expressed in very specific times and places during human development. Specifically, long noncoding RNA (lncRNA) genes were discovered to be incredibly specified in the cells they are expressed in where as messenger RNA (mRNA) are often expressed in many more tissues and cell types in the human body. This was first discovered by Cabili et al. Genes and Development 2011 in the Rinn laboratory.

Since this initial discovery several other laboratories have confirmed this finding, yet it was still controversial since lncRNAs have different properties and many different statistical approaches were needed to further test that lncRNAs are indeed more specified in when and where they are made by the human genome compared to mRNAs. A heroic effort by Loyal Goff performed dozens of analyses on big data and using numerous different statistical models. He demonstrated that indeed lncRNAs are more precisely regulated than mRNAs. Specifically, with a document which he entitled “on the tissue specificity of lncRNA”

This raised a new an important question: How are lncRNAs regulated (turned on and off) in such a unique and specified way compared to mRNAs? Especially since the mRNAs eventually are made into proteins that in fact turn on and off lncRNAs.

To take on this question the Rinn lab in Collaboration with laboratory of Marta Mele used a massively parallel reporter assay (MPRA) to test thousands of lncRNA and mRNA promoters (on/off switches). This study was recently published in the peer-reviewed journal Genome Research, the article addresses the question of the existence of an underlying code in mRNA and long noncoding RNA (IncRNA) enhancer and promoter sequences that is responsible for their established differences in tissue specificity and abundance.

Ultimately, the article suggests that simplicity of motif usage may be used to regulate specificity of expression. Thus, over a decade of research ultimately concluded that lncRNAs are more tissue and cell specific than mRNAs and surprisingly this complex regulation is founded in simplicity of promoter regulation; not complexity per previous dogma.