This topic will highlight molecular processes regulating non-coding RNA molecules.  Lessons from a diverse set of genetic model systems will be presented.  The impact and implications of these findings on our understanding of several human diseases and overall lifespan will be analyzed.  Importantly, articles within this topic will aim to review the literature while also presenting thought-provoking ideas and concepts.

University of Toronto

Beth Israel Deaconess Medical Center, Harvard Medical School

Frontiers in Genetics

Genetics of Aging

Non-coding RNA regulation: lessons from model organisms and impact on human health

This research topic highlights the great interest and cautious optimism surrounding our constantly expanding understanding of the roles played by non-coding RNA (ncRNA) molecules in fundamental biology as well as in human health, aging, and disease.In this topic, five review articles and one hypothesis/theory paper cover in breadth and depth the established, emerging, and controversial aspects of ncRNA biology. Claycomb discusses how we owe, at least in large part, today's broad interest in this area of biology to the discovery and characterization of RNA interference in the tiny soil worm Caenorhabditis elegans, a simple and elegant model organism that continues to be at the forefront of ncRNA research (<a href="http://dx.doi.org/10.3389/fgene.2014.00416">Youngman and Claycomb</a>). She also discusses how this worm provides a tractable genetic system in which researchers continue to study aging, epigenetic inheritance, and the role of ncRNA in such processes. Continuing with contributions from genetic model organisms to the field, Mekhail then discusses how yeast, fly, mouse, and human systems have helped uncover roles of ncRNA molecules in neural function and neurological disorders across the lifespan (<a href="http://dx.doi.org/10.3389/fgene.2015.00087">Szafranski et al.</a>). In particular, this article discusses the role of different classes of ncRNA including miRNA and lncRNA in healthy neural function and aging before highlighting how deleterious processes can also be triggered by ncRNA and/or its regulators in neurodegenerative diseases especially as we age. Suh then summarizes the rich connections between a great number of disease-linked miRNAs and the insulin growth factor 1 (IGF-1) signaling pathway, which regulates diverse processes from development to aging (<a href="http://dx.doi.org/10.3389/fgene.2014.00472">Jung and Suh</a>). Discussed connections between miRNAs and diseases including cancers, diabetes, and aging are astounding. This certainly highlights the therapeutic potential of miRNAs and miRNA-targeting nucleotides. Fish then discusses how networks of miRNAs and lncRNAs modulate NFkB signaling, a major driver of blood vessel inflammation (<a href="http://dx.doi.org/10.3389/fgene.2014.00422">Cheng et al.</a>). Such inflammation can start at a younger age but lead to heart attack and stroke later in life highlighting the therapeutic potential of ncRNA modulation to treat vascular inflammation and its associated complications across the lifespan. Mhlanga discusses how ncRNAs can be manipulated by pathogens such as the human immunodeficiency virus (HIV) (<a href="http://dx.doi.org/10.3389/fgene.2015.00108">Barichievy et al.</a>). This article reveals how ncRNA molecules are at the center of a power struggle between virus and host fighting for the regulatory potential of ncRNAs. Finally, Palazzo helps us take a step back and carefully assess the possibility that most ncRNA is junk transcriptional noise (<a href="http://dx.doi.org/10.3389/fgene.2015.00002">Palazzo and Lee</a>). Contrary to the first impression that this article is anti-ncRNA, this hypothesis and theory article should help the field better distinguish functional from junk ncRNA.In conclusion, I thank the authors and my co-guest editor for their contributions to this research topic. I also extend my most sincere thanks to the tireless researchers in the ncRNA field for their dedication to decipher what continues to be one of the most fascinating areas of biology. In addition to revealing secrets of human health, disease, and aging, this field is helping us better understand the evolution of processes that are so vital to our existence as a human species. By uncovering these processes, we learn more about who we are in an effort to extend our health span.The author confirms being the sole contributor of this work and approved it for publication.KM is supported by the Canadian Institutes of Health Research Open Operating Grant Program and the Ontario Early Researcher Award. KM holds the Canada Research Chair in Spatial Genome Organization.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Editorial: Non-coding RNA Regulation: Lessons from Model Organisms and Impact on Human Health

On October 28th 1943 Winston Churchill said “we shape our buildings, and afterward our buildings shape us” (<xref ref-type="bibr" rid="B45">Humes, 1994</xref>). Churchill was pondering how and when to rebuild the British House of Commons, which had been destroyed by enemy bombs on May 10th 1941. The old House had been small and insufficient to hold all its members, but was restored to its original form in 1950 in order to recapture the “convenience and dignity” that the building had shaped into its parliamentary members. The circular loop whereby buildings or dwellings are shaped and go on to shape those that reside in them is also true of pathogens and their hosts. As obligate parasites, pathogens need to alter their cellular host environments to ensure survival. Typically pathogens modify cellular transcription profiles and in doing so, the pathogen in turn is affected, thereby closing the loop. As key orchestrators of gene expression, non-coding RNAs provide a vast and extremely precise set of tools for pathogens to target in order to shape the cellular environment. This review will focus on host non-coding RNAs that are manipulated by the infamous intracellular pathogen, the human immunodeficiency virus (HIV). We will briefly describe both short and long host non-coding RNAs and discuss how HIV gains control of these factors to ensure widespread dissemination throughout the host as well as the establishment of lifelong, chronic infection.

On October 28th 1943 Winston Churchill said “we shape our buildings, and afterward our buildings shape us” (<a href="#B45" style="color:gray;">Humes, 1994</a>). Churchill was pondering how and when to rebuild the British House of Commons, which had been destroyed by enemy bombs on May 10th 1941. The old House had been small and insufficient to hold all its members, but was restored to its original form in 1950 in order to recapture the “convenience and dignity” that the building had shaped into its parliamentary members. The circular loop whereby buildings or dwellings are shaped and go on to shape those that reside in them is also true of pathogens and their hosts. As obligate parasites, pathogens need to alter their cellular host environments to ensure survival. Typically pathogens modify cellular transcription profiles and in doing so, the pathogen in turn is affected, thereby closing the loop. As key orchestrators of gene expression, non-coding RNAs provide a vast and extremely precise set of tools for pathogens to target in order to shape the cellular environment. This review will focus on host non-coding RNAs that are manipulated by the infamous intracellular pathogen, the human immunodeficiency virus (HIV). We will briefly describe both short and long host non-coding RNAs and discuss how HIV gains control of these factors to ensure widespread dissemination throughout the host as well as the establishment of lifelong, chronic infection.

Non-coding RNAs and HIV: viral manipulation of host dark matter to shape the cellular environment

Declining brain and neurobiological function is arguably one of the most common features of human aging. The study of conserved aging processes as well as the characterization of various neurodegenerative diseases using different genetic models such as yeast, fly, mouse, and human systems is uncovering links to non-coding RNAs. These links implicate a variety of RNA-regulatory processes, including microRNA function, paraspeckle formation, RNA–DNA hybrid regulation, nucleolar RNAs and toxic RNA clearance, amongst others. Here we highlight these connections and reveal over-arching themes or questions related to recently appreciated roles of non-coding RNA in neural function and dysfunction across lifespan.

Declining brain and neurobiological function is arguably one of the most common features of human aging. The study of conserved aging processes as well as the characterization of various neurodegenerative diseases using different genetic models such as yeast, fly, mouse, and human systems is uncovering links to non-coding RNAs. These links implicate a variety of RNA-regulatory processes, including microRNA function, paraspeckle formation, RNA&#x2013;DNA hybrid regulation, nucleolar RNAs and toxic RNA clearance, amongst others. Here we highlight these connections and reveal over-arching themes or questions related to recently appreciated roles of non-coding RNA in neural function and dysfunction across lifespan.

Non-coding RNA in neural function, disease, and aging

The genomes of large multicellular eukaryotes are mostly comprised of non-protein coding DNA. Although there has been much agreement that a small fraction of these genomes has important biological functions, there has been much debate as to whether the rest contributes to development and/or homeostasis. Much of the speculation has centered on the genomic regions that are transcribed into RNA at some low level. Unfortunately these RNAs have been arbitrarily assigned various names, such as “intergenic RNA,” “long non-coding RNAs” etc., which have led to some confusion in the field. Many researchers believe that these transcripts represent a vast, unchartered world of functional non-coding RNAs (ncRNAs), simply because they exist. However, there are reasons to question this Panglossian view because it ignores our current understanding of how evolution shapes eukaryotic genomes and how the gene expression machinery works in eukaryotic cells. Although there are undoubtedly many more functional ncRNAs yet to be discovered and characterized, it is also likely that many of these transcripts are simply junk. Here, we discuss how to determine whether any given ncRNA has a function. Importantly, we advocate that in the absence of any such data, the appropriate null hypothesis is that the RNA in question is junk.

The genomes of large multicellular eukaryotes are mostly comprised of non-protein coding DNA. Although there has been much agreement that a small fraction of these genomes has important biological functions, there has been much debate as to whether the rest contributes to development and/or homeostasis. Much of the speculation has centered on the genomic regions that are transcribed into RNA at some low level. Unfortunately these RNAs have been arbitrarily assigned various names, such as &#x201c;intergenic RNA,&#x201d; &#x201c;long non-coding RNAs&#x201d; etc., which have led to some confusion in the field. Many researchers believe that these transcripts represent a vast, unchartered world of functional non-coding RNAs (ncRNAs), simply because they exist. However, there are reasons to question this Panglossian view because it ignores our current understanding of how evolution shapes eukaryotic genomes and how the gene expression machinery works in eukaryotic cells. Although there are undoubtedly many more functional ncRNAs yet to be discovered and characterized, it is also likely that many of these transcripts are simply junk. Here, we discuss how to determine whether any given ncRNA has a function. Importantly, we advocate that in the absence of any such data, the appropriate null hypothesis is that the RNA in question is junk.