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Anais da Academia Brasileira de Ciências

Print version ISSN 0001-3765

An. Acad. Bras. Ciênc. vol.82 no.4 Rio de Janeiro Dec. 2010

http://dx.doi.org/10.1590/S0001-37652010000400016 

BIOLOGICAL SCIENCES

 

The central role of RNA in the genetic programming of complex organisms

 

 

John S. Mattick

Institute for Molecular Bioscience, University of Queensland, Brisbane 4072, Australia

Correspondence

 

 


ABSTRACT

Notwithstanding lineage-specific variations, the number and type of protein-coding genes remain relatively static across the animal kingdom. By contrast there has been a massive expansion in the extent of genomic non-proteincoding sequences with increasing developmental complexity. These non-coding sequences are, in fact, transcribed in a regulated manner to produce large numbers of large and small non-protein-coding RNAs that control gene expression at many levels including chromatin architecture, post-transcriptional processing and translation. Moreover, many RNAs are edited, especially in the nervous system, which may be the basis of epigenome-environment interactions and the function of the brain.

Key words: development, noncoding RNA, epigenome, gene regulation, RNA editing, brain.


RESUMO

Apesar das variações linhagem-específicas, o número e tipo de genes codificadores de proteínas permanecem relativamente estáticos no reino animal. Em contraste, houve uma expansão maciça da quantidade de sequências genômicas não-codificadoras de proteínas com o aumento da complexidade do desenvolvimento. Essas sequências não codificadoras são, de fato, transcritas de maneira regulada para produzirem numerosos RNAs grandes e pequenos não-codificadores de proteínas que controlam a expressão de genes em vários níveis, incluindo a arquitetura da cromatina, o processamento pós-transcricional e a tradução. Além disso, muitos RNAs são editados, especialmente no sistema nervoso, o que pode ser a base de interações epigenoma-ambiente e a função do cérebro.

Palavras-chave: desenvolvimento, RNA não-codificador, epi-genoma, regulação gênica, edição de RNA, cérebro.


 

 

INTRODUCTION

It appears that the genetic programming of complex organisms has been misunderstood for the past 50 years, because of the assumption - largely true for the unicellular prokaryotes, but apparently not for multicellular eukaryotes - that most genetic information is transacted by proteins. This assumption is based upon the central dogma which holds that 'DNA makes RNA makes protein', implying that RNA functions primarily as an intermediate between a gene and its encoded protein, which in turn are responsible for the core functions of the cell, including regulatory functions. Reciprocally it has been assumed that the vast tracts of non-protein-coding sequences that are present in animal and plant genomes are largely non-functional. However, this assumption may be incorrect (Mattick 1994), and the emerging evidence suggests that these non-coding sequences actually specify a vast and hitherto hidden layer of regulatory information that is transacted by RNAs, in conjunction with generic protein complexes that interact with them (Mattick 2001, 2003, 2004, 2007, Mattick and Gagen 2001).

 

INFORMATION SCALING IN COMPLEX ORGANISMS

The human genome specifies an anatomically complex and cognitively advanced organism comprised of ~ 1014 cells, with exquisitely precise architecture of its different muscles, bones, many organs and the brain, which itself contains ~ 1010 neurons each with an estimated 1014 synaptic connections in the neocortex alone (Andersen et al. 2003). Surprisingly the human genome contains only ~20,000 conventional protein-coding genes (Good-stadt and Ponting 2006, Clamp et al. 2007), which are similar in number and largely share orthologous functions with those in nematodes that have only ~ 1,000 somatic cells. Indeed, not withstanding clade-specific variations and innovations (such as RNA editing proteins, see below), the core proteome and extent of protein-coding sequences has not changed greatly since the origin ofthe metazoa, despite enormous increases in their developmental and cognitive complexity (Taft et al. 2007).

On the other hand, the extent of non-protein-coding DNA in the genome increases with increasing complexity, reaching 98.8% in humans (Taft et al. 2007), suggesting that much of the information required to program our development resides in these sequences, and is presumably regulatory in nature. Indeed theoretical considerations suggest that regulatory information scales quadrat-ically with organizational complexity in all functionally integrated systems (Mattick and Gagen 2005), which is supported by empirical data showing that the number of regulatory genes increases as a square function of the number of total genes in bacteria (Croft et al. 2003), contrary to the expectations of combinatoric control. Thus regulatory architecture increasingly dominates genomic information content as organismal complexity increases.

 

GLOBAL TRANSCRIPTION OF THE GENOME

Moreover, irrespective of the extent of non-protein-coding sequences, it is now evident that the majority of all genomes is transcribed, mainly into non-protein-coding RNAs (ncRNAs), of which there are tens if not hundreds of thousands in mammals (Carninci et al. 2005, Katayama et al. 2005), arranged in complex interlacing and overlapping patterns (for reviews see Frith et al. 2005, Mattick and Makunin 2006, Kapranov et al. 2007). These ncRNAs generally fall into two size classes: (i) small RNAs that are less than 200 nt, including infrastructural RNAs like tRNAs, rRNAs and small nuclear / spliceosomal RNAs (snRNAs), as well as various types of regulatory RNAs, including micro-RNAs (miRNAs), small interfering RNAs (siRNAs), piwi-interacting RNAs (piRNAs) and small nucleolar RNAs (snoRNAs) (Mattick and Makunin 2005); and (ii) long noncoding RNAs (lncRNAs) that can range from a few hundred bases up to well over 100 kilobases in length (Furuno et al. 2006, Pang et al. 2007, Mercer et al. 2009).

 

REGULATED EXPRESSION OF NONCODING RNA

These lncRNAs show tissue-specific and physiologically-responsive expression (Ravasi et al. 2006), as well as dynamic expression profiles in differentiating embryonal stem cells (Dinger et al. 2008b), neuronal cells (Mercer et al. 2010), T-cells (Pang et al. 2009), muscle cells (Sunwoo et al. 2009), and other developmental contexts in animals and plants (Amaral and Mattick 2008, Ben Amor et al. 2009, Dinger et al. 2009). They also show many other signatures of functionality, with increasing numbers of validated examples, as ell as altered expression in cancer and other diseases (for reviews see (Mattick 2009b, Mercer et al. 2009, Taft et al. 2010a).

Approximately half of all lncRNAs show highly specific expression patterns in different regions of the brain, and many are trafficked to specific sub-cellular locations (Mercer et al. 2008). Moreover particular ncRNAs are associated with known and novel sub-nuclear domains (Sone et al. 2007, Sunwoo et al. 2009), suggesting a key role for lncRNAs in cell biology that has yet to be explored. While ncRNAs exhibit a wide range of conservation (Pang et al. 2006), this is to be expected given that their sequences are subject to different structure-function constraints (i.e., may be more plastic) than proteins, and that regulatory innovation underpins much if not most of phenotypic variation (Pheasant and Mattick 2007). There is also an underexplored subterranean strata of differentially expressed repeat-derived RNAs (Lunyak et al. 2007, Faulkner et al. 2009), which may also play an important role in developmental regulation (Faulkner and Carninci 2009, Mattick et al. 2010).

 

RNA REGULATION OF EPIGENETIC PROCESSES

A major function of ncRNAs appears to be the regulation of the epigenetic processes that underpin differentiation and development (Amaral and Mattick 2008), by guiding relatively generic chromatin-modifying complexes to their sites of action (Mattick et al. 2009). Many chromatin-modifying proteins contain RNA binding domains, as indeed do major classes of transcription factors (Shi and Berg 1995, Mattick 2003, 2007, Bernstein and Allis 2005). An increasing number of lncRNAs have been shown to be associated with chromatinmodifying complexes and different forms of modified histones (Rinn et al. 2007, Dinger et al. 2008b, Nagano et al. 2008, Pandey et al. 2008, Terranova et al. 2008, Zhao et al. 2008, Khalil et al. 2009, Swiezewski et al. 2009). Indeed, ncRNA-directed regulatory circuits underpin most, if not all, complex epigenetic phenomena in eukaryotes, including RNA interference-related processes such as transcriptional and post-transcriptional gene silencing, position effect variegation, hybrid dysgenesis, chromosome dosage compensation, parental imprinting and allelic exclusion, parautation (see belo ), and possibly transvection and transinduction (see Mattick and Gagen 2001, Mattick 2009b). In addition exons are preferentially associated with nucleosomes in somatic and sperm cells in vertebrates (Nahkuri et al. 2009), indicating that epigenetic regulation acts not just the level of the gene, but at the level of individual exons, which potentially explains the basis of the long-standing mystery of how alternative splicing is regulated, a prediction that has recently gained experimental support (Luco et al. 2010).

 

MULTIPLE CLASSES OF SMALL RNA

Small RNAs of the miRNA, piRNA and siRNA families play important roles in a wide range of developmental and physiological processes in animals and plants (Bar-tel 2004, Jones-Rhoades et al. 2006, Stefani and Slack 2008, Ghildiyal and Zamore 2009), and many are dysregulated in diseases such as cancer (Esquela-Kerscher and Slack 2006, Medina and Slack 2008). Recently, we have discovered a number of new classes of small RNAs, including tiny RNAs associated with transcription initiation sites (tiRNAs) (Taft et al. 2009c) that appear to be related to nucleosome positioning (Taft et al. 2009a), similarly-sized RNAs associated with splice junctions (spliRNAs) (Taft et al. 2010b), and a range of small RNAs derived from snoRNAs (sdRNAs) (Taft et al. 2009b), some of which appear to function as miRNAs (Ender et al. 2008), indicating an interplay between the snoRNA- and miRNA-mediated regulatory systems (Politz et al. 2009, Taft et al. 2009b).

 

RNA COMMUNICATION AND PLASTICITY

Finally, it appears that RNA is trafficked between cells (Dinger et al. 2008a). It also appears to be the substrate for the transmission of environmental information into endogenous epigenetic networks, via RNA editing (Mattick 2010). RNA editing occurs via two classes of enzymes, the ADARs (one of which, ADAR3, is brain-specific) that catalyze adenosine deamination to inosine (Bass 2002, Valente and Nishikura 2005) and the APO-BECs (two of which, APOBEC1 and APOBEC3 are specific to mammals, with the latter having expanded under positive selection in the primate lineage) that act variously on RNA or DNA to catalyze cytosine or 5-methylcytosine deamination to uracil or thymine (Morgan et al. 2004, Sawyer et al. 2004, Zhang and Webb 2004, Mikl et al. 2005, Navaratnam and Sarwar 2006). RNA editing occurs in most if not all tissues, appears to play an important role in development (Bhutani et al. 2010, Sato et al. 2010), and is particularly active in the brain (Bass 2002, Valente and Nishikura 2005). Intriguingly, there is ~30 times more RNA editing observed in human than in mouse, the vast majority of which occurs in Alu primate-specific elements (Athanasiadis et al. 2004, Blow et al. 2004, Kim et al. 2004, Levanon et al. 2004). The amount of editing has also increased during primate evolution associated with new human-specific Alu insertions in genes of neuronal function (Paz-Yaacov et al. 2010). Alu sequences also appear to have been subject to positive selection (Lander et al. 2001), possibly associated with the evolution of advanced brain function, which also involves processes that are similar to those in the immune system (Mattick and Mehler 2008, Mattick 2010). Finally it appears that RNA is the mediator of transgenerational epigenetic inheritance, referred to as 'paramutation' (Chandler 2007), a process that is also influenced by editing (Nadeau 2009).

 

CONCLUSION

The emerging evidence suggests that, rather than oases of protein-coding sequences in a desert of junk, the genomes of humans and other complex organisms should be viewed as islands of protein-coding sequences in a sea of regulation (Mattick 2004, Ovcharenko et al. 2005), most of which is transacted by RNA (Amaral et al. 2008, Mattick 2010). Moreover it appears that RNA, rather than simply being an ephemeral intermediate between gene and protein, actually comprises the computational engine of the cell (Mattick 1994, Mattick and Gagen 2001) and the substrate for epigenome-environment interactions (Mattick 2010). It is a remarkably versatile molecule (Leontis and Westhof 2003, Lescoute and Westhof 2006, Cruz and Westhof 2009), with capacity to form sophisticated structures, possess catalytic functions and engage in sequence-specific interactions, which may be allosterically controlled and interact with various sorts of effector proteins, thereby coupling analog and digital functions (Mattick 2007, St Laurent and Wahlestedt 2007). What was dismissed as junk because it was not understood may hold the key to understanding human evolution, development and cognition, as well as our individual differences and susceptibilities to complex diseases (Mattick 2009a).

 

ACKNOWLEDGMENTS

This article is an extended summary of plenary lectures presented at the IRT 2010 (XIX International Round Table on Nucleosides, Nucleotides and Nucleic Acids), Lyon, France, and at the 56th Brazilian Congress of Genetics, Guarujá, Brazil. The author gratefully acknowledges the support of Australian Research Council Federation Fellowship FF0561986.

 

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Correspondence:

E-mail: j.mattick@imb.uq.edu.au

Manuscript received on September 17, 2010; accepted for publication on October 15, 2010

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