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(The FASEB Journal. 2005;19:875-879.)
© 2005 FASEB

A postulated role for microRNA in cellular differentiation

Isaac Bentwich

Rosetta Genomics, 10 Plaut Street, Rehovot 76706, Israel

Correspondence: E-mail: bentwich{at}rosettagenomics.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 A GENOMIC DIFFERENTIATION...
 CONCLUSIONS
 REFERENCES
 
Over the past two decades a variety of mechanisms regulating cellular differentiation have been uncovered. These include signaling by morphogens or membrane-associated ligands and asymmetric segregation of cytoplasmic components. Most of these processes are driven by protein coding genes. Here I describe another possible cellular differentiation mechanism that involves asymmetric segregation of microRNAs, a group of recently discovered non-protein coding genes that have been shown to be involved in differentiation.—Bentwich, I. A postulated role for microRNA in cellular differentiation.


Key Words: embryogenesis • UTR • genomic module • protein coding genes • microRNA gene cluster


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
A GENOMIC DIFFERENTIATION...
 CONCLUSIONS
 REFERENCES
 
MOST SOMATIC CELLS in an individual organism contain identical DNA, encoding all of the proteins in that organism; yet, through a process known as cellular differentiation, different cell types (liver cells, bone cells, etc.) express different proteins. Extensive research over the past two decades has described several mechanisms that play a major role in cellular differentiation and are briefly described below. Here I propose a novel cellular differentiation mechanism involving microRNA genes which may complement these known mechanisms. For clarity, this novel cellular differentiation mechanism is described below as though it were a primary mechanism.

Cellular differentiation has been shown to involve a vastly elaborate web of protein interactions, intercellular interactions, spatial protein concentration gradients, DNA methylation, and chromatin remodeling processes (the latter two of which are affected by various proteins). Differentiation thus entails a variety of mechanisms, all of which involve proteins that specifically modulate the expression of other proteins, which modulate the expression of yet other proteins, etc. (e.g., refs 1 , 2 ). There are numerous examples of one or more proteins, such as transcription factors, that induce cellular differentiation by promoting or inhibiting the expression of proteins specific for a particular cell type (e.g., refs 3 , 4 ). Proteins expressed by one cell may also modulate the expression of proteins in a neighboring cell, thereby influencing differentiation of that neighbor cell.

Intercellular interactions have been shown to participate in cellular differentiation processes that give rise to simple pattern formations, such as the development of the eye in Drosophila (5 , 6) and the vulva in Caenorhabditis elegans (7) . Embryology-related studies demonstrated that the concentration gradient of proteins expressed and secreted by one cell may induce cellular differentiation and pattern formation in nonadjacent cells (e.g., ref 8 ). Numerous recent studies have demonstrated the role of DNA methylation and histone modification (phosphorylation, acetylation, and methylation) in cellular differentiation and embryogenesis (9 , 10) . These processes have been shown to turn off transcription of the large number of genes not required in a particular differentiated cell. Stem cell research has discovered a rapidly growing number of proteins that modulate the differentiation of various types of stem cells (e.g., refs 4 , 11 ). Until recently, differentiation research has focused primarily on regulatory DNA sequences that are in relatively close upstream or downstream proximity to protein coding sequences, paying less attention to the other ~98% of the human genome, frequently dubbed "junk DNA" (12) . However, recent studies have shown that large portions of the non-protein coding regions are expressed and evolutionarily conserved across various species (13 , 14) . One such study showed that nearly half of the transcripts that were identified in the mouse apparently do not encode protein, and yet many are evolutionarily conserved in humans (15) . The fraction of protein coding DNA in the genome decreases with increasing organismal complexity (14) , from ~90% in bacteria (16) , to 68% in yeast (17) , 23–24% in nematodes (18) , and 1.5–2% in mammals (15 , 19) . Untranslated regions (UTRs), especially 3' UTRs, of orthologous genes from organisms as diverse as fish, birds, and mammals contain highly conserved sequences, which are believed to be involved in the post-transcriptional control of these genes (20 21 22) . The high level of interspecies conservation suggest that vast genomic sequences that do not encode proteins have important functions, which are now unknown and may play a significant role in encoding differentiation (13 , 14) .

Recently, an intriguing group of non-protein coding genes known as microRNA genes were discovered. MicroRNA genes, frequently found in operon-like clusters, encode short, ~22 nucleotide RNA segments, which typically inhibit translation of specific target genes, by binding to complementary binding sites found in the untranslated regions of the mRNA of these target genes (reviewed in ref 23 ). The first microRNA gene to be discovered was the lin-4 microRNA in C. elegans, which controls the timing of larval development (4 , 24 , 25) . Many microRNAs are associated with various differentiation and pattern formation processes in a wide range of organisms, including control of leaf and flower development in plants (see ref 23 ), neuronal patterning in C. elegans (26) , control of cell proliferation, cell death, and fat metabolism in flies (27 , 28) , and modulation of hematopoietic lineage differentiation in mammals (29) . It has been suggested that trans-acting microRNAs act similarly to transcription factors, forming cellular differentiation "codes" that affect cis-regulatory elements (30) . Recent studies suggest that microRNA genes are more abundant than previously believed (26 , 31) , numbering at least in the hundreds, and are likely to modulate the expression of many protein coding genes (23) .


   A GENOMIC DIFFERENTIATION ENCODING "LANGUAGE"
TOP
 ABSTRACT
 INTRODUCTION
 A GENOMIC DIFFERENTIATION...
CONCLUSIONS
 REFERENCES
 
Could cellular differentiation also be affected by a universal code or language that works in tandem with the above-mentioned mechanisms of cellular differentiation? The notion of a universal genomic differentiation coding language is not as far-fetched as it may sound. In the post-Watson and Crick era, we have come to take for granted the not-so-obvious fact that all proteins in nature, regardless of their drastically different structures, are genomically encoded by one surprisingly simple language (32) . Could a similarly universal genomic language participate in encoding differentiation? A logic-based assessment of cellular differentiation together with recent findings related to non-protein coding genes, particularly microRNA genes, provides several insights in accord with this notion and may enhance our understanding of cellular differentiation.

Modular differentiation coding
Underlying cellular differentiation is the following challenge: How does a parent cell divide and differentiate into a daughter cell that contains the exact same genome as the parent cell and yet expresses different proteins than those expressed by the parent cell? A logic-based evaluation of this challenge suggests two principles. 1) An extra-genomic element: Since the genome of the parent cell is identical to that of the daughter cell, and assuming there is no external organizing agent, this suggests the notion that the parent cell is passing to its daughter cell "something" outside of the genome (i.e., asymmetric segregation of a cytoplasmic component) that triggers the differentiation of the daughter cell (illustrated by A' in Fig. 1 ). 2) Modular code. Since this extra-genomic element cannot be assumed to contain all of the information required for the differentiation of the daughter cell and all of its descendents, it is suggested that a genomic differentiation encoding language would be modular. According to this line of thought, the genome comprises multiple modules (e.g., one module for each cell type or "developmental decision"; Fig. 1 ). It is suggested that there would be a mechanism whereby the above-mentioned extra-genomic element instructs a cell, at its inception, which of these "genomic modules" to activate, causing the cell to differentiate according to the instructions contained in the activated genomic module.



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  		Figure 1. The concept of modular differentiation coding. The genome comprises multiple genomic modules such as fibroblast (FIBRO), bone, cartilage (CARTIL.), nerve, muscle, and lymphocyte (LYMPH) genomics modules. There is one genomic module for each cell type or developmental decision. At the time of inception, an extra-genomic element (A') activates one such genomic module for each cell, thus determining the type of cell that will develop. In the example presented, extra-genomic element A' activates the fibroblast genomic module, inducing the differentiation of the cell into a fibroblast.

Genomic modules modulate protein expression
How does such a genomic module cause a cell to differentiate? Each genomic module is a genomic sequence that comprises a cluster of functionally related, short genomic elements, each of which specifically regulates the expression of one or more target genes (illustrated by 4, 2, and 1 in the fibroblast (FIBRO) genomic module in Fig. 2 ). When activated, the genomic module expresses this cluster of short genomic elements (4', 2', and 1' in Fig. 2 ), thereby regulating the expression of a group of functionally related genes (genes 4, 2, and 1 in Fig. 2 ), such as genes expressed by certain cell types. Such short genomic elements may also modulate the expression of other genomic modules, which in turn would regulate the expression of target genes, and may modulate expression of master controlling proteins, which determine cell type by modulating expression of proteins typical of that cell type (3 , 4) . The number of short genomic elements contained in the genomic modules would be expected to be very large so as to allow cell-specific modulation of expression of many of the known human proteins.



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  		Figure 2. A genomic record modulates cell-specific protein expression. Each genomic module encodes multiple short genomic elements (for example, 4', 2', and 1'), which may be microRNA segments. Each short genomic element regulates the expression of one or more genes (e.g., genes 4, 2, and 1). Thus, a genomic module may regulate the expression of a set of proteins associated with a cell type (such as a fibroblast), thereby determining the cell’s differentiation. The particular expression pattern of the protein translated from genes 4, 2, and 1 gives the cell the characteristics of a fibroblast.

MicroRNA gene clusters seem well suited to function as such genomic modules: As mentioned above, many microRNA genes are found in operon-like clusters (i.e., are processed from a longer common precursor) (33 , 34) . MicroRNAs modulate the expression of target proteins (27 , 35) , are associated with cellular differentiation (29 , 36) , and have been suggested to form a cellular differentiation code that affects cis-regulatory elements in a way that is similar to transcription factors (30) . The growing number of microRNA genes being discovered (26 , 31 , 37) and the current estimate that microRNAs modulate the expression of many protein coding genes (23) lend further support to their possible role as part of a broad system of genomic modules.

Modular hierarchy
But how does the parent cell determine the extra-genomic elements to be passed on to one or both of its daughter cells? According to the cellular differentiation mechanism presented here, these extra-genomic elements are encoded by the genomic module activated in that parent cell (Fig. 3 ). In turn, these two parent cell-derived extra-genomic elements activate corresponding (possibly different) genomic modules in the two daughter cells (B' and C' in Fig. 3 ), thus determining their differentiation and cell fate (bone and cartilage cells, respectively, in Fig. 3 ). Alternatively, the genomic module may encode only one extra-genomic element that is passed on asymmetrically to one of the daughter cells, causing it to differentiate. This latter alternative may be more plausible since it is in accord with the fact that usually only one of the daughter cells of a stem cell differentiates, whereas the other is identical to the parent stem cell. The resulting mechanism is a modular hierarchy or chain reaction: genomic modules use extra-genomic elements to activate other genomic modules in a cascading manner. Conceptually, this mechanism allows for cell fate determination of an unlimited lineage of cells that is not dependent on intercellular interaction.



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  		Figure 3. Modular hierarchy mechanism determines cell fate. The genome contains multiple genomic modules, such as fibroblast (FIBRO), bone, cartilage (CARTIL.), nerve, muscle, and lymphocyte (LYMPH) genomic modules. There is one genomic module, which may be a cluster of microRNA genes, for each cell type or developmental decision. A parent cell-derived extra-genomic element, possibly a microRNA, activates one such genomic module, thus determining that cell’s fate. The parent cell-derived microRNA extra-genomic elements to be transferred to daughter cells are themselves determined by the cell’s genomic module. In the example presented, the extra-genomic element A' activates the fibroblast genomic module inducing the differentiation of the cell into a fibroblast. Fibroblasts provide the extra-genomic element B' or C' to each daughter cell. B' activates the bone genomic module, and C' activates the cartilage genomic module. The conceptual mechanism provides cell fate determination of an unlimited lineage of cells.

This leads to an intriguing question: If indeed microRNA gene clusters function as genomic modules, and if genomic modules encode the parent cell-derived extra-genomic elements that trigger cellular differentiation, could it be that these parent cell-derived extra-genomic elements are microRNA genes? The notion of parent cell-derived extra-genomic RNA affecting cellular differentiation is not without foundation. Germ cells in many animal embryos have cytoplasmic regions, called the germ plasm, containing distinctive cytoplasmic granules that are asymmetrically transferred to daughter cells during cell division and participate in determining cell fate. In the nematode C. elegans, these granules are called P granules and contain RNA, the sequence and function of which is largely unknown (38 , 39) .


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 A GENOMIC DIFFERENTIATION...
 CONCLUSIONS
REFERENCES
 
The cellular differentiation mechanism described above represents a genomic differentiation coding model that may be summarized by the following.

1) Cellular differentiation may be influenced by selective expression of operon-like microRNA clusters (genomic modules) that modulate expression of cell type-specific proteins;

2) Expression of such microRNA operon-like clusters (genomic modules) may be modulated by one or more parent cell-derived microRNA (extra-genomic element) passed on asymmetrically during cell division from a parent cell to its daughter cell; and

3) This one or more parent cell-derived microRNA (extra-genomic element) may be encoded by an operon-like microRNA cluster (genomic module) expressed in the parent cell.

The genomic differentiation coding model augments the various known mechanisms of cellular differentiation by providing a simple, efficient "universal" cellular differentiation mechanism that is independent of interactions with neighboring cells. This chain reaction-like genomic code allows a virtually unlimited hierarchy of cells to divide differentially into daughter cells, expressing different sets of proteins typical of their respective cell types without any "external organizing agent."

Recent findings regarding microRNAs support several important tenets of this model: microRNAs are abundant, modulate expression of target proteins, frequently appear in operon-like clusters, are often associated with cellular differentiation, and in many cases are evolutionarily conserved.

Other predictions made by this model may help validate or disprove it. 1) Are microRNAs significantly more abundant than currently believed? 2) Do microRNAs modulate the expression of other microRNA clusters? 3) Are parent cell-derived microRNAs transferred during cell division? 4) Do such microRNAs that are transferred during cell division determine or affect cell fate of the daughter cell? These and other questions await further investigation. High-throughput microRNA expression detection assays are now available that are more sensitive than traditional expression detection assays (40) . Such assays, together with effective bioinformatic microRNA prediction engines, will be useful tools in addressing some of these questions. A landmark discovery half a century ago revealed a universal genomic language that encodes all proteins. Today, with the focus on the vast regions of the genome that do not encode proteins, the stage is set for a better understanding of cellular differentiation.


   ACKNOWLEDGMENTS
 
I would like to thank the Rosetta Genomics team members for their partnership on our journey to discover the scope of microRNA genes and for their dedication and friendship. I would also like to thank Wilfred Stein for our stimulating discussions on differentiation, and Zvi Bentwich and Wilfred Stein for reading the manuscript and for their helpful suggestions.

Received for publication December 19, 2004. Accepted for publication February 17, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 A GENOMIC DIFFERENTIATION...
 CONCLUSIONS
 REFERENCES
 

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