Meiotic, cryptic, and stable unannotated transcripts: Noncoding RNAs add to the epigenetic tool box controlling meiotic development

Less than 2% of the genome codes for the ≈20,000 genes found in humans. Rather than representing a genetic desert as originally thought, high-resolution expression profiling has found that these noncoding regions of the chromosome are actively transcribed, producing several types of noncoding RNAs (ncRNAs). Recent studies have found that these ncRNAs can be divided into several groups based on origin and/or function (1). For example, small ncRNAs (e.g., small interfering RNAs or microRNAs) negatively regulate gene expression by targeting specific mRNAs for destruction or preventing their translation. However, ncRNAs have also been shown to stimulate gene transcription by inducing changes in chromatin structure (2–4). In addition, ncRNAs regulate diverse processes, including chromosome segregation, cell cycle progression, and cellular differentiation (5, 6). In particular, several aspects of germ cell development are regulated by ncRNAs [reviewed in (7)]. For example, ablation of the small ncRNA processing pathway disrupts oocyte development (8, 9) whereas small ncRNAs (e.g., miR-122a) can target individual genes for silencing (10).

Previous studies in budding yeast have uncovered stable unannotated transcripts (SUTs) (11) and cryptic unstable transcripts (CUTs) in vegetative cells (12). In a report in PNAS, Lardenois et al. (13) identify and characterize ncRNAs produced during meiotic development in budding yeast. In this study, a unique class of ncRNAs, meiotic unannotated transcripts (MUTs), that accumulate only during meiotic development was discovered. These findings are remarkable in several ways. First, their exquisite timing, coupled with their genomic location, suggests a role for the MUTs in meiotic gene regulation. For example, MUTs were identified whose accumulation inversely mirrored that of a coding gene but were transcribed on the complementary strand, suggesting an antisense function (Fig. 1A). In other instances, MUT expression occurred on the same strand, with the potential to interfere with transcription (Fig. 1B). In addition, MUTs were observed that transverse DNA replication origins (Fig. 1C). This observation is interesting because previous studies have found that active transcription can interfere with the binding and/or function of proteins required for DNA replication (14, 15). Meiotic S-phase (meiS) possesses several characteristics that distinguish it from mitotic DNA replication. For example, meiS rereplication must be prevented both following normal meiS phase and between the two meiotic nuclear divisions. Genetic studies have found that the system controlling this block to rereplication is different in these two systems (16). Preventing origin firing via MUTs represents an interesting possibility to deliver a meiosis-specific answer to this meiotic problem. Finally, a large number of MUTs were found that are transcribed in regions of the chromosome without identifiable features (Fig. 1D). Potential regulatory roles for these transcripts are not known.

Fig. 1.

Proposed roles for ncRNA control of meiotic development. (A) Antisense MUT transcription contemporaneously with a meiotic ORF. (B) MUT transcription on the same strand as the ORF has the ability to disrupt promoter function. (C) Inactivation of a DNA replication origin (ORI) by MUT transcription. (D) MUT transcription in a featureless region of a chromosome. Potential functions of this transcript are unknown.

How Is the Regulator Regulated?

Rrp6p is an RNase that is a component of the conserved exosome complex required for many RNA processing tasks, including rRNA processing (17) and degrading CUTs (12). Lardenois et al. (13) find that Rrp6p levels are reduced early in meiotic progression coincident with the accumulation of MUTs. This led the authors to speculate that Rrp6p destruction is a potential mechanism for controlling MUT levels. This model is supported by the finding that deleting RRP6 resulted in constitutive expression of MUTs in vegetative cells and throughout meiosis. Rrp6p regulation mirrors that observed for the transcriptional repressor Ume6p, a negative regulator of early meiotic gene transcription (18). Entry into meiosis induces the destruction of Ume6p mediated by the anaphase promoting complex/cyclosome ubiquitin ligase (19). Taken together, these findings suggest a common regulatory theme for controlling meiotic induction and progression in that protein destruction is used to inhibit the inhibitors. Why use destruction rather than some other method to inactivate Rrp6p and Ume6p? Inactivation by destroying the proteins may more fully commit the cell to its decision to exit the cell cycle and induce meiotic development.

Epigenetics and Developmental Control

Similar to other differentiation programs, expression of the genes required for yeast meiosis is controlled by a transient transcription program. The importance of this program is underscored by the finding that many of the factors required for this process are essential for normal meiosis. For example, factors that control chromatin modifications, such as histone acetylation (Gcn5p), histone deacetylation (Rpd3p), and recruiters of these factors (Ume6p), are all essential for meiosis but are dispensable for mitotic cell division (18, 20, 21). Similarly, Rrp6p is necessary for meiotic progression but not for viability (22). These findings indicate a different requirement for epigenetic control when cells are differentiating as opposed to proliferating. Although many exist, one potential reason for this higher reliance on epigenetic control is that the execution of developmental programs requires an increase in regulatory complexity that is afforded by the expansion of ncRNA-dependent regulation (23). Such a model is supported by the increased ratio of ncRNA to total genome size observed as organisms become more complex even though the total number of genes remains similar (23). The ncRNA control of gene expression, DNA synthesis, and chromosome segregation (as well as other unknown processes) may add layers of control on a developmental process without requiring more regulators. Studies in model organisms, such as budding or fission yeasts, may provide insight into these questions.