Meta-Biol

• Pathways

In germ cells of humans and mice, precursors of PIWI-interacting RNAs (piRNAs) are transcribed from a few hundred sequence clusters, as well as individual transposons, intergenic regions, and genes in the genome. These longer transcripts are processed to yield piRNAs of 26-30 nucleotides independently of DICER, the enzyme responsible for microRNAs (miRNAs) and small interfering RNAs (siRNAs) (reviewed in Girard and Hannon 2008, Siomi et al. 2011, Ishizu et al. 2012, Pillai and Chuma 2012, Bortvin 2013, Chuma and Nakano 2013, Sato and Siomi 2013). The initial step in processing long transcripts to piRNAs is cleavage by PLD6 (MitoPLD), which generates the mature 5' end. The cleavage products of PLD6 are bound by either PIWIL1 (HIWI, MIWI) or PIWIL2 (HILI, MILI) in complexes with several other proteins. The 3' end is trimmed by an unknown exonuclease to generate the mature piRNA. PIWIL1:piRNA complexes appear to be involved in post-transcriptional silencing in the cytosol while PIWIL2:piRNA complexes generate further piRNAs from transposon transcripts and other transcripts in the cytosol. Cleavage products from PIWIL2:piRNA may be loaded into either PIWIL2 or PIWIL4 (HIWI2, MIWI2). Loading into PIWIL2 forms a step in a cytosolic amplification loop called the "ping-pong cycle" which yields further PIWIL2:piRNA complexes from cleaved precursor RNAs. Loading into PIWIL4 yields a complex also containing TDRD9 that translocates to the nucleus and directs DNA methylation of cognate loci, causing transcriptional silencing during spermatogenesis. Transcriptional silencing by piRNAs is necessary to limit transposition of endogenous transposons such as L1 elements in the genome.

In this module, the biology of various types of regulatory non-coding RNAs are described. Biogenesis and functions of small interfering RNAs (siRNAs) and microRNAs (miRNAs) are annotated. Biogenesis of PIWI-interacting small RNAs (piRNAs) and tRNA-derived small RNAs (tsRNAs) are also annotated.

Gene expression encompasses transcription and translation and the regulation of these processes. RNA Polymerase I Transcription produces the large preribosomal RNA transcript (45S pre-rRNA) that is processed to yield 18S rRNA, 28S rRNA, and 5.8S rRNA, accounting for about half the RNA in a cell. RNA Polymerase II transcription produces messenger RNAs (mRNA) as well as a subset of non-coding RNAs including many small nucleolar RNAs (snRNA) and microRNAs (miRNA). RNA Polymerase III Transcription produces transfer RNAs (tRNA), 5S RNA, 7SL RNA, and U6 snRNA. Transcription from mitochondrial promoters is performed by the mitochondrial RNA polymerase, POLRMT, to yield long transcripts from each DNA strand that are processed to yield 12S rRNA, 16S rRNA, tRNAs, and a few RNAs encoding components of the electron transport chain. Regulation of gene expression can be divided into epigenetic regulation, transcriptional regulation, and post-transcription regulation (comprising translational efficiency and RNA stability). Epigenetic regulation of gene expression is the result of heritable chemical modifications to DNA and DNA-binding proteins such as histones. Epigenetic changes result in altered chromatin complexes that influence transcription. Gene Silencing by RNA mostly occurs post-transcriptionally but can also affect transcription. Small RNAs originating from the genome (miRNAs) or from exogenous RNA (siRNAs) are processed and transferred to the RNA-induced silencing complex (RISC), which interacts with complementary RNA to cause cleavage, translational inhibition, or transcriptional inhibition.