Genetic studies have suggested that chromatin structure is involved in repression of the silent mating type loci in Saccharomyces cerevisiae. Chromatin mapping at nucleotide resolution of the transcriptionally silent HML␣ and the active MAT␣ shows that unique organized chromatin structure characterizes the silent state of HML␣. Precisely positioned nucleosomes abutting the silencers extend over the ␣1 and ␣2 coding regions. The HO endonuclease recognition site, nuclease hypersensitive at MAT␣, is protected at HML␣. Although two precisely positioned nucleosomes incorporate transcription start sites at HML␣, the promoter region of the ␣1 and ␣2 genes is nucleosome free and more nuclease sensitive in the repressed than in the transcribed locus. Mutations in genes essential for HML silencing disrupt the nucleosome array near HML-I but not in the vicinity of HML-E, which is closer to the telomere of chromosome III. At the promoter and the HO site, the structure of HML␣ in Sir protein and histone H4 N-terminal deletion mutants is identical to that of the transcriptionally active MAT␣. The discontinuous chromatin structure of HML␣ contrasts with the continuous array of nucleosomes found at repressed a-cell-specific genes and the recombination enhancer. Punctuation at HML␣ may be necessary for higher-order structure or karyoskeleton interactions. The unique chromatin architecture of HML␣ may relate to the combined requirements of transcriptional repression and recombinational competence.Transcriptional repression of the silent-mating-type loci is fundamental for the haploid yeast life cycle. The a or ␣ mating type is determined by expression of master regulatory genes of the active MAT locus near the centromere of chromosome III. Identical genes present at the HM (haploid mating) loci near the telomeres of the same chromosome, HML carrying ␣ information and HMR bearing a information, are not transcribed, thus preserving the unique mating type. The HM loci serve as donors during the gene interconversion event that allows a homothallic haploid cell to switch mating type, ensuring a diploid population in the wild. In addition to transcriptional repression, the DNA of the silenced HM loci is protected from HO endonuclease, which makes a double-strand break at the MAT HO site to initiate mating-type switching (40,46,55,75).Silencing of the HM-mating-type loci in Saccharomyces cerevisiae is remarkably similar to long-term, epigenetic inactivation of specific genomic domains in complex eukaryotes. Xchromosome inactivation (33) and gene imprinting (82) in mammalian cells, telomeric silencing (22) in yeast, and position effect variegation (reviewed by Henikoff [28]) in Drosophila melanogaster are examples of such parallel situations. Epigenetic states are thought to be achieved by chromosomal condensation into heterochromatin. The molecular events leading to such position-dependent, gene-independent transcriptional repression of a chromosomal region are not well understood. Silencing mechanisms in yeast are likely to involve a r...
Specific microRNAs (miRNAs), including miR-134, localize to neuronal dendrites, where they control synaptic protein synthesis and plasticity. However, the mechanism of miRNA transport is unknown. We found that the neuronal precursor-miRNA-134 (pre-miR-134) accumulates in dendrites of hippocampal neurons and at synapses in vivo. Dendritic localization of pre-miR-134 is mediated by the DEAH-box helicase DHX36, which directly associates with the pre-miR-134 terminal loop. DHX36 function is required for miR-134-dependent inhibition of target gene expression and the control of dendritic spine size. Dendritically localized pre-miR-134 could provide a local source of miR-134 that can be mobilized in an activitydependent manner during plasticity.
Genetic and biochemical evidence implicates chromatin structure in the silencing of the two quiescent mating-type loci near the telomeres of chromosome III in yeast. With high-resolution micrococcal nuclease mapping, we show that the HMRa locus has 12 precisely positioned nucleosomes spanning the distance between the E and I silencer elements. The nucleosomes are arranged in pairs with very short linkers; the pairs are separated from one another by longer linkers of ϳ20 bp. Both the basic amino-terminal region of histone H4 and the silent information regulator protein Sir3p are necessary for the organized repressive chromatin structure of the silent locus. Compared to HMRa, only small differences in the availability of the TATA box are present for the promoter in the cassette at the active MATa locus. Features of the chromatin structure of this silent locus compared to the previously studied HML␣ locus suggest differences in the mechanisms of silencing and may relate to donor selection during mating-type interconversion.The silencing of the haploid mating-type loci is a critical requirement for the yeast life cycle (10). Mating types in the yeast Saccharomyces cerevisiae are defined by a set of genes expressed at the active MAT locus near the center of chromosome III. MATa and MAT␣ differ by approximately 750-bp regions, designated Ya and Y␣, respectively, which contain the promoters for genes encoding the master regulatory proteins that define the unique mating type of the cell. Strains with the MATa allele express the a1 and a2 genes, while strains with the MAT␣ allele express the ␣1 and ␣2 genes. In addition to the active MAT locus, two almost identical HM loci are located near the telomeres of chromosome III. HML␣ is near the left telomere, while HMRa resides near the right telomere. These loci are transcriptionally silent and make no direct contribution to mating type. Rather, they serve as donors during yeast mating-type interconversion, or switching (7).The switching event is initiated by expression of the HO endonuclease. This enzyme recognizes and cleaves doublestranded DNA at a site at MAT. The break is repaired by replacing it with the Y region of one of the HM loci, usually that with information of the opposite mating type (18,22,27,41). Interestingly, identical HO sites present at the silent loci are not recognized by the endonuclease. Thus, DNA at the silent mating-type loci is present in a unique state, in which it is invisible to the endonuclease and transcription machinery but completely competent to participate in a recombinational event.Extensive genetic studies (20) led to a model in which proteins binding to cis-acting DNA elements flanking the loci, a number of interacting, non-DNA binding proteins, and histones cooperate to form a repressive, heterochromatin-like structure that packages DNA in a presumably inaccessible format. Heterochromatic condensation has been implicated in position effect variegation in Drosophila melanogaster (9) and X-chromosome inactivation (13) and gene imprinting...
Dendritic mRNA transport and local translation in the postsynaptic compartment play an important role in synaptic plasticity, learning and memory. Local protein synthesis at the synapse has to be precisely orchestrated by a plethora of factors including RNA binding proteins as well as microRNAs, an extensive class of small non-coding RNAs. By binding to complementary sequences in target mRNAs, microRNAs fine-tune protein synthesis and thereby represent critical regulators of gene expression at the post-transcriptional level. Research over the last years identified an entire network of dendritic microRNAs that fulfills an essential role in synapse development and physiology. Recent studies provide evidence that these small regulatory molecules are highly regulated themselves, at the level of expression as well as function. The importance of microRNAs for correct function of the nervous system is reflected by an increasing number of studies linking dysregulation of microRNA pathways to neurological disorders. By focusing on three extensively studied examples (miR-132, miR-134, miR-138), this review will attempt to illustrate the complex regulatory roles of dendritic microRNAs at the synapse and their implications for pathological conditions.
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