MicroRNAs (miRNAs) perform a variety of functions in insect biology, ranging from cell proliferation and apoptosis, to oogenesis and development. In the cockroach Blatella germanica, miRNAs have been shown to have a role in metamorphosis, with miRNA depletion preventing metamorphosis altogether. However, which miRNAs are involved in metamorphosis regulation, and which targets they act on, is still unknown.
In this study, Jesus Lozano and colleagues from Pompeu Fabra University in Barcelona sought to further understand the precise regulatory roles of miRNAs in insect metamorphosis. The authors found that:
These data indicate that miR-2 family miRNAs permit metamorphosis by scavenging Kr-h1 transcripts during metamorphosis. This highlights an elegant role for a specific miRNA family in regulating insect metamorphosis.
Read the full paper at PNAS, March 2015.
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Hepatitis C virus acts as a sponge to sequester host miR-122
Binding of miR-122, an abundant liver miRNA, to hepatitis C virus (HCV) RNA is required for viral replication due to its role in stimulating protein translation and protecting the HCV RNA from degradation.
In this study, a team led by Charles Rice from Rockefeller University sought to understand the global effects of HCV infection on endogenous miRNA targets. By producing global miRNA:target interaction maps during HCV infection, the authors found that:
This paper demonstrates that HCV acts to sequester miR-122, and that this leads to de-repression of miR-122 targets in the host transcriptome. The authors speculate that miR-122 sequestration in chronic HCV infection might be a molecular link between HCV infection and liver dysfunction.
Read the full paper at Cell, March 2015.
In this study, Claudio Alarcón and colleagues from the Laboratory of Systems Cancer Biology at Rockefeller University investigated the mechanisms involved in DGCR8 recognition and binding to pri-miRNAs. By examining miRNA processing in mammalian cells, the authors found that:
Taken together, these results indicate that METTL3 targets m6A to pre-miRNA sequences, and DGCR8 then interacts with m6A methylated RNA. The paper identifies m6A as a novel regulator of miRNA processing, allowing the microprocessor complex composed of DGCR8 and Drosha to recognize its specific substrates.
Find the full paper in Nature, March 2015.
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CHD8 regulates a network of high risk autism spectrum disorder genes
Loss of function mutations in chromatin modifiers have been shown to be associated with autism spectrum disorder (ASD). In particular, CHD8, a gene encoding chromatin helicase is strongly associated with ASD risk.
Other high risk ASD genes have been identified, and these have been shown to be co-expressed during neurodevelopment.
In this study, a team led by James Noonan from Yale School of Medicine explored the role of CHD8 in regulating ASD risk genes in human neurodevelopment. Using chromatin immunoprecipitation (ChIP) coupled to high-throughput sequencing (ChIP-seq), the authors mapped CHD8 binding sites in the human midfetal brain, neural stem cells and mouse embryonic cortex.
The authors found that:
The data presented in this study provides evidence that CHD8 directly regulates a conserved network of ASD risk genes in human and mouse neurodevelopment, and that loss of CHD8 contributes to ASD by perturbing this gene network.
Read the full paper in Nature Communications, March 2015.
New technique to pinpoint transcription factor binding sites
Understanding how combinations of transcription factors control gene expression requires single-nucleotide mapping of transcription factor binding. Although approaches to achieve this currently exist, ChIP-exo and ChIP-seq are hampered by technical difficulties and resolution issues.
A team led by Julia Zeitlinger at Stower's Institute for Medical Research, Missouri developed ChIP-nexus (chromatin immunoprecipitation experiments with nucleotide resolution through exonuclease, unique barcode and single ligation), a new technique to improve mapping of genome-wide transcription factor binding. This technique combines the standard ChIP-exo protocol with the library preparation protocol from iCLIP to improve the efficiency of incorporating DNA fragments into the library.
To showcase this technique, the authors tested four proteins and found that:
HIV-1 integration into the host genome occurs at the edge of the nucleus
A crucial step in the lifecycle of human immunodeficiency virus type 1 (HIV-1) is its integration into the host genome. Evidence from previous work suggests that HIV-1 integrates into certain transcriptionally active genes; however, how HIV-1 selects target genes has previously not been determined.
To further understand the relevant factors determining HIV-1 integration sites, a team led by Marina Lusic and Mauro Giacca from the International Centre for Genetic Engineering and Biotechnology, Italy used three-dimensional immuno-DNA fluorescence in situ hybridization (FISH) to look at the position of HIV-1 integration sites in the nucleus of CD4+ T cells. They found that:
This paper provides a three-dimensional view of HIV integration into the host genome, and demonstrates that HIV target genes are transcriptionally active and are typically positioned less than 1 µm from the nuclear edge. The authors suggest that it is likely that HIV integrates into the first open chromatin it encounters; a factor likely to be related to the short life of viral integrase.
Read the full paper in Nature, March 2015.
Characterizing enhancer elements using Cas9-histone demethylase
Enhancers are implicated in the regulation of development and cellular function. Although there is a pressing need to functionally annotate cell-type specific enhancers involved in cell function regulation, this has been hindered by a lack of suitable technology.
To combat this, Nicola Kearnes and colleagues from the University of Massachusetts used a nuclease deficient Cas9 (dCas9)-histone demethylase LSD1 fusion to characterize the role of enhancer elements in embryonic stem cell (ESC) fate. They found that:
Neural stem cell diffrerentiation is regulated by long non-coding RNAs
Neural stem cells (NSCs) differentiate to produce intermediate progenitors that divide to become young neurons. Although long non-coding RNAs (lncRNAs) have major biological functions, lncRNAs that control the crucial transition between NSCs and neurogenic progenitors have not been identified.
In this study, Alexander Ramos and colleagues from the University of California, San Francisco investigated the role of a specific lncRNA, Pnky, in neural development. By looking at Pnky function in the embryonic and postnatal brain, the authors found that:
Read the full text in Cell Stem Cell, March 2015.