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Retinal cell layer uniformity is conferred by miRNA-lncRNA interaction
The retina consists of a series of nuclear layers: the photoreceptor layer resides on the outer part, followed by the inner nuclear and the ganglion cell layers. The thickness of each layer is remarkably uniform, suggesting that allocation of cells is tightly controlled.
To investigate the molecular mechanisms governing uniformity in retinal cell layers, Jacek Krol and colleagues from the Friedrich Miescher Institute for Biomedical Research, ETH Zurich and the University of Basel looked at the role of non-coding RNAs. By investigating the relationship between long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in photoreceptors during mouse postnatal development, they found that:
The authors propose a model in which Crb1 is expressed at a high level in early photoreceptors, ensuring strong adhesion between glia and photoreceptors. After retinal layers reach their final thickness, suppressed expression of Crb1 by miR-183/96/182—which accumulates in response to Rncr4—weakens the adhesion belt.
Read the full paper in Nature Communications, June 2015.
Interested in non-coding RNA research? Take a look at our non-coding RNA and miRNA resources.
DNA is stably 5-fC modified in vivo
5-Formylcytosine (5-fC) is DNA modification produced from the TET enzyme-mediated oxidation of 5-hydroxymethylcytosine (5-hmC), which is in turn produced from the oxidation of 5-methylcytosine (5-mC). Although it is thought that a role of oxidized cytosine bases is to serve as intermediates of enzyme-mediated DNA methylation, it has also been shown that 5-hmC can be a stable DNA modification.
To explore the possibility that 5-fC, too, might be a stable rather than active DNA intermediate, a team led by Shankar Balasubramanian from the University of Cambridge studied the dynamics of 5-fC in genomic DNA in vivo. They found that:
Overall, this research indicates that 5-fC can be a stable DNA modification. As 5-fC has been shown to have a large number of binding proteins and even alter the structure of DNA, the authors argue that stably 5-fC-modified DNA could have profound consequences for gene expression regulation that may be distinct to those caused by 5-mC and 5-hmC.
Read the full paper in Nature Chemical Biology, June 2015.
Pseudouridine is a widespread and dynamic mRNA modification
Out of over 100 known RNA modifications, pseudouridine (Ψ) is the most abundant. This modification is already known to have numerous roles, including in translational fidelity and mRNA splicing; however, its prevalence and function in mRNA is poorly understood.
mRNA is present in low amounts, and this creates a technical challenge for detecting transcriptome-wide pseudouridylation events. By developing a new pseudouridylation profiling method (CeU-seq) that uses biotin pulldown to pre-enrich Ψ-containing RNA, Xiaoyu Li and colleagues from Peking University found that:
The data presented in this paper have highlighted that Ψ is widespread and dynamically regulated on mRNA as well as other forms of RNA. By developing a new technique for the detection of pseudouridylation on mRNA, the authors have paved the way for future studies to further understand the biological relevance of this widespread RNA modification.
Read the full paper in Nature Chemical Biology, June 2015.
Intasome lifts DNA from the histone surface to allow retroviral integration
Retroviruses have the ability to integrate into nucleosomal DNA, despite the limited availability of nucleosomes and constraints to DNA conformation. Retroviral integration is catalyzed by the intasome complex, which is associated with the ends of viral DNA. However, how the intasome interfaces with chromosomal DNA to allow retroviral integration into nucleosomes is currently unknown.
Using single-particle cryo-electron microscopy, a team led by Peter Cherepanov from the Francis Crick Institute and Imperial College London determined the structure of the prototype foamy virus (PFV) intasome-nucleosome interface. They found that:
This research suggests a molecular basis for the capture of nucleosomal DNA by the intasome, and demonstrates that by lifting DNA from the histone surface, retroviral integration can be achieved within relatively inaccessible nucleosomes.
Read the full paper in Nature, June 2015.
Extensive epigenetic reprogramming of human primordial germ cells
Epigenetic reprogramming of mammalian primordial germ cells (PGCs) restores full germline potency and erases genomic imprints and epimutations, making it essential for development.
To investigate epigenetic reprogramming in the human germline, a team led by Azim Surani studied transcriptome transitions and epigenetic reprogramming in week 4–9 human PCGs (hPCGs) in vivo, and in an in vitro model for hPGC-like cells (hPGCLCs). They found that:
Overall, this paper has established that a distinct network of gene regulation results in extensive epigenetic reprogramming in hPGCs. The finding that certain loci can escape DNA demethylation suggests that these might be candidates for transgenerational epigenetic inheritance.
Read the full paper in Cell, June 2015.
Interested in epigenetics and development? Watch our webinar on epigenetic mechanisms in early mammalian development.
Long non-coding RNAs are differentially expressed in the developing and adult brain
The mammalian brain is enormously complex, and brain development relies on specification and differentiation of an array of different neuronal and glial cell types. Long non-coding RNAs (lncRNAs) have been implicated in this process; however, the in vivo expression dynamics and molecular pathways regulated by these loci are unclear.
To shed some light on the role of lncRNAs in brain development, a team led by John Rinn from Harvard University developed a map of lncRNA expression dynamics and regulatory effects in the developing and mature mouse brain. By investigating 13 null mutant mouse models, the team found that:
These results show that lncRNAs are differentially expressed in time and space and in certain cases can affect the expression of neighboring protein coding genes. These data pave the way for future research into the functional relevance of these genes in neural development and disease.
Read the full paper in PNAS, June 2015.
Interested in finding out more about John Rinn's research? Read our interview.
Link between histone modifications and DNA methylation in embryonic stem cells
DNA methylation and histone modification are two prominent forms of epigenetic regulation. There is evidence that these two distinct modifications are linked, but detailed mechanistic and functional links between the two have not previously been established.
To investigate the relationship between histone modifications and DNA methylation, a team led by David Allis from the Rockefeller University solved a 2.4 crystal structure of the ATRX-DNMT3-DNMT3L domain of Dnmt3a (ADD3a) in complex with the histone H3 N-terminus. They found that:
The structure-based approach taken by the authors in this paper has highlighted the important link between histone modifications and DNA methylation, and has given insights into the role of histone modifications in establishing DNA methylation patterns.
View the full paper in Molecular Cell, June 2015.
A new role for H2A.Z.2 in malignant melanoma
Histone H2A.Z is a highly conserved variant of H2A, and has two separate isoforms; H2A.Z.1 and H2A.Z.2. Isoform-specific functions remain unclear and previous investigations into these isoforms have either focused on H2A.Z.1 or not differentiated between isoforms.
A team led by Emily Bernstein from Icahn School of Medicine at Mount Sinai investigated the role of H2A.Z.1 in malignant melanoma. They found that:
The research presented in this study shows H2A.Z.1 and H2A.Z.2 to have different roles in melanoma. Melanoma is a notoriously hard to treat form of cancer, and these results suggest that BET inhibition in combination with H2A.Z.2 depletion may form the basis of a future therapy effective melanoma therapy.
Read the full paper in Molecular Cell, June 2015.