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A unified model of what it takes to be a miRNA gene
The first step of miRNA synthesis is to generate primary miRNAs (pri-miRNAs) through transcription of miRNA genes. pri-miRNA transcripts contain stem loop regions that are then cleaved by the Microprocessor complex to form pre-miRNAs. However, the miRNA features that dictate the choice of step-loops for initial processing is currently unclear.
To understand the sequence and structural features that define pri-miRNAs, Wenwen Fang and David Bartel from Massachusetts Institute of Technology assessed the cleavage efficiencies of over 50,000 variants of three human pri-miRNAs. They found that:
The results presented in this paper provide a simplified and unified model of what it takes to be a miRNA gene, and have demonstrated that these principles can be used to generate artificial pri-miRNAs that can be processed into functional miRNAs.
Read the full paper in Molecular Cell, October 2015.
m6A at the 5’UTR mediates translation during heat shock
N6-methyladenosine (m6A) is the most abundant mRNA modification and is implicated in diverse biological functions. Although the 5’ untranslated region (5’UTR) of miRNAs is relatively less methylated, little is understood about how 5’UTR methylation is regulated.
To understand both the regulation and function of methylation at the 5’UTR, a team led by Shu-Bing Qian from Cornell University, New York sought to understand the impact of heat shock stress on m6A modification in mouse embryonic fibroblasts (MEFs) and HeLa cells. They found that:
These results suggest a role for m6A in mediating mRNA translation independent of the m7G cap. Contrary previous research, this paper indicates that m6A is a dynamic rather than static mark.
Read the full paper in Nature, October 2015.
Panoramix is a Piwi component that is essential for piRNA-dependent silencing
Nuclear Piwi proteins transcriptionally silence transposons in germ cells. This is thought to be dependent on Piwi-interacting RNA (piRNA)-guided recognition of nascent transposon transcripts. However, the components of Piwi effector complexes at target loci is currently unknown.
A team led by Gregory Hannon from the University of Cambridge sought to further understand the precise mechanisms by which nuclear Piwi transcriptionally silences transposons in Drosophila ovaries. They found that:
These results show that CG9754 is a component of Piwi complexes that is essential for piRNA-dependent silencing. The authors name this protein Panoramix after the mentor who empowers the comic book character Asterix and suggest that this protein may act as an adaptor between the piRNA pathway and the general silencing machinery.
Read the full paper in Science, October 2015.
New technique for single-cell ChIP analysis
Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is a widely used method for mapping genome-wide protein-DNA interactions. However, a limitation of this technique is that it provides averaged profiles that are insensitive to variability between individual cells. Consequently, the extent of chromatin-state heterogeneity is currently unexplored.
By combining microfluidics, DNA barcoding and next-generation sequencing, a team led by Bradley Bernstein from Massachusetts General Hospital and the Broad Institute of MIT and Harvard developed a new technique to collect chromatin data at single-cell resolution. The group used this technique to profile lysine methylation in a mixed population of cells. They found that:
This new method with permit the analysis of chromatin states between individual cells and overcomes a major limitation of existing ChIP technologies. Techniques such as this will improve our understanding of the chromatin states of cell populations.
Read the full paper in Nature Biotechnology, October 2015.
Lack of sleep in donors may affect success of hematopoietic stem cell transplantation
Hematopoietic cell transplantation is commonly carried out for various malignant and non-malignant diseases. There is growing evidence of circadian regulation of hematopoietic stem cells (HSCs); however the effect of sleep deprivation on transplantation has not previously been investigated.
A team led by Luis de Lecea from Stanford University, California investigated the effects of sleep deprivation on HSCs. They found that:
The authors have demonstrated that sleep deprivation reduces the success rate of haematopoietic stem cell transplantation in mice and suggests molecular mechanisms underpinning this. The study highlights the potential importance of adequate donor sleep for successful hematopoietic cell transplantation.
Read the full text in Nature Communications, October 2015.
New PRC2 crystal structure determined
Polycomb repressive complex 2 (PRC2) is an important epigenetic regulator that catalyzes histone trimethylation at H3K27. Activity of this complex is stimulated in a positive feedback loop by H3K27me3. Misregulation of PRC2 is implicated in human disease, including some cancers. For example PRC2 activity is inhibited by a histone missense mutation—H3K27M— that is found in certain pediatric brain cancers.
Despite the importance of PRC2 in epigenetic regulation and human disease, very little is known about the structure of this complex. In this paper, Lianying Jiao and Xin Liu from the University of Texas Southwestern Medical Center determined the crystal structure of PRC2 in complex with a stimulating H3K27me3 peptide and a H3K27M cancer mutant. Their structure provided the following mechanistic insights:
This research has uncovered the structural basis for PRC2 activity and regulation. The authors show that regulatory signals are integrated at the active site to enable complex regulation by a large numbers of factors.
Read the full paper and a research summary in Science, October 2015.
Watch our webinar to find out about the role of Polycomb group proteins in cancer.
Differential DNA methylation defines leukemia stem cell subgroups
Acute myeloid leukaemia (AML) is a malignancy of the bone marrow and is initiated by leukemia stem cells (LSCs). Although LSCs are able to engraft in immunodeficient mice, the blast cells LSCs give rise to have lost these stem cell properties. LSCs and blasts are clonally related, suggesting that the differences in properties between these cell types may be conferred by epigenetic variations.
To investigate this possibility, a team led by Andrew Feinberg from John Hopkins University School of Medicine, Maryland looked at the DNA methylation signatures of LSCs and blasts. They found that:
In this paper, the researchers have identified an epigenetic signature that may represent a therapeutic target to improve patient survival in AML.
Read the full paper in Nature Communications, October 2015.
Point mutations in SIRT6 can lead to cancer development
SIRT6 is a sirtuin that has histone deacetylation activity and also acts as a tumor suppressor. Although this protein is often downregulated or deleted in human cancers, no point mutations have previously been identified. This has hindered progress in our understanding of the tumor-suppressive role of SIRT6.
In this paper, a team led by Raul Mostoslavsky from Harvard Medical School, Massachusetts characterize eight tumor-associated point mutations in SIRT6. They found that:
The research presented in this paper provides strong evidence for a tumor-suppressing role of SIRT6 and identifies specific cancer-associated mutations.
Read the full text in Cell Reports, October 2015.