Michelle Mei Fung Chan

A unique regulatory phase of DNA methylation in the early mammalian embryo

DNA methylation is highly dynamic during mammalian embryogenesis. It is broadly accepted that the paternal genome is actively depleted of 5-methylcytosine at fertilization, followed by passive loss that reaches a minimum at the blastocyst stage. However, this model is based on limited data, and so far no base-resolution maps exist to support and refine it. Here we generate genome-scale DNA methylation maps in mouse gametes and from the zygote through post-implantation. We find that the oocyte already exhibits global hypomethylation, particularly at specific families of long interspersed element 1 and long terminal repeat retroelements, which are disparately methylated between gametes and have lower methylation values in the zygote than in sperm. Surprisingly, the oocyte contributes a unique set of differentially methylated regions (DMRs)—including many CpG island promoters—that are maintained in the early embryo but are lost upon specification and absent from somatic cells. In contrast, sperm-contributed DMRs are largely intergenic and become hypermethylated after the blastocyst stage. Our data provide a genome-scale, base-resolution timeline of DNA methylation in the pre-specified embryo, when this epigenetic modification is most dynamic, before returning to the canonical somatic pattern.

DNA methylation dynamics of the human preimplantation embryo.

In mammals, cytosine methylation is predominantly restricted to CpG dinucleotides and stably distributed across the genome, with local, cell-type-specific regulation directed by DNA binding factors. This comparatively static landscape is in marked contrast with the events of fertilization, during which the paternal genome is globally reprogrammed. Paternal genome demethylation includes the majority of CpGs, although methylation remains detectable at several notable features. These dynamics have been extensively characterized in the mouse, with only limited observations available in other mammals, and direct measurements are required to understand the extent to which early embryonic landscapes are conserved. We present genome-scale DNA methylation maps of human preimplantation development and embryonic stem cell derivation, confirming a transient state of global hypomethylation that includes most CpGs, while sites of residual maintenance are primarily restricted to gene bodies. Although most features share similar dynamics to those in mouse, maternally contributed methylation is divergently targeted to species-specific sets of CpG island promoters that extend beyond known imprint control regions. Retrotransposon regulation is also highly diverse, and transitions from maternally to embryonically expressed elements. Together, our data confirm that paternal genome demethylation is a general attribute of early mammalian development that is characterized by distinct modes of epigenetic regulation.

Assessment of metagenomic assembly using simulated next generation sequencing data

Due to the complexity of the protocols and a limited knowledge of the nature of microbial communities, simulating metagenomic sequences plays an important role in testing the performance of existing tools and data analysis methods with metagenomic data. We developed metagenomic read simulators with platform-specific (Sanger, pyrosequencing, Illumina) base-error models, and simulated metagenomes of differing community complexities. We first evaluated the effect of rigorous quality control on Illumina data. Although quality filtering removed a large proportion of the data, it greatly improved the accuracy and contig lengths of resulting assemblies. We then compared the quality-trimmed Illumina assemblies to those from Sanger and pyrosequencing. For the simple community (10 genomes) all sequencing technologies assembled a similar amount and accurately represented the expected functional composition. For the more complex community (100 genomes) Illumina produced the best assemblies and more correctly resembled the expected functional composition. For the most complex community (400 genomes) there was very little assembly of reads from any sequencing technology. However, due to the longer read length the Sanger reads still represented the overall functional composition reasonably well. We further examined the effect of scaffolding of contigs using paired-end Illumina reads. It dramatically increased contig lengths of the simple community and yielded minor improvements to the more complex communities. Although the increase in contig length was accompanied by increased chimericity, it resulted in more complete genes and a better characterization of the functional repertoire. The metagenomic simulators developed for this research are freely available.

Mouse Ooplasm Confers Context-Specific Reprogramming Capacity

Enucleated oocytes have the distinctive ability to reprogram somatic nuclei back to totipotency. Here, we investigate genome-scale DNA methylation patterns after nuclear transfer and compare them to the dynamics at fertilization. We identify specific targets for DNA demethylation after nuclear transfer, such as germline-associated promoters, as well as unique limitations that include certain repetitive element classes.

Ashy dermatosis (erythema dyschromicum perstans) induced by omeprazole: a report of three cases.

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Correction: Evolutionary principles of modular gene regulation in yeasts

[This corrects the article DOI: 10.7554/eLife.00603.].

Treatment and outcomes of melanoma in Asia: Results from the National Cancer Centre Singapore.

Acral melanoma (AM) and mucosal melanoma (MM) make up more than half of melanomas in Asia but comprise only 5% of cases in Caucasians, where cutaneous melanoma (CM) predominates. AM and MM are thought to be genetically and biologically distinct from CM. We report the characteristics and outcomes of melanoma patients from the National Cancer Centre Singapore.

Acute Generalized Exanthematous Pustulosis Caused by Daptomycin

Daptomycin, a lipopeptide antibiotic with similar action as vancomycin, is used to treat complicated skin and soft tissue infections caused by resistant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, penicillin-resistant streptococci, and vancomycin-resistant enterococci. Acute generalized exanthematous pustulosis (AGEP), characterized by acute onset of numerous sterile, nonfollicular pinhead sized pustules, is common secondary to drugs, in particular, antibiotics. We present the first case of AGEP following the use of daptomycin.

An Unusual Cause of Headache and Sudden Death of a Young Sailor—Postmortem Computed Tomography and Histological Findings of a Fatal Retroperitoneal Malignant Mixed Germ Cell Tumor

A 26‐year‐old Caucasian sailor, with no past medical history aside from headache for the last 1 week, was found dead in his cabin. The body was stored in a refrigerator on board and disembarked for autopsy 3 days later. Autopsy showed a large, nodular, necrotic and hemorrhagic retroperitoneal mass, and smaller hemorrhagic nodules in the brain, lungs, liver, and left kidney, with the brain being markedly edematous. Both testes were descended and normal. Histologically, the retroperitoneal mass showed a malignant mixed germ cell tumor comprising choriocarcinoma, embryonal carcinoma, and teratoma components. Retroperitoneal extragonadal germ cell tumors are uncommon, and this case of a young male who presented with headache and sudden death due to metastases is extremely rare.

Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma Presenting with Vaginal Sloughing and Ulcerated Skin Nodule

Malignant lymphomas presenting in the female genital tract are extremely rare. We report a case of Epstein‐Barr virus associated diffuse large B‐cell lymphoma of the genital tract and skin in a 60‐year‐old woman on long‐term azathioprine.