272 research outputs found
Resolution of the type material of the Asian elephant, Elephas maximus Linnaeus, 1758 (Proboscidea, Elephantidae)
The understanding of Earthâs biodiversity depends critically on the accurate identification and nomenclature of
species. Many species were described centuries ago, and in a surprising number of cases their nomenclature or type
material remain unclear or inconsistent. A prime example is provided by Elephas maximus, one of the most iconic
and well-known mammalian species, described and named by Linnaeus (1758) and today designating the Asian
elephant. We used morphological, ancient DNA (aDNA), and high-throughput ancient proteomic analyses to
demonstrate that a widely discussed syntype specimen of E. maximus, a complete foetus preserved in ethanol, is
actually an African elephant, genus Loxodonta. We further discovered that an additional E. maximus syntype,
mentioned in a description by John Ray (1693) cited by Linnaeus, has been preserved as an almost complete skeleton
at the Natural History Museum of the University of Florence. Having confirmed its identity as an Asian elephant
through both morphological and ancient DNA analyses, we designate this specimen as the lectotype of E. maximus
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Genome-wide determination of drug localization
A vast number of small-molecule ligands, including therapeutic drugs under development and in clinical use, elicit their effects by binding specific proteins associated with the genome. An ability to map the direct interactions of a chemical entity with chromatin genome-wide could provide new and important insights into chemical perturbation of cellular function. Here we describe a method that couples ligand-affinity capture and massively parallel DNA sequencing (Chem-seq) to identify the sites bound by small chemical molecules throughout the human genome. We show how Chem-seq can be combined with ChIP-seq to gain unique insights into the interaction of drugs with their target proteins throughout the genome of tumor cells. These methods provide a powerful approach to enhance understanding of therapeutic action and characterize the specificity of chemical entities that interact with DNA or genome-associated proteins
Methods to study splicing from high-throughput RNA Sequencing data
The development of novel high-throughput sequencing (HTS) methods for RNA
(RNA-Seq) has provided a very powerful mean to study splicing under multiple
conditions at unprecedented depth. However, the complexity of the information
to be analyzed has turned this into a challenging task. In the last few years,
a plethora of tools have been developed, allowing researchers to process
RNA-Seq data to study the expression of isoforms and splicing events, and their
relative changes under different conditions. We provide an overview of the
methods available to study splicing from short RNA-Seq data. We group the
methods according to the different questions they address: 1) Assignment of the
sequencing reads to their likely gene of origin. This is addressed by methods
that map reads to the genome and/or to the available gene annotations. 2)
Recovering the sequence of splicing events and isoforms. This is addressed by
transcript reconstruction and de novo assembly methods. 3) Quantification of
events and isoforms. Either after reconstructing transcripts or using an
annotation, many methods estimate the expression level or the relative usage of
isoforms and/or events. 4) Providing an isoform or event view of differential
splicing or expression. These include methods that compare relative
event/isoform abundance or isoform expression across two or more conditions. 5)
Visualizing splicing regulation. Various tools facilitate the visualization of
the RNA-Seq data in the context of alternative splicing. In this review, we do
not describe the specific mathematical models behind each method. Our aim is
rather to provide an overview that could serve as an entry point for users who
need to decide on a suitable tool for a specific analysis. We also attempt to
propose a classification of the tools according to the operations they do, to
facilitate the comparison and choice of methods.Comment: 31 pages, 1 figure, 9 tables. Small corrections adde
Targeting transcription regulation in cancer with a covalent CDK7 inhibitor
Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.National Institutes of Health (U.S.) (Grant HG002668)National Institutes of Health (U.S.) (Grant CA109901
Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas
RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO4 we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features
Histone H3 globular domain acetylation identifies a new class of enhancers
Histone acetylation is generally associated with active chromatin, but most studies have focused on the acetylation of histone tails. Various histone H3 and H4 tail acetylations mark the promoters of active genes. These modifications include acetylation of histone H3 at lysine 27 (H3K27ac), which blocks Polycomb-mediated trimethylation of H3K27 (H3K27me3). H3K27ac is also widely used to identify active enhancers, and the assumption has been that profiling H3K27ac is a comprehensive way of cataloguing the set of active enhancers in mammalian cell types. Here we show that acetylation of lysine residues in the globular domain of histone H3 (lysine 64 (H3K64ac) and lysine 122 (H3K122ac)) marks active gene promoters and also a subset of active enhancers. Moreover, we find a new class of active functional enhancers that is marked by H3K122ac but lacks H3K27ac. This work suggests that, to identify enhancers, a more comprehensive analysis of histone acetylation is required than has previously been considered
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