Deletion of Induces Xanthinuria with Obstructive Nephropathy and Major Metabolic Disorders in Mice.

Background: Xanthinuria type II is a rare autosomal purine disorder. This recessive defect of purine metabolism remains an under-recognized disorder.

Methods: Mice with targeted disruption of the molybdenum cofactor sulfurase () gene were generated to enable an integrated understanding of purine disorders and evaluate pathophysiologic functions of this gene which is found in a large number of pathways and is known to be associated with autism.

Genetic interactions of G-quadruplexes in humans.

G-quadruplexes (G4) are alternative nucleic acid structures involved in transcription, translation and replication. Aberrant G4 formation and stabilisation is linked to genome instability and cancer. G4 ligand treatment disrupts key biological processes leading to cell death.

lncRNA Spehd Regulates Hematopoietic Stem and Progenitor Cells and Is Required for Multilineage Differentiation.

Long non-coding RNAs (lncRNAs) show patterns of tissue- and cell type-specific expression that are very similar to those of protein coding genes and consequently have the potential to control stem and progenitor cell fate decisions along a differentiation trajectory. To understand the roles that lncRNAs may play in hematopoiesis, we selected a subset of mouse lncRNAs with potentially relevant expression patterns and refined our candidate list using evidence of conserved expression in human blood lineages. For each candidate, we assessed its possible role in hematopoietic differentiation in vivo using competitive transplantation.

Erratum: Asparagine bioavailability governs metastasis in a model of breast cancer.

This corrects the article DOI: 10.1038/nature25465.

Asparagine bioavailability governs metastasis in a model of breast cancer.

Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites. A combination of differential expression and focused in vitro and in vivo RNA interference screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, asparagine synthetase expression in a patient's primary tumour was most strongly correlated with later metastatic relapse.

lncRNA requirements for mouse acute myeloid leukemia and normal differentiation.

A substantial fraction of the genome is transcribed in a cell-type-specific manner, producing long non-coding RNAs (lncRNAs), rather than protein-coding transcripts. Here, we systematically characterize transcriptional dynamics during hematopoiesis and in hematological malignancies. Our analysis of annotated and de novo assembled lncRNAs showed many are regulated during differentiation and mis-regulated in disease.

A CRISPR Resource for Individual, Combinatorial, or Multiplexed Gene Knockout.

We have combined a machine-learning approach with other strategies to optimize knockout efficiency with the CRISPR/Cas9 system. In addition, we have developed a multiplexed sgRNA expression strategy that promotes the functional ablation of single genes and allows for combinatorial targeting. These strategies have been combined to design and construct a genome-wide, sequence-verified, arrayed CRISPR library.

A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis.

Cancer metastasis requires that primary tumour cells evolve the capacity to intravasate into the lymphatic system or vasculature, and extravasate into and colonize secondary sites. Others have demonstrated that individual cells within complex populations show heterogeneity in their capacity to form secondary lesions. Here we develop a polyclonal mouse model of breast tumour heterogeneity, and show that distinct clones within a mixed population display specialization, for example, dominating the primary tumour, contributing to metastatic populations, or showing tropism for entering the lymphatic or vasculature systems.

A computational algorithm to predict shRNA potency.

The strength of conclusions drawn from RNAi-based studies is heavily influenced by the quality of tools used to elicit knockdown. Prior studies have developed algorithms to design siRNAs. However, to date, no established method has emerged to identify effective shRNAs, which have lower intracellular abundance than transfected siRNAs and undergo additional processing steps.