Volume 43 Issue 7, July 2011

Large-scale mapping of chromatin state and transcription factor binding have uncovered many broad chromatin domains along linear genomic DNA, but it is unclear how these functional domains are organized in three-dimensional nuclear space. A new study now shows that many domains exist as loops connected by CCTC-binding factor (CTCF), providing new insights into the higher-order structure of chromatin organization in the nucleus.

Transcription of genomic loci containing protein-coding genes often yields not only cognate mRNAs but also assorted noncoding RNAs (ncRNAs), which typically map in the vicinity of transcription start sites. A new study shows that far from being random byproducts of gene expression, many long ncRNAs (lncRNAs) are synthesized in a coordinate fashion and control important cellular processes, such as survival in the face of DNA damage.

Although there are only 22,000 human genes, most express multiple mRNA isoforms through alternative splicing and selection of alternative 5′ and 3′ ends. A new study identifies the role of alternative splicing in maintaining neuronal excitability in the adult mouse brain.

David Wong, Howard Chang and colleagues report the identification of long noncoding RNAs transcribed from the promoters of cell cycle genes. Many of these RNAs have periodic expression during the cell cycle and are regulated by oncogenic stimuli, stem cell differentiation or DNA damage.

Chia-Lin Wei, Yijun Ruan and colleagues used chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) to determine the CTCF-chromatin interactome in mouse embryonic stem cells.

Stefan Somlo and colleagues show that the polycystic liver disease genes Prkcsh and Sec63 are required for the proper biogenesis of polycystin complexes. They further show that a Pkd1 transgene can rescue the cystic phenotype of Prkcsh and Sec63 mutant mice, identifying polycystin-1 as the central determinant of cyst formation.

Fernando Pardo-Manuel de Villena, Gary Churchill and colleagues provide a high-resolution phylogenetic map of mouse inbred strains based on comparisons to wild-caught mice. They show that the genomes of classical strains are overwhelmingly derived from Mus musculus domesticus whereas wild-derived laboratory strains include a broad sampling of diversity from multiple subspecies with pervasive introgression. The subspecific origin, haplotype diversity and identity-by-descent map of laboratory strains can be visualized at http://msub.csbio.unc.edu/PhylogenyTool.html.

Balázs Papp and colleagues construct a genetic interaction map of yeast metabolism and use a genome-scale systems biology model to examine the structure of the metabolic network. They use an automated machine-learning method to reconcile differences between the experimental and computational genetic interaction maps. In contrast to previous studies, they do not find evidence for prevalent positive interactions in essential metabolic genes.

Alberto Cascón, Mercedes Robledo and colleagues show that MAX germline mutations confer susceptibility to hereditary pheochromocytoma. This finding supports a key role for MAX and its interaction partners in tumors of neural crest cell origin.

Marc Ladanyi and colleagues show that the nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma (MPM). They further show that knockdown of BAP1 in MPM cell lines affects E2F and Polycomb target genes, implicating transcriptional deregulation in disease pathogenesis.

Hans-Guido Wendel and colleagues identify five miRNAs that are capable of promoting T-ALL in a mouse model and that account for the majority of miRNA expression in human T-ALL. They show that these miRNAs produce overlapping and cooperative effects on tumor suppressor genes implicated in the pathogenesis of T-ALL.

Dongxin Lin and colleagues report a genome-wide association study for esophageal squamous-cell carcinoma in Chinese populations. They identify three new susceptibility loci at 5q11, 6p21 and 21q22.

Omar Albagha, Stuart Ralston and colleagues report the identification of three new loci associated with risk for Paget's disease of bone.

Xue-Jun Zhang, Zhi-Rong Yao and colleagues report a genome-wide association study for atopic dermatitis in the Chinese Han population. They identified two new susceptibility loci at 5q22 and 20q13.

Markus Schürks and colleagues report a genome-wide association study for common migraine. They identify three new susceptibility loci at PRDM16, TRPM8 and LRP1.

Gerard Schellenberg and colleagues report a genome-wide association study for progressive supranuclear palsy, a movement disorder with prominent tau neuropathology. They identified three new risk loci and confirmed the known risk locus at MAPT.

The Rbfox family of RNA binding proteins mediate alternative splicing. Douglas Black and colleagues show that targeted deletion of the mouse Rbfox1 gene in the CNS alters splice isoforms of a subset of genes and is associated with neural hyperexcitability with spontaneous and drug-induced seizures.

Matthew Hurles and colleagues report the first direct comparative analysis of male and female germline mutation rates from whole-genome sequences of two parent-offspring trios sequenced as part of the 1000 Genomes Project. They identify variation in paternal and maternal mutation rates between these two families.

Xiaofeng Cao and colleagues report that REF6 is a histone H3 lysine 27 demethylase in Arabidopsis. REF6 demethylates H3K27me3 and H3K27me2 and ref6 mutant plants resemble mutations in H3K27me3-mediated gene silencing.