Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes

SummarySomatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC−/− background. XPC−/− cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk

Chinese journals: a guide for epidemiologists.

Chinese journals in epidemiology, preventive medicine and public health contain much that is of potential international interest. However, few non-Chinese speakers are acquainted with this literature. This article therefore provides an overview of the contemporary scene in Chinese biomedical journal publication, Chinese bibliographic databases and Chinese journals in epidemiology, preventive medicine and public health. The challenge of switching to English as the medium of publication, the development of publishing bibliometric data from Chinese databases, the prospect of an Open Access publication model in China, the issue of language bias in literature reviews and the quality of Chinese journals are discussed. Epidemiologists are encouraged to search the Chinese bibliographic databases for Chinese journal articles.Published versio

Transcriptional Profiling of the Dose Response: A More Powerful Approach for Characterizing Drug Activities

The dose response curve is the gold standard for measuring the effect of a drug treatment, but is rarely used in genomic scale transcriptional profiling due to perceived obstacles of cost and analysis. One barrier to examining transcriptional dose responses is that existing methods for microarray data analysis can identify patterns, but provide no quantitative pharmacological information. We developed analytical methods that identify transcripts responsive to dose, calculate classical pharmacological parameters such as the EC50, and enable an in-depth analysis of coordinated dose-dependent treatment effects. The approach was applied to a transcriptional profiling study that evaluated four kinase inhibitors (imatinib, nilotinib, dasatinib and PD0325901) across a six-logarithm dose range, using 12 arrays per compound. The transcript responses proved a powerful means to characterize and compare the compounds: the distribution of EC50 values for the transcriptome was linked to specific targets, dose-dependent effects on cellular processes were identified using automated pathway analysis, and a connection was seen between EC50s in standard cellular assays and transcriptional EC50s. Our approach greatly enriches the information that can be obtained from standard transcriptional profiling technology. Moreover, these methods are automated, robust to non-optimized assays, and could be applied to other sources of quantitative data

Use of alternate promoters for tissue-specific expression of the gene coding for connexin32

The promoter of rat connexin32 (Cx32), the gap junction protein found in liver, was studied in transgenic mice. Cx32 transgenes, containing 2.5-kb of sequence upstream from the promoter, exon I, the entire 6.1-kb intron and the beginning of the coding sequence linked to the gene encoding luciferase (Luc), were found to be expressed in mouse in the same tissue-specific manner as previously reported for Cx32. Another construct lacking the promoter, but retaining 1.8 kb from the 3′ end of the intron, was found to be expressed specifically in the nervous system. This result suggested that a second promoter, different from that used in liver, functions in nervous tissue. The use of this promoter in normal rats was corroborated by sequence analysis of reverse-transcribed PCR products obtained from rat nervous tissue RNA. The second promoter drives the synthesis of a second Cx32 mRNA species that is processed to remove a small 345-bp intron that shares its acceptor splice site with the large intron. This finding could have implications for the genetic basis of the X-linked form of Charcot-Marie-Tooth disease (CMT-X) in those patients that do not exhibit mutations in the Cx32-coding region