Nuclear factor I-A represses expression of the cell adhesion molecule L1

<p>Abstract</p> <p>Background</p> <p>The neural cell adhesion molecule L1 plays a crucial role in development and plasticity of the nervous system. Neural cells thus require precise control of L1 expression.</p> <p>Results</p> <p>We identified a full binding site for nuclear factor I (NFI) transcription factors in the regulatory region of the mouse <it>L1 </it>gene. Electrophoretic mobility shift assay (EMSA) showed binding of nuclear factor I-A (NFI-A) to this site. Moreover, for a brain-specific isoform of NFI-A (NFI-A bs), we confirmed the interaction <it>in vivo </it>using chromatin immunoprecipitation (ChIP). Reporter gene assays showed that in neuroblastoma cells, overexpression of NFI-A bs repressed L1 expression threefold.</p> <p>Conclusion</p> <p>Our findings suggest that NFI-A, in particular its brain-specific isoform, represses <it>L1 </it>gene expression, and might act as a second silencer of L1 in addition to the neural restrictive silencer factor (NRSF).</p

A system to extract abbreviation-expansion pairs from biomedical literature

We present a system to identify abbreviation expansion pairs from scientific articles. We work with the Genomics track of the TREC collection. Authors report abbreviations in two places - an abbreviations section and within the body of a scientific article. Articles with an abbreviations section had fewer abbreviations than those that did not have an abbreviations section (an average of 7.1 versus 13.2 abbreviations per article). For articles that do have an abbreviations section, authors report 98.2% of the abbreviations present in the document in that section. Inspired by Schwartz & Hearst's earlier work our program identified 2.1 million abbreviations from 162,259 documents. A manual inspection of a randomly selected set of articles revealed that our system achieved 86.7% precision and 81.9% recall

L1CAM expression in endometrial carcinomas is regulated by usage of two different promoter regions

<p>Abstract</p> <p>Background</p> <p>The L1 cell adhesion molecule (L1CAM) was originally identified as a neural adhesion molecule involved in axon guidance. In many human epithelial carcinomas L1CAM is overexpressed and thereby augments cell motility, invasion and metastasis formation. L1CAM positive carcinomas are associated with bad prognosis. Recent data point out that L1CAM is regulated in a fashion similar to epithelial-mesenchymal transition (EMT). Previous studies have implied the transcription factors Slug and/or β-catenin in <it>L1CAM </it>transcriptional regulation. However, the regulation of human L1CAM expression at the transcriptional level is not well understood.</p> <p>Results</p> <p>To better understand the molecular basis of <it>L1CAM </it>transcriptional regulation, we carried out a detailed characterization of the human <it>L1CAM </it>promoter. We identified two transcription start sites, the first in front of a non-translated exon 0 (promoter 1) and the other next to the first protein-coding exon 1 (promoter 2). Both sites could be verified in endometrial carcinoma (EC) cell lines and appear to be used in a cell-type specific manner. The two identified promoter regions showed activity in luciferase reporter assays. Chromatin-IP analyses confirmed the <it>in silico </it>predicted E-boxes, binding sites for transcription factors Snail and Slug, as well as Lef-1 sites, which are related to β-catenin-mediated transcriptional regulation, in both promoters. Overexpression of β-catenin exclusively augmented activity of promoter 1 whereas Slug enhanced promoter 1 and 2 activity suggesting that both promoters can be active. Overexpression of β-catenin or Slug could upregulate L1CAM expression in a cell-type specific manner.</p> <p>Conclusions</p> <p>Our results, for the first time, provide evidence that the L1CAM gene has two functionally active promoter sites that are used in a cell-type specific manner. Slug and β-catenin are involved <it>L1CAM </it>transcriptional regulation. Nevertheless, Slug rather than β-catenin levels are correlated with L1CAM expression in EC cell lines. Our findings suggest that the <it>L1CAM </it>transcriptional regulation is more complex than anticipated and this study provides the basis for a better understanding of L1CAM regulation in non-neuronal/tumor cells.</p

Local regulation of DNA methylation by the transcription factor REST

Transcriptional regulation in eukaryotes is realized through intricate interactions between transcription factors and chromatin. DNA methylation constitutes a chromatin modification that is associated with transcriptional silencing (Deaton and Bird, 2011). Whole-genome methylation profiling in mammals has revealed widespread cytosine methylation with characteristic hypomethylation at cis-regulatory elements. Hypomethylation is typically present within CpG islands and distal CpG-poor regions (Stadler et al., 2011). Previous investigations have shown, that some DNA-binding factors like the RE1-silencing transcription factor (REST) directly reduce methylation at these sites. However, how DNA-binding factors mediate such local methylation changes remains largely unknown. Hence, I studied the regulation of DNA methylation by the transcription factor REST in mouse embryonic stem cells (mESCs). I ectopically expressed different REST mutants and profiled DNA methylation at distal REST binding sites. While the full-length protein is necessary and sufficient to reduce methylation at its binding sites, REST’s DNA-binding domain lacks this ability. Instead, hypomethylation at binding sites required DNA-binding factors with interaction domains. The N-terminal REST mutant for example recruits SIN3A to binding sites and shows strong DNA demethylation ability. These experiments suggest that hypomethylation is not an obligatory consequence of protein binding, but rather requires interaction domains, reflecting the potential involvement of cofactors. I inquired whether TET enzymes contribute to reduced methylation within REST binding sites. Complete Tet1/2/3 deficiency in mouse stem cells caused a strong localized hypermethylation in the immediate vicinity of the REST motif. Whether TET proteins are recruited to REST binding sites through common cofactors or indirect mechanisms remains to be determined. I also characterized chromatin accessibility and nucleosome positioning in the different REST mutant re-expression cells. Interestingly, REST mutants that were competent to decrease DNA methylation also increased chromatin accessibility and nucleosome positioning. This could potentially link the chromatin remodeling ability of transcription factors to hypomethylation around binding sites. In summary, the presented study dissected REST induced methylation patterns around binding sites and described several of its required molecular components. This presents an example for a dynamic interplay between genetic and epigenetic information