Early experiences affect brain function and behavior at adulthood. Being reared in a communal nest (CN), consisting of a single nest where three mothers keep their pups together and share care-giving behavior from birth to weaning (postnatal day [PND] 25), provides an highly socially stimulating environment to the developing pup. Communal nest characterizes the natural ecologic niche of many rodent species including the mouse. At adulthood, CN reared mice, compared to mice reared in standard nesting laboratory condition (SN), show an increase in BDNF protein levels and longer survival of BrdU-positive cells in the hippocampus. Open field and elevated plus maze results indicate that CN mice, although showing levels of exploratory and locomotor activity similar to those of SN mice, displayed increased anxiety-like behavior, performing more thigmotaxis in the open field and spending less time in the open arms of the plus maze. Furthermore, CN mice displayed higher levels of immobility behavior in the forced swim test. Overall, these findings show that CN, an highly stimulating early social environment, increases adult neuronal plasticity, as suggested by high BDNF levels and augmented number of newly generated cells in the hippocampus, which is associated to an increased anxiety- and "depression"-like behavior. These findings are discussed in the framework of the neurotrophin hypothesis of depression.

Myc is a well-known transcription factor with important roles in cell cycle, apoptosis, and cellular transformation. Long noncoding RNAs (lncRNAs) have recently emerged as an important class of regulatory RNAs. Here, we show that lncRNAs are a main component of the Myc-regulated transcriptional program using the P493-6 tetracycline-repressible myc model. We demonstrate that both Myc-induced mRNAs and lncRNAs are significantly enriched for Myc binding sites. In contrast to Myc-repressed mRNAs, Myc-repressed lncRNAs are significantly enriched for Myc binding sites. Subcellular localization analysis revealed that compared to mRNAs, lncRNAs more often have a specific subcellular localization with a markedly higher percentage of nuclear enrichment within the Myc-repressed lncRNA set. Parallel analysis of differentially expressed lncRNAs and mRNAs identified 105 juxtaposed lncRNA-mRNA pairs, indicative for regulation in cis. To support the potential relevance of the Myc-regulated lncRNAs in cellular transformation, we analyzed their expression in primary Myc-high and Myc-low B-cell lymphomas. In total, 54% of the lncRNAs differentially expressed between the lymphoma subsets were identified as Myc-regulated in P493-6 cells. This study is the first to show that lncRNAs are an important factor within the Myc-regulated transcriptional program and indicates a marked difference between Myc-repressed lncRNAs and mRNAs.-Winkle, M., van den Berg, A., Tayari, M., Sietzema, J., Terpstra, M., Kortman, G., de Jong, D., Visser, L., Diepstra, A., Kok, K., Kluiver, J. Long noncoding RNAs as a novel component of the Myc transcriptional network. FASEB J. 29, 2338-2346 (2015). www.fasebj.org

Clear cell renal cell carcinomas are characterized by 3p loss, and by inactivation of Von Hippel Lindau (VHL), a tumorsuppressor gene located at 3p25. Recently, SETD2, located at 3p21, was identified as a new candidate ccRCC tumor-suppressor gene. The combined mutational frequency in ccRCC tumors of VHL and SETD2 suggests that there are still undiscovered tumor-suppressor genes on 3p. We screened all genes on 3p for mutations in 10 primary ccRCC tumors using exome-sequencing. We identified inactivating mutations in VHL, PBRM1, and BAP1. Sequencing of PBRM1 in ccRCC-derived cell lines confirmed its frequent inactivation in ccRCC. PBRM1 encodes for BAF180, the chromatin targeting subunit of the SWI/SNF complex. BAP1 encodes for BRCA1 associated protein-1, involved in histone deubiquitination. Taken together, the accumulating data suggest an important role for aberrant chromatin regulation in ccRCC development.

Primary human cells from different donors vary in their susceptibility to in vitro infection with HIV-1. In order to perform genetic analysis to identify host factors that affect HIV-1 susceptibility, it is important that a clear phenotype is defined. Here, we report a standardized method to study variation for in vitro HIV-1 infection in monocyte-derived macrophages (MDM) from large numbers of individuals. With this assay, HIV-1 susceptibility of MDM from 489 different donors shows more than 3 log variation and a good correlation with the 32 base pair deletion in the CCR5 co-receptor (ccr5 Delta 32 genotype) of the donors. However, in 7 of 12 donors completely resistant to infection with CCR5-using HIV-1, this was not explained by the ccr5 Delta 32 genotype, showing evidence that other host factors are likely to influence HIV-1 replication in MDM. Infections with VSV-G pseudotyped HIV-1 indeed confirmed the existence of post-entry level restrictions in MDM.