Despite biochemical and genetic data suggesting that E2F and pRB (pocket protein) families regulate transcription via chromatin-modifying factors, the precise mechanisms underlying gene regulation by these protein families have not yet been defined in a physiological setting. In this study, we have investigated promoter occupancy in wild-type and pocket protein-deficient primary cells. We show that corepressor complexes consisting of histone deacetylase (HDAC1) and mSin3B were specifically recruited to endogenous E2F-regulated promoters in quiescent cells. These complexes dissociated from promoters once cells reached late G 1 , coincident with gene activation. Interestingly, recruitment of HDAC1 complexes to promoters depended absolutely on p107 and p130, and required an intact E2F-binding site. In contrast, mSin3B recruitment to certain promoters did not require p107 or p130, suggesting that recruitment of this corepressor can occur via E2F-dependent and -independent mechanisms. Remarkably, loss of pRB had no effect on HDAC1 or mSin3B recruitment. p107/p130 deficiency triggered a dramatic loss of E2F4 nuclear localization as well as transcriptional derepression, which is suggested by nucleosome mapping studies to be the result of localized hyperacetylation of nucleosomes proximal to E2F-binding sites. Taken together, these findings show that p130 escorts E2F4 into the nucleus and, together with corepressor complexes that contain mSin3B and/or HDAC1, directly represses transcription from target genes as cells withdraw from the cell cycle.

We performed a genome scan at an average resolution of 8 cM in 719 Finnish sib pairs with type 2 diabetes. Our strongest results are for chromosome 20, where we observe a weighted maximum LOD score (MLS) of 2.15 at map position 69.5 cM from pter and secondary weighted LOD-score peaks of 2.04 at 56.5 cM and 1.99 at 17.5 cM. Our next largest MLS is for chromosome 11 (MLS = 1.75 at 84.0 cM), followed by chromosomes 2 (MLS = 0.87 at 5.5 cM), 10 (MLS = 0.77 at 75.0 cM), and 6 (MLS = 0.61 at 112.5 cM), all under an additive model. When we condition on chromosome 2 at 8.5 cM, the MLS for chromosome 20 increases to 5.50 at 69.0 cM (P=.0014). An ordered-subsets analysis based on families with high or low diabetes-related quantitative traits yielded results that support the possible existence of disease-predisposing genes on chromosomes 6 and 10. Genomewide linkage-disequilibrium analysis using microsatellite marker data revealed strong evidence of association for D22S423 (P=.00007). Further analyses are being carried out to confirm and to refine the location of these putative diabetes-predisposing genes.

Over the past half-century, we have gained significant insights into the molecular biology of long-term memory storage at the level of the synapse. In recent years, our understanding of the cellular architecture supporting long-term memory traces has also substantially improved. However, the molecular biology of consolidation at the level of neuronal systems has been relatively neglected. In this opinion article, we first examine our current understanding of the cellular mechanisms of synaptic consolidation. We then outline areas requiring further investigation on how cellular changes contribute to systems consolidation. Finally, we highlight recent findings on the cellular architecture of memory traces in rodents and how the application of new technologies will expand our understanding of systems consolidation at the neural circuit level. In the coming years, this research focus will be critical for understanding the evolution of long-term memories and for enabling the development of novel therapeutics which embrace the dynamic nature of memories.

The generalization of fear memories is an adaptive neurobiological process that promotes survival in complex and dynamic environments. When confronted with a potential threat, an animal must select an appropriate defensive response based on previous experiences that are not identical, weighing cues and contextual information that may predict safety or danger. Like other aspects of fear memory, generalization is mediated by the coordinated actions of prefrontal, hippocampal, amygdalar, and thalamic brain areas. In this review article, we describe the current understanding of the behavioral, neural, genetic, and biochemical mechanisms involved in the generalization of fear. Fear generalization is a hallmark of many anxiety and stress-related disorders, and its emergence, severity, and manifestation are sex-dependent. Therefore, to improve the dialog between human and animal studies as well as to accelerate the development of effective therapeutics, we emphasize the need to examine both sex differences and remote timescales in rodent models.

The E2F transcription factors mediate the activation or repression of key cell cycle regulatory genes under the control of the retinoblastoma protein (pRB) tumor suppressor and its relatives, p107 and p130. Here we investigate how E2F4, the major "repressive" E2F, contributes to pRB's tumor-suppressive properties. Remarkably, E2F4 loss suppresses the development of both pituitary and thyroid tumors in Rb(+/-) mice. Importantly, E2F4 loss also suppresses the inappropriate gene expression and proliferation of pRB-deficient cells. Biochemical analyses suggest that this tumor suppression occurs via a novel mechanism: E2F4 loss allows p107 and p130 to regulate the pRB-specific, activator E2Fs. We also detect these novel E2F complexes in pRB-deficient cells, suggesting that they play a significant role in the regulation of tumorigenesis in vivo.