Intermittent fasting is one of the most effective dietary restriction regimens that extend life span in C. elegans and mammals. Fasting-stimulus responses are key to the longevity response; however, the mechanisms that sense and transduce the fasting stimulus remain largely unknown. Through a comprehensive transcriptome analysis in C. elegans, we find that along with the FOXO transcription factor DAF-16, AP-1 (JUN-1/FOS-1) plays a central role in fasting-induced transcriptional changes. KGB-1, one of the C. elegans JNKs, acts as an activator of AP-1 and is activated in response to fasting.
A critical requirement for research using model organisms is a well-defined and consistent diet. There is currently no complete chemically defined (holidic) diet available for Drosophila melanogaster. We describe a holidic medium that is equal in performance to an oligidic diet optimized for adult fecundity and lifespan. This holidic diet supports development over multiple generations but at a reduced rate. Over 7 years of experiments, the holidic diet yielded more consistent experimental outcomes than did oligidic food for egg laying by females.
Proceedings of the National Academy of Sciences of the United States of America
Loss of the protective function of telomeres has previously been hypothesized to cause a DNA damage response. Here, we report a genome-wide expression response, the telomerase deletion response (TDR), that occurs when telomeres can no longer be maintained by telomerase. The TDR shares features with other DNA damage responses and the environmental stress response. Unexpectedly, another feature of the TDR is the up-regulation of energy production genes, accompanied by a proliferation of mitochondria.
Proceedings of the National Academy of Sciences of the United States of America
Recent studies have demonstrated a role for telomerase in driving tumor progression, but its mechanism of action remains unclear. Here we show that stable, ribozyme-mediated suppression of mouse telomerase RNA reduced telomerase RNA expression, telomerase activity, and telomere length, which significantly reduced tumor invasion and metastatic potential. Our studies reveal that previously unidentified effects of telomerase may mediate its tumor-promoting effects.
Inhibition of the up-regulated telomerase activity in cancer cells has previously been shown to slow cell growth but only after prior telomere shortening. Previously, we have reported that, unexpectedly, a hairpin short interfering RNA specifically targeting human telomerase RNA rapidly inhibits the growth of human cancer cells independently of p53 or telomere length and without bulk telomere shortening (Li, S., Rosenberg, J. E., Donjacour, A. A., Botchkina, I. L., Hom, Y. K., Cunha, G. R., and Blackburn, E. H. (2004) Cancer Res. 64, 4833-4840).
BACKGROUND: Schizophrenia is frequently accompanied by hypometabolism and altered gene expression in the prefrontal cortex. Cellular metabolism regulates chromatin structure, including covalent histone modifications, which are epigenetic regulators of gene expression. OBJECTIVE: To test the hypothesis that down-regulated metabolic gene expression is associated with histone modification changes in the prefrontal cortex of subjects with schizophrenia.
The ways in which gene transcription is investigated have undergone radical change since the turn of the millennium. Piece-meal approaches focussed upon model genes have increasingly been complemented by genome-wide approaches that allow interrogation of multiple cohorts of genes or even entire genomes. This sea change has been founded upon the increasing availability of whole genome sequences and the attendant evolution of microarray based discovery platforms.
Histone deactylase enzymes are responsible for the deacetylation of histone tails, and consequently influence gene regulation through their ability to modify chromatin structure surrounding promoter regions. We analyzed the microarray collection of the National Brain Databank to investigate differential expression of these enzymes in the prefrontal cortices of control, schizophrenia and bipolar subjects. HDAC1 expression levels were significantly higher in schizophrenia versus normal subjects.
CONTEXT: Although most of the effort to understand the neurobiology of depressive states and suicide has focused on neuronal processes, recent studies suggest that astroglial dysfunction may play an important role. A truncated variant of the tropomyosin-related kinase B (TrkB.T1) is expressed in astrocytes, and brain-derived neurotrophic factor-TrkB signaling has been linked to mood disorders. OBJECTIVE: To test the hypothesis that TrkB.T1 expression is downregulated in suicide completers and that this downregulation is mediated by an epigenetic process.
PURPOSE OF REVIEW: This is a review examining recent data from the study of the postmortem central nervous system (CNS) of patients with schizophrenia. RECENT FINDINGS: Studies on the human CNS transcriptome suggest changes in pro-inflammatory pathways and myelination in schizophrenia, whereas changes in the proteome suggest that pathways involved in energy and metabolism may be particularly stressed.
