Cracking the histone code

The 'histone code' is the collection of covalent modifications to histone tails that act combinatorially to affect chromatin structure and transcription. The histone code expands the information potential of the genome. Modification of histones in the form of acetylation, deacetylation and methylation is enzymatically regulated. Recently, Yang Shi and colleagues reported the first evidence for a histone demethylase enzyme (Cell 119, 941–953; 2004). Lysine-specific demethylase 1 (LSD1) demethylates methylated histone lysine residues (Lys4) by an oxidation reaction and generates unmodified lysine and formaldehyde. LSD1 is similar in sequence to metabolic amine oxidases but localizes to the nucleus and associates with repressive chromatin complexes. Shi et al. also showed that inhibition of LSD1 by RNA interference causes derepression of silenced neuronal-specific genes in HeLa cells. These initial studies hint at the potentially important role of LSD1 in controlling transcriptional regulation, for example, during cellular differentiation or X-chromosome inactivation. The recent identification of histone H3 Lys4 methylase upregulated in many cancers (Nat. Cell Biol. 6, 731–740; 2004) indicates that LSD1 may also have a role in preventing tumorigenesis. EN

Follow the RNA

The modified adenovirus ONYX-015 lacks the E1B-55K gene product and shows promise in clinical trials as a treatment for cancer. Its mechanism of action, however, has remained unclear. The E1B-55K protein inactivates p53, and ONYX-015 was originally designed to replicate selectively in cancer cells with mutant p53. But its replicative capacity in cell culture does not always correlate with p53 status, nor does response in treated individuals. Clodagh O'Shea and colleagues now show that the tumor selectivity of ONYX-015 depends on the ability of the host cell to facilitate late viral RNA export (Cancer Cell 6, 611–623; 2004). Primary cells infected by ONYX-015 have supraphysiological levels of p53, but p53-dependent transcription is unaffected. As p53 function seems not to explain the oncolytic action of the virus, O'Shea et al. turned to the other function of E1B-55K, which is to promote the export of late viral RNAs. An RNA fluorescence in situ hybridization assay enabled them to show that there is a defect in the accumulation of these RNAs in infected cells. Tumor cells that support ONYX-015 replication show efficient export of viral RNAs, suggesting that this particular modified virus will be most effective in treating cancers that provide this function. AP

TPH2 variant and depression

TPH2 catalyzes the rate-limiting step in the synthesis of serotonin, a key brain neurotransmitter. Many psychiatric disorders, including depression and schizophrenia, are linked to imbalances in serotonergic neurotransmission. Marc Caron and colleagues now report a functional variant of TPH2 associated with increased risk of unipolar major depression (Neuron 45, 11–16; 2005). The risk allele, found in 1.4% of controls (n = 219) and 10.3% of cases (n = 87), encodes a TPH2 variant (R441H) showing an 80% reduction in enzymatic activity. Most individuals carrying the risk allele also showed a positive family history of psychiatric illness and a decreased responsiveness to selective serotonin reuptake inhibitors. These findings suggest that the TPH2 R441H variant may predispose to a range of psychiatric conditions and modulate pharmacological responses to the many classes of drugs targeting the brain serotonergic system. Although much work remains to validate these findings, functional evidence in mice supports the idea that TPH2 has a key role in regulating brain serotonin levels. Thus, the reduced activity of the TPH2 R441H variant may contribute to the pathophysiology of a broad range of psychiatric disorders and have a key role in modulating treatment outcomes. KV

Cytogenetics by array

Cri du chat is a syndrome of developmental defects caused by deletions in chromosome 5p. The phenotypes—the characteristic “cat-like” cry, dysmorphic facial features, mental retardation and developmentally delayed speech—have a confusing relationship to the extent of chromosomal deletion. Now, Dan Pinkel and colleagues (Am. J. Hum. Genet. 76, 312–326; 2005) have used spotted microarrays of overlapping BAC clones to examine 5p deletions that cause the syndrome by the technique of comparative genome hybridization. This painstaking correlation of phenotype to genotype was made possible by standardizing the assessment of adult and developmental phenotypes and by using DNA samples from peripheral blood mononuclear cells without Epstein-Barr virus immortalization. In this way, nonoverlapping regions responsible for the cry, speech delay and facies were defined. Furthermore, the authors were able to establish three regions where progressively greater deletions result in an increasing degree of mental retardation. Most notably, they found additional chromosomal gains and losses in the cases where the degree of mental retardation was more severe than would be expected from the small 5p deletion found. MA

Copy number and HIV/AIDS

The population-specific gene dose of CCL3L1, encoding a chemokine that is a ligand for the major coreceptor for human immunodeficiency virus (HIV-1) CCR5, is correlated with an individual's susceptibility to HIV-1 infection as well as progression to disease (Science advance online publication 6 January 2005; 10.1126/science1101160). Enrique Gonzalez and colleagues analyzed blood samples from 4,308 HIV-positive and -negative individuals from diverse populations. The authors screened for segmental duplications of CCL3L1, found nonrandomly distributed within and between populations. Individuals with fewer than their population's average number of copies were more susceptible to infection as well as rapid progression to disease. The absolute copy number did not correlate to either, highlighting the importance of population-specific genetic effects. Each additional copy of CCL3L1 lowered the risk of infection by 4.5–10.5%, depending on the population. As much as 42% of infection and 30% of the rapid progression to disease in the populations examined were attributable to combined variation in CCL3L1 and CCR5. This work suggests that extra copies of CCL3L1 may allow for increased binding of CCR5, reducing the amount of receptor on white blood cells that is available to recognize HIV. OB

Research Highlights written by Myles Axton, Orli Bahcall, Emily Niemitz, Alan Packer, and Kyle Vogan