A number of large-scale efforts are underway to define the relationships between genes and proteins in various species. But, few attempts have been made to systematically classify all such relationships at the phenotype level. Also, it is unknown whether such a phenotype map would carry biologically meaningful information. We have used text mining to classify over 5000 human phenotypes contained in the Online Mendelian Inheritance in Man database. We find that similarity between phenotypes reflects biological modules of interacting functionally related genes. These similarities are positively correlated with a number of measures of gene function, including relatedness at the level of protein sequence, protein motifs, functional annotation, and direct protein-protein interaction. Phenotype grouping reflects the modular nature of human disease genetics. Thus, phenotype mapping may be used to predict candidate genes for diseases as well as functional relations between genes and proteins. Such predictions will further improve if a unified system of phenotype descriptors is developed. The phenotype similarity data are accessible through a web interface at http://www.cmbi.ru.nl/MimMiner/.

We used ChIP-Seq to map ERa-binding sites and to profile changes in RNA polymerase II (RNAPII) occupancy in MCF-7 cells in response to estradiol (E2), tamoxifen or fulvestrant. We identify 10 205 high confidence ERa-binding sites in response to E2 of which 68% contain an estrogen response element (ERE) and only 7% contain a FOXA1 motif. Remarkably, 596 genes change significantly in RNAPII occupancy (59% up and 41% down) already after 1 h of E2 exposure. Although promoter proximal enrichment of RNAPII (PPEP) occurs frequently in MCF-7 cells (17%), it is only observed on a minority of E2-regulated genes (4%). Tamoxifen and fulvestrant partially reduce ERa DNA binding and prevent RNAPII loading on the promoter and coding body on E2-upregulated genes. Both ligands act differently on E2-downregulated genes: tamoxifen acts as an agonist thus downregulating these genes, whereas fulvestrant antagonizes E2-induced repression and often increases RNAPII occupancy. Furthermore, our data identify genes preferentially regulated by tamoxifen but not by E2 or fulvestrant. Thus (partial) antagonist loaded ERa acts mechanistically different on E2-activated and E2-repressed genes. IntroductionEstradiol (E2) is a key regulator in the growth and differentiation of many target tissues and is involved in the development and progression of breast cancer (Anderson, 2002). Its genomic activity is to a large extent mediated by the estrogen receptor a (ERa; NR3A1), a member of the nuclear receptor super family. ERa regulates expression of target genes classically by binding directly to its cognate sequence, the estrogen response element (ERE). ERa binds to its cognate-binding sites as homodimer, recruits co-factors and activates or represses transcription in response to E2 (Shang et al, 2000). Alternatively, nonclassical regulation involves protein-protein interactions with other DNA-binding proteins such as Sp1, AP-1 and NF-kB. Identification of the ERa target gene network regulated by agonist and/or antagonist treatment is essential to understand the role of ERa in normal physiological processes and in cancer.Several gene expression profiling studies in MCF-7 cells identified E2-responsive genes in the range of 100-1500 (Charpentier et al, 2000;Coser et al, 2003;Frasor et al, 2003;Rae et al, 2005;Carroll et al, 2006;Kininis et al, 2007;Kwon et al, 2007;Lin et al, 2007;Stender et al, 2007), whereas large scale ERa ChIP profiling showed that ERa interacts with many thousands genomic regions (Carroll et al, 2006;Kininis et al, 2007;Lin et al, 2007). This discordance is in part due to the fact that mRNA levels do not necessarily reflect gene activity because it is subject to degradation and regulation, and that likely not all ERa-binding sites are active under all conditions. Genome-wide profiling of RNA polymerase II (RNAPII) occupancy, however, does provide a much more direct readout and, thus, could yield insights beyond what is typically obtained by mRNA expression profiling.Recent studies have shown that the promoters of a large number...

Epigenome profiling has led to the paradigm that promoters of active genes are decorated with H3K4me3 and H3K9ac marks. To explore the epigenome of Plasmodium falciparum asexual stages, we performed MS analysis of histone modifications and found a general preponderance of H3/H4 acetylation and H3K4me3. ChIPon-chip profiling of H3, H3K4me3, H3K9me3, and H3K9ac from asynchronous parasites revealed an extensively euchromatic epigenome with heterochromatin restricted to variant surface antigen gene families (VSA) and a number of genes hitherto unlinked to VSA. Remarkably, the vast majority of the genome shows an unexpected pattern of enrichment of H3K4me3 and H3K9ac. Analysis of synchronized parasites revealed significant developmental stage specificity of the epigenome. In rings, H3K4me3 and H3K9ac are homogenous across the genes marking active and inactive genes equally, whereas in schizonts, they are enriched at the 5 end of active genes. This study reveals an unforeseen and unique plasticity in the use of the epigenetic marks and implies the presence of distinct epigenetic pathways in gene silencing/activation throughout the erythrocytic cycle.chromatin ͉ epigenetics ͉ malaria P lasmodium falciparum, the protozoan parasite causing malaria, exhibits a complex life cycle characterized by invasion of different cell types and hosts. During the Ϸ48 h of the intraerythrocytic cycle, a merozoite invades a red blood cell (RBC) and develops into the ring stage, which is followed by the trophozoite stage. Nuclear division marks the beginning of the schizont stage, which results in the formation of up to 32 merozoites that can invade new RBCs (1). Global analysis of transcription (2, 3) and protein expression (4, 5) of the parasite have revealed a high level of coordination in gene expression during the different stages of the life cycle. The absence of chromosomal clustering among genes with similar transitory expression profiles indicates that genes are regulated individually.