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Flow cytometry estimates of genome sizes among species ofDrosophilashow a 3-fold variation, ranging from ∼127 Mb inDrosophila mercatorumto ∼400 Mb inDrosophila cyrtoloma. However, the assembled portion of the Muller F Element (orthologous to the fourth chromosome inDrosophila melanogaster) shows a nearly 14-fold variation in size, ranging from ∼1.3 Mb to > 18 Mb. Here, we present chromosome-level long read genome assemblies for fourDrosophilaspecies with expanded F Elements ranging in size from 2.3 Mb to 20.5 Mb. Each Muller Element is present as a single scaffold in each assembly. These assemblies will enable new insights into the evolutionary causes and consequences of chromosome size expansion.

Transposable elements (TEs) are selfish DNA sequences that can replicate themselves in their host's genome. Hosts have evolved specialized strategies for mitigating the deleterious consequences of TE activity. In Drosophila, the piRNA pathway is the primary transposable element (TE) control pathway. However, many TEs are only expressed in specific cell types, raising the possibility that transcription factors (TFs) also regulate TEs in a sequence-specific manner. Indeed, recent studies in mammals have identified TF families that regulate TE expression in parallel with small RNA pathways, but the contribution of such factors to TE expression regulation in Drosophila remains poorly understood. We leveraged natural expression variation across genetic backgrounds in wild populations of Drosophila to test the hypothesis that TE expression should correlate with the expression of such trans-acting factors. We analyzed coexpression relationships between individual host genes and TEs while controlling for factors that commonly influence TE expression estimates. Our analysis indicates that the expression of some TFs is predictive of TE expression. We find evidence that some of these factors act as regulators of known TE silencing genes, while others may act by binding TE-derived sequences distributed throughout the genome. These results provide a list of candidates for future examination of host/TE interplay, including studies of TF co-option or instances of TE-mediated expansion of host gene regulatory networks.

Topologically associating domains (TADs) are thought to play an important role in preventing gene misexpression by spatially constraining enhancer–promoter contacts. The deleterious nature of gene misexpression implies that TADs should, therefore, be conserved among related species. Several early studies comparing chromosome conformation between species reported high levels of TAD conservation; however, more recent studies have questioned these results. Furthermore, recent work suggests that TAD reorganization is not associated with extensive changes in gene expression. Here, we investigate the evolutionary conservation of TADs among 11 species of Drosophila. We use Hi-C data to identify TADs in each species and employ a comparative phylogenetic approach to derive empirical estimates of the rate of TAD evolution. Surprisingly, we find that TADs evolve rapidly. However, we also find that the rate of evolution depends on the chromatin state of the TAD, with TADs enriched for developmentally regulated chromatin evolving significantly slower than TADs enriched for broadly expressed, active chromatin. We also find that, after controlling for differences in chromatin state, highly conserved TADs do not exhibit higher levels of gene expression constraint. These results suggest that, in general, most TADs evolve rapidly and their divergence is not associated with widespread changes in gene expression. However, higher levels of evolutionary conservation and gene expression constraints in TADs enriched for developmentally regulated chromatin suggest that these TAD subtypes may be more important for regulating gene expression, likely due to the larger number of long-distance enhancer–promoter contacts associated with developmental genes.

Transposable elements (TEs) must replicate in germline cells to pass novel insertions to offspring. In Drosophila melanogaster ovaries, TEs can exploit specific developmental windows of opportunity to evade host silencing and increase their copy numbers. However, TE activity and host silencing in the distinct cell types of Drosophila testis are not well understood. Here, we reanalyze publicly available single-cell RNA-seq datasets to quantify TE expression in the distinct cell types of the Drosophila testis. We develop a method for identification of TE and host gene expression modules and find that a distinct population of early spermatocytes expresses a large number of TEs at much higher levels than other germline and somatic components of the testes. This burst of TE expression coincides with the activation of Y chromosome fertility factors and spermatocyte-specific transcriptional regulators, as well as downregulation of many components of the piRNA pathway. The TEs expressed by this cell population are specifically enriched on the Y chromosome and depleted on the X chromosome, relative to other active TEs. These data suggest that some TEs may achieve high insertional activity in males by exploiting a window of opportunity for mobilization created by the activation of spermatocyte-specific and Y chromosome-specific transcriptional programs., In this study, Lawlor et al. show that transposons on the Drosophila Y chromosome have evolved to exploit a specific stage of spermatogenesis when the Y chromosome is decondensed and the piRNA pathway is downregulated.

The brush border is comprised of microvilli surface protrusions on the apical surface of epithelia. This specialized structure greatly increases absorptive surface area and plays crucial roles in human health. However, transcriptional regulatory networks controlling brush border genes are not fully understood. Here, we identify that hepatocyte nuclear factor 4 (HNF4) transcription factor is a conserved and important regulator of brush border gene program in multiple organs, such as intestine, kidney and yolk sac. Compromised brush border gene signatures and impaired transport were observed in these tissues upon HNF4 loss. By ChIP-seq, we find HNF4 binds and activates brush border genes in the intestine and kidney. H3K4me3 HiChIP-seq identifies that HNF4 loss results in impaired chromatin looping between enhancers and promoters at gene loci of brush border genes, and instead enhanced chromatin looping at gene loci of stress fiber genes in the intestine. This study provides comprehensive transcriptional regulatory mechanisms and a functional demonstration of a critical role for HNF4 in brush border gene regulation across multiple murine epithelial tissues., Brush border gene regulation in various different tissues is incompletely understood. Here, the authors show HNF4 regulates the brush border gene program in multiple organs, such as intestine, kidney and yolk sac, and also intestinal chromatin looping in these tissues between promoters and enhancers.

Transposable elements (TEs) must replicate in germline cells to pass novel insertions to offspring. In Drosophila melanogaster ovaries, TEs can exploit specific developmental windows of opportunity to evade host silencing and increase their copy numbers. However, TE activity and host silencing in the distinct cell types of the Drosophila melanogaster testis are not well understood. We reanalyzed publicly available single-cell RNA-seq datasets to quantify TE expression in the distinct cell types of the Drosophila testis. We developed a novel method for identification of TE and host gene expression programs and find that a distinct population of early spermatocytes expresses a large number of TEs at much higher levels than other germline and somatic components of the testes. This burst of TE expression coincides with the activation of Y chromosome fertility factors and spermatocyte-specific transcriptional regulators, as well as downregulation of many components of the piRNA pathway. The TEs expressed by this cell population are enriched on the Y chromosome and depleted on the X chromosome relative to other active TEs. These data suggest that some TEs may achieve high insertional activity in males by exploiting a window of opportunity for mobilization created by the activation of spermatocyte-specific and Y-chromosome-specific transcriptional programs.

Topologically associating domains, or TADs, are functional units that organize chromosomes into 3D structures of interacting chromatin. TADs play an important role in regulating gene expression by constraining enhancer-promoter contacts; there is evidence that deletion of TAD boundaries leads to aberrant expression of neighboring genes. While the mechanisms of TAD formation have been well-studied, current knowledge on the extent of TAD conservation across species is inconclusive. Due to the integral role TADs play in gene regulation, their structure and organization is expected to be conserved during evolution. However, more recent research suggests that TAD structures diverge relatively rapidly. We use Hi-C chromosome conformation capture to measure evolutionary conservation of whole TADs and TAD boundary elements between D. melanogaster and D. triauraria, two early-branching species from the melanogaster species group which diverged ~15 million years ago. We find that 75% of TAD boundaries are orthologous while only 25% of TAD domains are conserved and these are enriched for Polycomb-repressed chromatin. Our results show that TADs have been reorganized since the common ancestor of D. melanogaster and D. triauraria, yet the sequence elements that specify TAD boundaries remain highly conserved. We propose that evolutionary divergence in 3D genome organization results from shuffling of conserved boundary elements across chromosomes, breaking old TADs and creating new TAD architectures. This result supports the existence of distinct TAD subtypes: some may be evolutionarily flexible while others remain highly conserved due to their importance in restricting gene-regulatory element interactions.

Co-evolution between transposable elements (TEs) and their hosts can be antagonistic, where TEs evolve to avoid silencing and the host responds by reestablishing TE suppression, or mutualistic, where TEs are co-opted to benefit their host. TheTART-ATE functions as an important component of Drosophila telomeres, but has also reportedly inserted into theD. melanogasternuclear export factor genenxf2. We find that, rather than inserting intonxf2, TART-Ahas actually captured a portion ofnxf2sequence. We show that Nxf2 is involved in suppressingTART-Aactivity via the piRNA pathway and thatTART-Aproduces abundant piRNAs, some of which are antisense to thenxf2transcript. We propose that capturingnxf2sequence allowedTART-Ato target thenxf2gene for piRNA-mediated repression and that these two elements are engaged in antagonistic co-evolution despite the fact thatTART-Ais serving a critical role for its host genome.

Illumina sequencing has allowed for population-level surveys of transposable element (TE) polymorphism via split alignment approaches, which has provided important insight into the population dynamics of TEs. However, such approaches are not able to identify insertions of uncharacterized TEs, nor can they assemble the full sequence of inserted elements. Here, we use nanopore sequencing and Hi-C scaffolding to produce de novo genome assemblies for two wild strains of Drosophila melanogaster from the Drosophila Genetic Reference Panel (DGRP). Ovarian piRNA populations and Illumina split-read TE insertion profiles have been previously produced for both strains. We find that nanopore sequencing with Hi-C scaffolding produces highly contiguous, chromosome-length scaffolds, and we identify hundreds of TE insertions that were missed by Illumina-based methods, including a novel micropia-like element that has recently invaded the DGRP population. We also find hundreds of piRNA-producing loci that are specific to each strain. Some of these loci are created by strain-specific TE insertions, while others appear to be epigenetically controlled. Our results suggest that Illumina approaches reveal only a portion of the repetitive sequence landscape of eukaryotic genomes and that population-level resequencing using long reads is likely to provide novel insight into the evolutionary dynamics of repetitive elements.

N6-methyladenine (6mA or m6dA) is a DNA modification that has long been known to play an important role in a variety of biological functions in prokaryotes. This modification has only recently been described in eukaryotes, where it seems to have evolved species-specific functions ranging from nucleosome positioning to transposon repression. In Drosophila, 6mA has been shown to be important for enforcing the tissue specificity of neuronal genes in the brain and suppressing transposable element expression in the ovaries. In this study, we have analyzed the raw signal data from nanopore sequencing to identify 6mA positions in the D. melanogaster genome at single-base resolution. We find that this modification is enriched upstream from transcription start sites, within the introns and 3′ UTRs of genes, as well as in simple repeats. These 6mA positions are enriched for sequence motifs that are recognized by known transcriptional activators involved in development, such as Bicoid and Caudal, and the genes that carry this modification are enriched for functions involved in development, regulation of transcription, and neuronal activity. These genes show high expression specificity in a variety of tissues besides the brain, suggesting that this modification may play a more general role in enforcing the specificity of gene expression across many tissues, throughout development, and between the sexes.

SUMMARY Cells in renewing tissues exhibit dramatic transcriptional changes as they differentiate. The contribution of chromatin looping to tissue renewal is incompletely understood. Enhancer-promoter interactions could be relatively stable as cells transition from progenitor to differentiated states; alternatively, chromatin looping could be as dynamic as the gene expression from their loci. The intestinal epithelium is the most rapidly renewing mammalian tissue. Proliferative cells in crypts of Lieberkühn sustain a stream of differentiated cells that are continually shed into the lumen. We apply chromosome conformation capture combined with chromatin immunoprecipitation (HiChIP) and sequencing to measure enhancer-promoter interactions in progenitor and differentiated cells of the intestinal epithelium. Despite dynamic gene regulation across the differentiation axis, we find that enhancer-promoter interactions are relatively stable. Functionally, we find HNF4 transcription factors are required for chromatin looping at target genes. Depletion of HNF4 disrupts local chromatin looping, histone modifications, and target gene expression. This study provides insights into transcriptional regulatory mechanisms governing homeostasis in renewing tissues., In Brief Chen et al. provide a survey of enhancer-promoter 3D looping in the intestinal epithelium by HiChIP, in vivo. They find that enhancer-promoter interactions are highly dependent upon the key intestinal transcription factor HNF4. Their findings provide insights into transcriptional regulatory mechanisms governing homeostasis in renewing tissues., Graphical Abstract

Topologically associating domains, or TADs, are functional units that organize chromosomes into 3D structures of interacting chromatin. TADs play an important role in regulating gene expression by constraining enhancer-promoter contacts and there is evidence that deletion of TAD boundaries leads to aberrant expression of neighboring genes. While the mechanisms of TAD formation have been well-studied, current knowledge on the patterns of TAD evolution across species is limited. Due to the integral role TADs play in gene regulation, their structure and organization is expected to be conserved during evolution. However, more recent research suggests that TAD structures diverge relatively rapidly. We use Hi-C chromosome conformation capture to measure evolutionary conservation of whole TADs and TAD boundary elements between D. melanogaster and D. triauraria, two early-branching species from the melanogaster species group which diverged ∼15 million years ago. We find that the majority of TADs have been reorganized since the common ancestor of D. melanogaster and D. triauraria, via a combination of chromosomal rearrangements and gain/loss of TAD boundaries. TAD reorganization between these two species is associated with a localized effect on gene expression, near the site of disruption. By separating TADs into subtypes based on their chromatin state, we find that different subtypes are evolving under different evolutionary forces. TADs enriched for broadly expressed, transcriptionally active genes are evolving rapidly, potentially due to positive selection, whereas TADs enriched for developmentally-regulated genes remain conserved, presumably due to their importance in restricting gene-regulatory element interactions. These results provide novel insight into the evolutionary dynamics of TADs and help to reconcile contradictory reports related to the evolutionary conservation of TADs and whether changes in TAD structure affect gene expression., Author summary Chromosomes are organized inside the three-dimensional nucleus in a hierarchical fashion, from the wrapping of DNA around nucleosomes to the presence of compartments of active and inactive chromatin. Here, we focus on domains of interacting chromatin known as topologically associating domains, or TADs. TADs are dozens to hundreds of kilobases in size and tend to contain genes with similar epigenetic states. While much research has been done on the mechanisms of TAD formation, less is known about the role of TADs in genome evolution. The research that does exist is contradictory, with some studies claiming that TADs are highly conserved and others reporting that TADs diverge rapidly. We compared the TAD locations between two Drosophila species and found that the majority have been reorganized. We also identified TAD subtypes that differ in terms of their evolutionary conservation: TADs that contain developmental genes are less likely to be reorganized while TADs that contain broadly expressed genes evolve rapidly. We found that TAD reorganization has an effect on gene expression, but only for genes located near the site of disruption. These results provide new insight into the evolution of 3D genome organization and help to reconcile previous contradictions in the literature.

Similar to many diurnal animals, Drosophila melanogaster exhibits a mid-day siesta that is more robust as temperature increases, an adaptive response that aims to minimize the deleterious effects from exposure to heat. This temperature-dependent plasticity in mid-day sleep levels is partly based on the thermal sensitive splicing of an intron in the 3′ untranslated region (UTR) of the circadian clock gene termed period (per). In this study, we evaluated a possible role for the serine/arginine-rich (SR) splicing factors in the regulation of dmpi8 splicing efficiency and mid-day siesta. Using a Drosophila cell culture assay we show that B52/SRp55 increases dmpi8 splicing efficiency, whereas other SR proteins have little to no effect. The magnitude of the stimulatory effect of B52 on dmpi8 splicing efficiency is modulated by natural variation in single nucleotide polymorphisms (SNPs) in the per 3′ UTR that correlate with B52 binding levels. Down-regulating B52 expression in clock neurons increases mid-day siesta and reduces dmpi8 splicing efficiency. Our results establish a novel role for SR proteins in sleep and suggest that polymorphisms in the per 3′ UTR contribute to natural variation in sleep behavior by modulating the binding efficiencies of SR proteins.

Background Many diurnal animals exhibit a mid-day ‘siesta’, generally thought to be an adaptive response aimed at minimizing exposure to heat on warm days, suggesting that in regions with cooler climates mid-day siestas might be a less prominent feature of animal behavior. Drosophila melanogaster exhibits thermal plasticity in its mid-day siesta that is partly governed by the thermosensitive splicing of the 3’-terminal intron (termed dmpi8) from the key circadian clock gene period (per). For example, decreases in temperature lead to progressively more efficient splicing, which increasingly favors activity over sleep during the mid-day. In this study we sought to determine if the adaptation of D. melanogaster from its ancestral range in the lowlands of tropical Africa to the cooler temperatures found at high altitudes involved changes in mid-day sleep behavior and/or dmpi8 splicing efficiency. Results Using natural populations of Drosophila melanogaster from different altitudes in tropical Africa we show that flies from high elevations have a reduced mid-day siesta and less consolidated sleep. We identified a single nucleotide polymorphism (SNP) in the per 3’ untranslated region that has strong effects on dmpi8 splicing and mid-day sleep levels in both low and high altitude flies. Intriguingly, high altitude flies with a particular variant of this SNP exhibit increased dmpi8 splicing efficiency compared to their low altitude counterparts, consistent with reduced mid-day siesta. Thus, a boost in dmpi8 splicing efficiency appears to have played a prominent but not universal role in how African flies adapted to the cooler temperatures at high altitude. Conclusions Our findings point towards mid-day sleep behavior as a key evolutionary target in the thermal adaptation of animals, and provide a genetic framework for investigating daytime sleep in diurnal animals which appears to be driven by mechanisms distinct from those underlying nighttime sleep. Electronic supplementary material The online version of this article (doi:10.1186/s12862-017-0880-8) contains supplementary material, which is available to authorized users.

Effect of altitude on period length in Cameroon and Kenya flies. (DOCX 15 kb)

List of African lines used in this study. (DOCX 26 kb)

The effects of altitude on the daily wake-sleep profiles in females are similar to that observed in male flies. (a-h) Shown are group averages of the daily activity rhythms (a-d) and daily sleep levels (e-h) for adult female flies from low (red) and high (blue) altitudes representing several different locations in Cameroon (a, b, e, f) and Kenya (c, d, g, h). The fly lines used in this experiment were, CO1, CO16, CM16, CM54, KO6, KO10M, KM16 and KM20 (Additional file 1: Table S1). Flies were kept at 25 °C and entrained to five days of 12 h light/12 h dark cycles (LD) followed by constant dark conditions (DD). For each country, the locomotor activity data of individual flies (16 flies per line) from the same altitude group (low or high) were pooled. (a-d) To facilitate comparisons, the peak value in daily activity for each fly was set to 1.0 and the normalized profiles superimposed. For LD, the last three days’ worth of data was pooled; for DD, the first day is shown (DD1). Horizontal bars at bottom of panels denote 12-h periods of light (white bar), dark (black bar) and ‘subjective daytime’ in DD (gray bar). ZT, zeitgeber time (hr); CT, circadian time (hr). (PDF 32 kb)

In recent decades forensic fingerprinting of oil-spill hydrocarbons has emerged as an important tool for correlating oils and for evaluating their source and character. Two long-term hydrocarbon spills, an off-road diesel spill (Mandan, ND) and a crude oil spill (Bemidji, MN) experiencing methanogenic biodegradation were previously shown to be undergoing an unexpected progression of homologous n-alkane and n-alkylated cyclohexane loss. Both exhibited degradative losses proceeding from the high-molecular-weight end of the distributions, along with transitory concentration increases of lower-molecular-weight homologs. Particularly in the case of the diesel fuel spill, these methanogenic degradative patterns can result in series distributions that mimic lower cut refinery fuels or admixture with lower cut fuels. Forensic fingerprinting in this long-term spill must therefore rely on more recalcitrant series, such as polycyclic aromatic hydrocarbon or drimane sesquiterpane profiles, to prove if the spilled oil...

STUDY OBJECTIVES D. melanogaster is an excellent animal model to study how the circadian (≅24-h) timing system and sleep regulate daily wake-sleep cycles. Splicing of a temperature-sensitive 3'-terminal intron (termed dmpi8) from the circadian clock gene period (per) regulates the distribution of daily activity in Drosophila. The role of dmpi8 splicing on daily behavior was further evaluated by analyzing sleep. DESIGN Transgenic flies of the same genetic background but expressing either a wild-type recombinant per gene or one where the efficiency of dmpi8 splicing was increased were exposed to different temperatures in daily light-dark cycles and sleep parameters measured. In addition, transgenic flies were briefly exposed to a variety of sensory-mediated stimuli to measure arousal responses. RESULTS Surprisingly, we show that the effect of dmpi8 splicing on daytime activity levels does not involve a circadian role for per but is linked to adjustments in sensory-dependent arousal and sleep behavior. Genetically altered flies with high dmpi8 splicing efficiency remain aroused longer following short treatments with light and non-photic cues such as mechanical stimulation. CONCLUSIONS We propose that the thermal regulation of dmpi8 splicing acts as a temperature-calibrated rheostat in a novel arousal mechanism, so that on warm days the inefficient splicing of the dmpi8 intron triggers an increase in quiescence by decreasing sensory-mediated arousal, thus ensuring flies minimize being active during the hot midday sun despite the presence of light in the environment, which is usually a strong arousal cue for diurnal animals.

The FK506-binding protein (FKBP) family of immunophilins consists of proteins with a variety of protein–protein interaction domains and versatile cellular functions. Analysis of the functions of immunophilins has been the focus of studies in recent years and has led to the identification of various molecular pathways in which FKBPs play an active role. All FKBPs contain a domain with prolyl cis/trans isomerase (PPIase) activity. Binding of the immunosuppressant molecule FK506 to this domain inhibits their PPIase activity while mediating immune suppression through inhibition of calcineurin. The larger members, FKBP51 and FKBP52, interact with Hsp90 and exhibit chaperone activity that is shown to regulate steroid hormone signalling. From these studies it is clear that FKBP proteins are expressed ubiquitously but show relatively high levels of expression in the nervous system. Consistent with this expression, FKBPs have been implicated with both neuroprotection and neurodegeneration. This review will focus on recent studies involving FKBP immunophilins in Alzheimer’s-disease-related pathways.

Sustained increases in life expectancy have underscored the importance of managing diseases with a high incidence in late life, such as various neurodegenerative conditions. Alzheimer's disease (AD) is the most common among these, and consequently significant research effort is spent on studying it. Although a lot is known about the pathology of AD and the role of β-amyloid (Aβ) peptides, the complete network of interactions regulating Aβ metabolism and toxicity still eludes us. To address this, we have conducted genetic interaction screens using transgenic Drosophila expressing Aβ and we have identified mutations that affect Aβ metabolism and toxicity. These analyses highlight the involvement of various biochemical processes such as secretion, cholesterol homeostasis, and regulation of chromatin structure and function, among others, in mediating toxic Aβ effects. Several of the mutations that we identified have not been linked to Aβ toxicity before and thus constitute novel potential targets for AD intervention. We additionally tested these mutations for interactions with tau and expanded-polyglutamine overexpression and found a few candidate mutations that may mediate common mechanisms of neurodegeneration. Our data offer insight into the toxicity of Aβ and open new areas for further study into AD pathogenesis

Nocardia sp. C-14-1, isolated from acrylic fiber wastewater, can degrade long-chain alkanes and succinonitrile efficiently. Here we report the characterization of an indigenous plasmid pC1. The overall nucleotide sequence of pC1 consisted of 5841 bp. The five ORFs, encoding a DNA recombinase, replication protein (Rep(pC1)) and three proteins of unknown function, were predicted on pC1. The Rep(pC1) displayed its homology with the Rep of Rhodococcus large plasmid p33701, suggesting a theta type of replication. An Escherichia coli plasmid (containing the single rep(pC1) gene) propagated autonomously in low copy number in Nocardia or Rhodococcus, suggesting that rep(pC1) was an essential gene for plasmid replication. The plasmid (containing the single rep(pC1) gene) presented as inheritance unstable hints that other pC1 loci were required for the stable inheritance of plasmids. By comparison of the plasmid-borne Rep proteins, we classify Rhodococcus or Nocardia plasmids into four groups.

Succinonitrile used as a sole source of carbon and nitrogen, two bacterium strains, named as J-1-3 and J-13-1, which had high degrading capacity for succinonitrile were isolated and screened out from acrylic fiber wastewater and biofilm in its treatment structure. Through morphological and biochemical method, the two strains were primarily identified as Pseudomonas spp. By tests in shaking flasks, it was determined that the strains can be optimum growth at 30 degrees C, with shaker rotary speed which indirectly reflected aeration capacity at 250 r/min, inoculum amount of 0.1%, and initial pH6. On the optimum conditions for growth, the degradation experiments on different initial concentrations of succinonitrile were carried out. The results indicate that the two strains, especially J-13-1 had high degrading efficiency for succinonitrile. With the initial concentration of succinonitrile at ca. 6000, 8000 and 10,000 mg/L, the degrading rates of succinonitrile by strain J-13-1 reached to 100% after 12.5 h, 14 h and 16 h, respectively.

FK506 binding proteins (FKBPs), also called immunophilins, are prolyl-isomerases (PPIases) that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alzheimer's Amyloid Precursor Protein (APP). Originally identified in hematopoietic cells, FKBP52 is much more abundantly expressed in neurons, including the hippocampus, frontal cortex, and basal ganglia. Given the fact that the high molecular weight immunophilin FKBP52 is highly expressed in CNS regions susceptible to Alzheimer's, we investigated its role in Abeta toxicity. Towards this goal, we generated Abeta transgenic Drosophila that harbor gain of function or loss of function mutations of FKBP52. FKBP52 overexpression reduced the toxicity of Abeta and increased lifespan in Abeta flies, whereas loss of function of FKBP52 exacerbated these Abeta phenotypes. Interestingly, the Abeta pathology was enhanced by mutations in the copper transporters Atox1, which interacts with FKBP52, and Ctr1A and was suppressed in FKBP52 mutant flies raised on a copper chelator diet. Using mammalian cultures, we show that FKBP52 (-/-) cells have increased intracellular copper and higher levels of Abeta. This effect is reversed by reconstitution of FKBP52. Finally, we also found that FKBP52 formed stable complexes with APP through its FK506 interacting domain. Taken together, these studies identify a novel role for FKBP52 in modulating toxicity of Abeta peptides.