ZFTA fusion oncoproteins drive tumorigenesis through transcriptional condensates
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE266375 | GEO | 2025/07/21
REPOSITORIES: GEO
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Project description:The transcription factor SREBP2, plays a specific and non-redundant role in cholesterol metabolism, autophagy of lipid droplets and apoptosis regulation. Under cholesterol-depletion condition, nuclear SREBP2 (nSREBP2) is released after proteolytic cleavage, enters nucleus and activates cholesterogenic genes expression. Here, we report that the nSREBP2 forms discrete nuclear condensates through its N-terminal intrinsically disordered region (IDR) and works together with transcription coactivators BRD4 and p300, partly on super-enhancers, for the transcriptional activation of SREBP2 target genes. The substitution of a critical and conserved phenylalanine (F) to alanine (A) within the IDR abolished the formation of nSREBP2 condensates. Conversely, the condensate formation and efficient transcription activation were rescued by fusion with a phase separation driving FUS-IDR. Knock-in of the F to A substitution in mice compromised the feeding-induced nSREBP2 activity and lowered the cholesterol levels. Furthermore, a SNP of SREBF2 in humans leading to single amino acid change, P183S, showed less nuclear condensate formation and lower transcriptional activity, underscoring the physiological relevance of nSREBP2 condensates. Together, this study reveals that nuclear condensates driven by the N terminal IDR of nSREBP2 facilitate the efficient activation of lipogenic genes and play an important role in cholesterol homeostasis.
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Project description:The transcription factor SREBP2, plays a specific and non-redundant role in cholesterol metabolism, autophagy of lipid droplets and apoptosis regulation. Under cholesterol-depletion condition, nuclear SREBP2 (nSREBP2) is released after proteolytic cleavage, enters nucleus and activates cholesterogenic genes expression. Here, we report that the nSREBP2 forms discrete nuclear condensates through its N-terminal intrinsically disordered region (IDR) and works together with transcription coactivators BRD4 and p300, partly on super-enhancers, for the transcriptional activation of SREBP2 target genes. The substitution of a critical and conserved phenylalanine (F) to alanine (A) within the IDR abolished the formation of nSREBP2 condensates. Conversely, the condensate formation and efficient transcription activation were rescued by fusion with a phase separation driving FUS-IDR. Knock-in of the F to A substitution in mice compromised the feeding-induced nSREBP2 activity and lowered the cholesterol levels. Furthermore, a SNP of SREBF2 in humans leading to single amino acid change, P183S, showed less nuclear condensate formation and lower transcriptional activity, underscoring the physiological relevance of nSREBP2 condensates. Together, this study reveals that nuclear condensates driven by the N terminal IDR of nSREBP2 facilitate the efficient activation of lipogenic genes and play an important role in cholesterol homeostasis.
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Project description:C2H2 zinc finger proteins represent the largest and most enigmatic class of human transcription factors. Their C2H2 arrays are highly variable, indicating that most will have unique DNA binding motifs. However, most of the binding motifs have not been directly determined. We have determined the binding sites and motifs of 119 C2H2 zinc finger proteins and the expression pattern of 80 cell lines overexpressing C2H2 zinc finger proteins in order to study the role of C2H2 zinc finger proteins in gene regulation. We expressed GFP-tagged C2H2-ZF proteins in stable transgenic HEK293 cells. Total RNA was isolated using Trizol and sequencing libraries were constructed using TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Gold or TruSeq RNA Library Preparation Kit v2.
2016-10-25 | E-GEOD-76495 | biostudies-arrayexpress
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Project description:Cys2-His2 zinc finger proteins (ZFPs) are the largest group of transcription factors in higher metazoans. A complete characterization of these ZFPs and their associated target sequences is pivotal to fully annotate transcriptional regulatory networks in metazoan genomes. As a first step in this process, we have characterized the DNA-binding specificities of 130 Zinc finger sets from Drosophila melanogaster using a bacterial one-hybrid system. This data set contains the DNA-binding specificities for at least one encoded ZFP from 71 unique genes and 22 alternate splice isoforms. This represents the largest block of characterized ZFPs from any organism described to date. These recognition motifs can be used to predict genomic binding sites and potential regulatory targets for these factors within the fruit fly genome. We have characterized subsets of fingers from these ZFPs to define the correct orientation and register of the zinc fingers on their defined binding sites. By correlating individual fingers with motif subsites, we can assign finger specificity throughout each ZFP. This reveals the diversity of recognition potential within the naturally-occurring zinc fingers of a single organism, where the characterized fingers can specify 47 of the 64 possible DNA triplets. To confirm the utility of our finger recognition models, we have employed subsets of Drosophila fingers in combination with an existing archive of zinc finger modules to create ZFPs with novel DNA-binding specificity. These finger combinations can be used to create novel functional Zinc Finger Nucleases for editing vertebrate genomes. Illumina sequencing of Barcoded Binding sites obtained after B1H selection of Cys2-His2 zinc finger proteins cloned as a C-terminal fusions to the omega subunit of E. coli RNA polymerase in the B1H system.
2012-12-06 | E-GEOD-42709 | biostudies-arrayexpress
Project description:Nutritional status influences feeding behaviors, food preferences and taste sensations. For example, zinc-deficient rats have been reported to show reduced and cyclic food intake patterns with increased preferences for NaCl. Although some impairments of the central nervous and endocrine systems have been speculated to be involved in these phenomena, the effects of short-term zinc deficiency on the brain have not been well examined to date. In this study, we performed a comprehensive analysis of the gene expression patterns in the rat diencephalon, which is a portion of the brain that includes the hypothalamus and thalamus, after short-term zinc deficiency and also during zinc recovery. The rats showed reduced and cyclic food intake patterns with increased salt preferences after a 10-day dietary zinc deficiency. A comparative analysis of their diencephalons using cDNA microarrays revealed that approximately 1% of the genes expressed in the diencephalons showed significantly altered expression levels. On the other hand, a 6-day zinc supplementation following the deprivation allowed for the recovery to initial food intake behaviors and salt preferences. The expression levels of most of the genes that had been altered by exposure to zinc deficient conditions were also recovered. These results show that feeding behaviors, taste preferences and gene expression patterns in the diencephalon respond quickly to changing zinc levels. This suggests that the gene expression changes observed in the diencephalon and the accompanying functional changes may be related to the development of deviations in feeding behaviors and increased preferences for NaCl in zinc-deficient rats. Four-week-old male Sprague-Dawley rats were purchased from Charles River Japan (Yokohama, Japan). Fifteen rats were individually housed in a stainless steel cage in a room with constant humidity at 22 ± 1 °C under a 12 h light-dark cycle (lights on at 8:00). Zinc-deficient diets (# D19488M, Research Diets, New Brunswick, NJ, USA) were based on the AIN-93G diet and contained 0.6 mg zinc / 1000 g diet (Table 1). For the control zinc-sufficient diets, zinc sulfate supplements were provided with up to 30.0 mg zinc / 1000 g diet. Rats were fed the control diets ad libitum for 1 week for adaptation and then were divided into two groups matched for body weight. For the zinc-deficient experiment, rats in the ZD group (n =9) were allowed to eat the zinc-deficient diets ad libitum. The rats in the PF group (n = 6) were pair-fed the control diets to match the intake of the ZD rats. Two fluid bottles with deionized water were attached to each cage for the entire experiment with the exception of the 48 h preference test, in which 300 mM NaCl was provided from days 6 to 8. Zinc was limited for 10 days to reduce the effects of differences in salt intake in the preference test between the two groups. For the zinc recovery experiment, the ZR (n = 9) and ZRPF (n = 6) groups were subjected to the same conditions as above. Briefly, after 1 week of adaptation, ZR rats were fed the zinc-deficient diets ad libitum, and ZRPF rats were pair-fed the control diets for 10 days. After that, the rats in both the ZR and ZRPF groups were fed the fixed amount (13 g) of the control diets for the 6 day zinc recovery period to avoid any differences in food intake between the two groups that would be caused by pair-feeding because the previous report showed rapidly increased food intake following the initiation of the zinc-sufficient diets after zinc deficiency [1]. The diet amounts were restricted to the average consumption of the ZR group on the last day of the zinc-deficient period. The 48 h two-bottle preference tests for 300 mM NaCl were performed from days 6 to 8 during the deficient period and from days 14 to 16 during the recovery period. The analysis removed one rat from the ZRPF group showing more than a 0.5 of preference ratio to the 300 mM NaCl solution and three rats from the ZR group showing less than 0.5 preference ratios as assessed by a preference test that was conducted during days 6 to 8. At the end of each experiment, the rats were deeply anesthetized with pentobarbital sodium. Blood samples were collected from the carotid arteries and stored at -80 °C. The brains were quickly removed from the bodies after decapitation, and the diencephalons were separated by forceps on ice. The diencephalons were washed in ice-cold phosphate-buffered saline (PBS), treated with RNAlater (Invitrogen, Carlsbad, CA, USA), and stored at -20 °C. The serum zinc concentrations were analyzed with an ICP-AES (SPS 1200 VR, Seiko Instruments, Chiba, Japan). The Animal Care Committee of the University of Tokyo approved all animal experiments. Four average rats from each group were selected based on body weights, plasma zinc concentrations, and salt preferences.
2011-12-01 | E-GEOD-31430 | biostudies-arrayexpress