Dataset Information

The hepatic integrated stress response to asparaginase corresponds with transcriptional signatures that differ with age.

ABSTRACT: Clinical reports describing increased liver toxicity in adult versus pediatric patients treated with the anti-leukemic drug asparaginase suggest that hepatic stress responses differ with age. We utilized RNA sequencing to comparatively examine the liver transcriptomes of juvenile (2 wk old) and adult (8 and 16 wk old) mice following chronic exposure to asparaginase. Liver RNA from 2 and 16 week old mice were sent Sulzberger Columbia Genome Center for cDNA library preparation and sequencing at the same time as liver RNA from 8 week old mice (GSE92364). Asparaginase exposure altered the liver transcriptomes only modestly whereas age had a massive global influence. Unbiased exploration into the effect of age on drug responses revealed that the integrated stress response (ISR) represented a common, core molecular signature regardless of age. ISR engagement in juveniles corresponded with transcriptional signatures of downregulated lipid biosynthesis and increased sequestration of iron. In contrast, adults showed ISR activation alongside upregulation of Saa1 and Saa2 inflammatory markers, serine/glycine metabolism, and folate cycle suggesting mitochondrial stress. We also observed sporadic enrichment in RNA gene signatures reflecting altered nucleotide metabolism of adults in response to the drug. Taken together, our data show that maturity to adulthood does not alter the ISR gene signature to asparaginase. Instead, age-related changes in cellular resource capacity and turnover may be the determining factor in guiding hepatic stress responses to asparaginase.

ORGANISM(S): Mus musculus

PROVIDER: GSE122243 | GEO | 2018/12/25

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Microarray analysis of male and female CD-1 mouse liver was carried out at 3, 4, and 8 wk of age to elucidate developmental changes in gene expression from the pre-pubertal period to young adulthood. A large number of sex-biased and sex-independent genes showed significant changes during this developmental period. Notably, sex-independent genes involved in cell cycle, chromosome condensation, and DNA replication were down regulated from 3 wk to 8 wk, while genes associated with metal ion binding, ion transport and kinase activity were up regulated. A majority of genes showing sex differential expression in adult liver did not display sex differences prior to puberty, at which time extensive changes in sex-specific gene expression were seen, primarily in males. Thus, in male liver, 76% of male-specific genes were up regulated and 47% of female-specific genes were down regulated from 3 to 8 wk of age, whereas in female liver 67% of sex-specific genes showed no significant change in expression. In both sexes, genes up regulated from 3 to 8 wk were significantly enriched (p < E-76) in the set of genes positively regulated by the liver transcription factor HNF4M-NM-1, as determined in a liver-specific HNF4M-NM-1 knockout mouse model, while genes down regulated during this developmental period showed significant enrichment (p < E-65) for negative regulation by HNF4M-NM-1. Significant enrichment of the developmentally regulated genes in genes subject to positive and negative regulation by pituitary hormone was also observed. Nine sex-specific transcription factors showed pubertal changes in expression and may contribute to the developmental changes that onset after 3-4 wk. Overall, the observed changes in gene expression during postnatal liver development reflect the deceleration of liver growth and the induction of specialized liver functions, with widespread changes in sex-specific gene expression primarily occurring in male liver. Liver RNA isolated from the following six groups of CD-1 mice was used in the present study: 3 wk old male (M) mice (n = 10; 5 per each pool) and female (F) mice (n = 10; 5 per each pool); 4 wk old male mice (n = 12; 6 per each pool) and female mice (n = 12; 6 per each pool); 8 wk old male mice (n = 12; 6 per each pool) and female mice (n = 12; 6 per each pool). These RNA pools were used in seven separate sets of competitive hybridization experiments: 1) 3 wk M vs. 3 wk F; 2) 4 wk M vs. 4 wk F; 3) 8 wk M vs. 8 wk F; 4) 3 wk M vs. 8 wk M; 5) 4 wk M vs. 8 wk M; 6) 3 wk F vs. 8 wk F; 7) 4 wk F vs. 8 wk F. Fluorescent labeling of RNA and hybridization of the Alexa 555-labeled (green) and Alexa 647-labeled (red) aRNA samples to Agilent Mouse Gene Expression 4x44k v2 microarrays (Agilent Technology, Palo Alto, CA; catalog # G4846A-026655) were carried out, with dye swapping for each of the seven hybridization experiments to eliminate dye bias. Two microarrays, one for each mixed cDNA sample, were hybridized for each of the seven fluorescent reverse pairs, giving a total of 14 microarrays.

Project description:We identified genes expressed in mouse liver that are regulated by Cux2, a highly female-specific liver transcription factor whose expression is regulated by sex-dependent plasma GH patterns. Using adenovirus to overexpress Cux2 (Adeno-Cux2) in male liver, we show that Cux2 represses ~35% of male-biased genes and induces/de-represses ~35% of female-biased genes. Adeno-CMV was used as a control for adenoviral infection. (Published in Molec Cell Biology, TL Conforto et al, 2012) Liver RNA isolated from the following eight groups of mice was used in the present study: (1) 8 wk old untreated male (M) mice (n = 10; 5 per each pool); (2) 8 wk old untreated female mice (F) mice (n = 11; 5 or 6 per each pool); (3) 8 wk old male mice treated with Adeno-Cux2 and euthanized 5 days later (n = 12; 6 per each pool); (4) 8 wk old female mice treated with Adeno-Cux2 and euthanized 5 days later (n = 8; 4 per each pool); (5) 8 wk old male mice treated with Adeno-CMV and euthanized 5 days later (n = 13; 6 or 7 per each pool); (6) 8 wk old female mice treated with Adeno-CMV and euthanized 5 days later (n = 7; 3 or 4 per each pool); (7) 8 wk old male mice treated with Adeno-Cux2 and euthanized 3 days later (n=11; 5 or 6 per each pool); (8) 8 wk old male mice treated with Adeno-CMV and euthanized 3 days later (n=11; 5 or 6 per pool). These RNA pools were used in four separate sets of competitive hybridization experiments: 1) 8 wk untreated M vs. 8 wk untreated F; 2) 8 wk M + Ad-Cux2 (5 day) vs. 8 wk M + Ad-CMV (5 day); 3) 8 wk F + Ad-Cux2 (5 day) vs. 8 wk F + Ad-CMV (5 day); 4) 8 wk M + Ad-Cux2 (3 day) vs. 8 wk M + Ad-CMV (3 day). Fluorescent labeling of RNA and hybridization of the Alexa 555-labeled (green) and Alexa 647-labeled (red) RNA samples to Agilent Mouse Gene Expression 4x44k v1 microarrays (Agilent Technology, Palo Alto, CA; catalog # G4122F-014868) were carried out, with dye swapping for each of the three hybridization experiments to eliminate dye bias. Two microarrays, one for each mixed cDNA sample, were hybridized for each of the four fluorescent reverse pairs, giving a total of 8 microarrays.

Dataset Information

The hepatic integrated stress response to asparaginase corresponds with transcriptional signatures that differ with age.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure