Genome-wide analysis of ARNT/HIF binding sites in BeWo cells cultured under low oxygen
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE209936 | GEO | 2023/03/20
REPOSITORIES: GEO
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Project description:The adaptation of regimented exercise in skeletal muscle including muscular hypertrophy and enhanced strength decline significantly with aging. Transcriptome analysis following RNA sequencing reveals extensive activation of hypoxia-related genes in young exercised mice versus the sedentary, but absent in aged exercised mice. Particularly, less expression of aryl hydrocarbon receptor translocator (ARNT) was observed in response to exercise in aged mice. Young mice underwent skeletal muscle-specific knockout of ARNT (ARNT mKO) obtain deficient benefit from exercise resembling the aged mice. The deletion of ARNT associated with decreased expression of Notch1 intracellular domain(N1ICD) impair muscle hypertrophy and regeneration. Administration of ML228, a systematic agonist of ARNT, rescued skeletal muscle adaptabilities in old mice, which was suppressed by administrating N1ICD inhibitor(DAPT). These results suggest that the loss of skeletal muscle ARNT is partially responsible for diminished response to exercise in aging and activation of hypoxia signaling holds promise for rescuing the adaptability in aged muscle.
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Project description:The aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT) activated complex regulates genes in response to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). AHR has also emerged as a potential therapeutic target for the treatment of human diseases and different cancers, including breast cancer. To better understand AHR and ARNT signaling in breast cancer cells, we used chromatin immunoprecipitation linked to high throughput sequencing to identify AHR- and ARNT-binding sites across the genome in TCDD treated MCF-7 cells. We identified 2,594 AHR-bound, 1,352 ARNT-bound and 882 high confidence AHR/ARNT co-bound regions. No significant differences in the genomic distribution of AHR and ARNT were observed. Approximately 60% of the co-bound regions contained at least one core AHRE, 5'-GCGTG-3'. AHR/ARNT peak density was the highest within 1 kb of transcription start sites (TSS); however, a number of AHR/ARNT co-bound regions were located as far as 100 kb from TSS. De novo motif discovery identified a symmetrical variation of the AHRE (5'-GTGCGTG-3'), as well as FOXA1 and SP1 binding motifs. Microarray analysis identified 104 TCDD responsive genes where 98 genes were up-regulated by TCDD. Of the 104 regulated genes, 69 (66.3%) were associated with an AHR- or ARNT-bound region within 100 kb of their TSS. Overall our study identified AHR/ARNT co-bound regions across the genome, revealed the importance but not absolute requirement for an AHRE in AHR/ARNT interactions with DNA, and identified a modified AHRE motif, thereby increasing our understanding of AHR/ARNT signaling pathway. Examination of genome-wide AHR and ARNT binding pattern in MCF-7
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Project description:The aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT) activated complex regulates genes in response to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). AHR has also emerged as a potential therapeutic target for the treatment of human diseases and different cancers, including breast cancer. To better understand AHR and ARNT signaling in breast cancer cells, we used chromatin immunoprecipitation linked to high throughput sequencing to identify AHR- and ARNT-binding sites across the genome in TCDD treated MCF-7 cells. We identified 2,594 AHR-bound, 1,352 ARNT-bound and 882 high confidence AHR/ARNT co-bound regions. No significant differences in the genomic distribution of AHR and ARNT were observed. Approximately 60% of the co-bound regions contained at least one core AHRE, 5'-GCGTG-3'. AHR/ARNT peak density was the highest within 1 kb of transcription start sites (TSS); however, a number of AHR/ARNT co-bound regions were located as far as 100 kb from TSS. De novo motif discovery identified a symmetrical variation of the AHRE (5'-GTGCGTG-3'), as well as FOXA1 and SP1 binding motifs. Microarray analysis identified 104 TCDD responsive genes where 98 genes were up-regulated by TCDD. Of the 104 regulated genes, 69 (66.3%) were associated with an AHR- or ARNT-bound region within 100 kb of their TSS. Overall our study identified AHR/ARNT co-bound regions across the genome, revealed the importance but not absolute requirement for an AHRE in AHR/ARNT interactions with DNA, and identified a modified AHRE motif, thereby increasing our understanding of AHR/ARNT signaling pathway.
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Project description:We used hydrogen-deuterium exchange mass spectrometry (HDX-MS) to investigate the influence of OEA on HIF-3A-ARNT.HDX-MS data indicated that OEA binding stabilized multiple residues within the Gβ and Fα regions of HIF-3A PAS-B domain.It is possible that the stabilized Gβ and Fα function as an “interlayer” to further contact with the AB-loop of ARNT.
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