SMARCA5 deficiency reprograms AKR1B1-mediated endogenous fructose metabolism to eradicate leukemia stem cells in acute myeloid leukemia
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ABSTRACT:
PROVIDER: PRJNA901174 | ENA |
REPOSITORIES: ENA
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Project description:A significant variation in chromatin accessibility is an epigenetic feature in leukemia cells. However, the regulators and consequences of the chromatin accessibility variations in leukemia remain elusive. Here we identified SMARCA5, a core ATPase of the ISWI chromatin remodeling complex, as the primary regulator of chromatin accessibility in acute myeloid leukemia (AML) by CRISPR-Cas9 library screening. We found that SMARCA5 is required for self-renewal of leukemia stem cells and myeloid leukemogenesis. Mechanistically, SMARCA5 promotes the transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1 to its promoter. Clinical sample analysis has shown that high expression of AKR1B1 predicts a poor prognosis in AML patients. Interestingly, AKR1B1-mediated endogenous fructose metabolism is reprogrammed by Smarca5 in AML. Overexpression of AKR1B1 rescued the leukemogenesis impaired by Smarca5 deficiency. Moreover, pharmacological inhibition of AKR1B1 displayed significant therapeutic effects in the AML patient-derived xenograft (PDX) mouse model. Thus, our findings link chromatin state dynamics regulated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming, and uncover an essential role of AKR1B1 in AML, which may provide a therapeutic target for AML patients.
2023-10-04 | GSE217881 | GEO
Project description:We hypothesize that the ISWI ATPase Smarca5 plays a role in hematopoietic stem cell development via its interaction partners, and to study the role, we used a mouse model with transgenic expression of SMARCA5 coupled with mass spectrometry analysis. The study uses transgenic SMARCA5 mouse model with conditional hypomorphic allele (lower expression on protein level compared to controls) incorporated into Rosa26 locus, transgenic allele uses endogenous Rosa26 promoter. The transgenic human SMARCA5 protein has a FLAG tag at its C-terminus, which allows specific immunoprecipitation and also differentiation from the endogenous protein (human and mouse SMARCA5 are almost identical at the protein level). To ensure the highest possible expression of the transgenic allele, we used a model that also had one endogenous Smarca5 allele deleted. Various organs (thymus, spleen, brain, kidney, liver, testes, muscle, fetal liver) were isolated from transgenic mice, lysed and then immunoprecipitated using anti-FLAG antibody. The immunoprecipitates were then analyzed using mass spectrometry to determine SMARCA5 interactomes in various tissues. Transgenic human SMARCA5 was confirmed to form all the expected complexes and capable of replacing the functions of the mouse protein. For details, see the publication of Turkova et al. 2024 in Communications Biology.
2024-06-22 | PXD049034 | Pride
Project description:Identify and eradicate leukemia stem cells in T-cell acute lymphoblastic leukemia by PD-1 therapy
| PRJNA890196 | ENA
Project description:Gene expression profiling of mouse cerebellum in which the experimental strain conditionally lack the Smarca5 gene that encodes for the catalytic subunit of multiple chromatin remodeling complexes. Deletion of Smarca5 was restricted to those cells expressing Cre-recombinase driven by the Nestin promoter. Comparison of gene expression in P0 cerebella of Smarca5 cKO mice versus wild type controls. Three samples of each strain were used in a total of 4 replicates.
2014-04-30 | E-GEOD-42369 | biostudies-arrayexpress
Project description:Gene expression profiling of mouse cerebellum in which the experimental strain conditionally lack the Smarca5 gene that encodes for the catalytic subunit of multiple chromatin remodeling complexes. Deletion of Smarca5 was restricted to those cells expressing Cre-recombinase driven by the Nestin promoter. Comparison of gene expression in P10 cerebella of Smarca5 cKO mice versus wild type controls. Three samples of each strain were used in a total of 3 replicates.
2014-04-30 | E-GEOD-42370 | biostudies-arrayexpress
Project description:Genetic models suggested that SMARCA5 was required for DNA templated events including transcription, DNA replication and DNA repair. We engineered a degron tag into the endogenous alleles of SMARCA5, a catalytic component of the imitation switch (ISWI) complexes, in three different human cell lines to define the effects of rapid degradation of this key regulator. Degradation of SMARCA5 was associated with a rapid increase in global nucleosome repeat length, which may allow greater chromatin compaction. However, there were few changes in nascent transcription within the first 6hr of degradation. Nevertheless, we demonstrated a requirement for SMARCA5 to control nucleosome repeat length at G1/S and during the S phase. SMARCA5 co-localized with CTCF and H2A.Z, and we found a rapid loss of CTCF DNA binding and disruption of nucleosomal phasing around CTCF binding sites. This spatiotemporal analysis indicates that SMARCA5 is continuously required for maintaining nucleosomal spacing.
2023-03-01 | GSE160468 | GEO
Project description:Genetic models suggested that SMARCA5 was required for DNA templated events including transcription, DNA replication and DNA repair. We engineered a degron tag into the endogenous alleles of SMARCA5, a catalytic component of the imitation switch (ISWI) complexes, in three different human cell lines to define the effects of rapid degradation of this key regulator. Degradation of SMARCA5 was associated with a rapid increase in global nucleosome repeat length, which may allow greater chromatin compaction. However, there were few changes in nascent transcription within the first 6hr of degradation. Nevertheless, we demonstrated a requirement for SMARCA5 to control nucleosome repeat length at G1/S and during the S phase. SMARCA5 co-localized with CTCF and H2A.Z, and we found a rapid loss of CTCF DNA binding and disruption of nucleosomal phasing around CTCF binding sites. This spatiotemporal analysis indicates that SMARCA5 is continuously required for maintaining nucleosomal spacing.
2023-03-01 | GSE160459 | GEO
Project description:Genetic models suggested that SMARCA5 was required for DNA templated events including transcription, DNA replication and DNA repair. We engineered a degron tag into the endogenous alleles of SMARCA5, a catalytic component of the imitation switch (ISWI) complexes, in three different human cell lines to define the effects of rapid degradation of this key regulator. Degradation of SMARCA5 was associated with a rapid increase in global nucleosome repeat length, which may allow greater chromatin compaction. However, there were few changes in nascent transcription within the first 6hr of degradation. Nevertheless, we demonstrated a requirement for SMARCA5 to control nucleosome repeat length at G1/S and during the S phase. SMARCA5 co-localized with CTCF and H2A.Z, and we found a rapid loss of CTCF DNA binding and disruption of nucleosomal phasing around CTCF binding sites. This spatiotemporal analysis indicates that SMARCA5 is continuously required for maintaining nucleosomal spacing.
2023-03-01 | GSE160458 | GEO
Project description:Genetic models suggested that SMARCA5 was required for DNA templated events including transcription, DNA replication and DNA repair. We engineered a degron tag into the endogenous alleles of SMARCA5, a catalytic component of the imitation switch (ISWI) complexes, in three different human cell lines to define the effects of rapid degradation of this key regulator. Degradation of SMARCA5 was associated with a rapid increase in global nucleosome repeat length, which may allow greater chromatin compaction. However, there were few changes in nascent transcription within the first 6hr of degradation. Nevertheless, we demonstrated a requirement for SMARCA5 to control nucleosome repeat length at G1/S and during the S phase. SMARCA5 co-localized with CTCF and H2A.Z, and we found a rapid loss of CTCF DNA binding and disruption of nucleosomal phasing around CTCF binding sites. This spatiotemporal analysis indicates that SMARCA5 is continuously required for maintaining nucleosomal spacing.
2023-03-01 | GSE160469 | GEO
Project description:Genetic models suggested that SMARCA5 was required for DNA templated events including transcription, DNA replication and DNA repair. We engineered a degron tag into the endogenous alleles of SMARCA5, a catalytic component of the imitation switch (ISWI) complexes, in three different human cell lines to define the effects of rapid degradation of this key regulator. Degradation of SMARCA5 was associated with a rapid increase in global nucleosome repeat length, which may allow greater chromatin compaction. However, there were few changes in nascent transcription within the first 6hr of degradation. Nevertheless, we demonstrated a requirement for SMARCA5 to control nucleosome repeat length at G1/S and during the S phase. SMARCA5 co-localized with CTCF and H2A.Z, and we found a rapid loss of CTCF DNA binding and disruption of nucleosomal phasing around CTCF binding sites. This spatiotemporal analysis indicates that SMARCA5 is continuously required for maintaining nucleosomal spacing.
2023-03-01 | GSE220778 | GEO