Identification of a dynamic core transcriptional network in t(8;21) AML regulating differentiation block and self-renewal
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE60131 | GEO | 2014/09/24
SECONDARY ACCESSION(S): PRJNA257530
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-09-24 | E-GEOD-60131 | biostudies-arrayexpress
Project description:Oncogenic transcription factors such as RUNX1/ETO, which is generated by the chromosomal translocation t(8;21), subvert normal blood cell development by impairing differentiation and driving malignant self-renewal. Here, we use digital footprinting and chromatin immunoprecipitation sequencing (ChIP-seq) to identify the core RUNX1/ETO-responsive transcriptional network of t(8;21) cells. We show that the transcriptional program underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind to identical DNA sites in a mutually exclusive fashion. Perturbation of this equilibrium in t(8;21) cells by RUNX1/ETO depletion leads to a global redistribution of transcription factor complexes within preexisting open chromatin, resulting in the formation of a transcriptional network that drives myeloid differentiation. Our work demonstrates on a genome-wide level that the extent of impaired myeloid differentiation in t(8;21) is controlled by the dynamic balance between RUNX1/ETO and RUNX1 activities through the repression of transcription factors that drive differentiation.
| S-EPMC4487811 | biostudies-literature
Project description:The leukemogenic fusion protein RUNX1/ETO impairs myeloid differentiation and drives malignant self-renewal. Here we use digital footprinting and ChIP-sequencing to identify the core RUNX1/ETO responsive transcriptional network of t(8;21) cells. We show that the transcriptional programme underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind in a mutually exclusive fashion to identical genomic sites. Perturbation of this equilibrium by RUNX1/ETO knockdown results in a global reassembly of transcription factor complexes within pre-existing open chromatin and the formation of a new C/EBP-alpha-dominated transcriptional network driving myeloid differentiation. Our work demonstrates that the block in myeloid differentiation in t(8;21) is caused by the dynamic balance between RUNX1/ETO and RUNX1 activities and the repression of C/EBP-alpha and highlights the core targets of epigenetic reprogramming in t(8;21) AML. ChIP-sequencing and DNAse1-sequencing was used for the identification of a dynamic core transcriptional network in t(8;21) AML
2014-09-24 | E-GEOD-60130 | biostudies-arrayexpress
Project description:The leukemogenic fusion protein RUNX1/ETO impairs myeloid differentiation and drives malignant self-renewal. Here we use digital footprinting and ChIP-sequencing to identify the core RUNX1/ETO responsive transcriptional network of t(8;21) cells. We show that the transcriptional programme underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind in a mutually exclusive fashion to identical genomic sites. Perturbation of this equilibrium by RUNX1/ETO knockdown results in a global reassembly of transcription factor complexes within pre-existing open chromatin and the formation of a new C/EBP-dominated transcriptional network driving myeloid differentiation. Our work demonstrates that the block in myeloid differentiation in t(8;21) is caused by the dynamic balance between RUNX1/ETO and RUNX1 activities and the repression of C/EBP and highlights the core targets of epigenetic reprogramming in t(8;21) AML. ChIP-sequencing, DNAse1-sequencing and RNA-sequncing was used for the identification of a dynamic core transcriptional network in t(8;21) AML This submission represents the RNA-Seq component of the study
2014-09-24 | E-GEOD-54478 | biostudies-arrayexpress
Project description:The leukemogenic fusion protein RUNX1/ETO impairs myeloid differentiation and drives malignant self-renewal. Here we use digital footprinting and ChIP-sequencing to identify the core RUNX1/ETO responsive transcriptional network of t(8;21) cells. We show that the transcriptional programme underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind in a mutually exclusive fashion to identical genomic sites. Perturbation of this equilibrium by RUNX1/ETO knockdown results in a global reassembly of transcription factor complexes within pre-existing open chromatin and the formation of a new C/EBP-alpha-dominated transcriptional network driving myeloid differentiation. Our work demonstrates that the block in myeloid differentiation in t(8;21) is caused by the dynamic balance between RUNX1/ETO and RUNX1 activities and the repression of C/EBP-alpha and highlights the core targets of epigenetic reprogramming in t(8;21) AML.
2014-09-24 | GSE60130 | GEO
Project description:The leukemogenic fusion protein RUNX1/ETO impairs myeloid differentiation and drives malignant self-renewal. Here we use digital footprinting and ChIP-sequencing to identify the core RUNX1/ETO responsive transcriptional network of t(8;21) cells. We show that the transcriptional programme underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind in a mutually exclusive fashion to identical genomic sites. Perturbation of this equilibrium by RUNX1/ETO knockdown results in a global reassembly of transcription factor complexes within pre-existing open chromatin and the formation of a new C/EBP-dominated transcriptional network driving myeloid differentiation. Our work demonstrates that the block in myeloid differentiation in t(8;21) is caused by the dynamic balance between RUNX1/ETO and RUNX1 activities and the repression of C/EBP and highlights the core targets of epigenetic reprogramming in t(8;21) AML.
2014-09-24 | GSE54478 | GEO
Project description:Identification of a dynamic core transcriptional network in t(8;21) AML regulating differentiation block and self-renewal
| PRJNA257530 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-05-16 | E-GEOD-49252 | biostudies-arrayexpress
Project description:Embryonic stem cell (ESC) self-renewal and pluripotency is controlled by the coordinated action of transcription factors and chromatin regulators. Compared to the pluripotency transcription factors, the function of the chromatin regulators, especially the ATP-dependent chromatin remodelers, remains poorly understood in ESCs. Here, we show that INO80, a SWI/SNF family chromatin remodeling complex, is essential for ESC self-renewal, pluripotency, somatic cell reprogramming, and embryonic development. Ino80, the ATPase of the complex, forms an auto-regulatory loop with the ESC master transcription factors Oct4, Nanog, and Sox2. More importantly, it co-occupies the enhancer regions of most key pluripotency genes with the master transcription factors, and positively regulates their expression by maintaining an open chromatin structure. Our data suggests that INO80 is an integral component of the pluripotency transcription network, and plays a critical role in both the maintenance and establishment of pluripotency Mouse J1 cells were transfected with non-targeting (NT), Ino80, Ino80b, Ino80c or Ino80e siRNAs, and RNA was isolated 96 hours after transfection. agent: non-targeting siRNA: Mock_1, Mock_2 agent: Ino80 siRNA: Ino80a_1, Ino80a_2 agent: Ino80b siRNA: Ino80b_1, Ino80b_2 agent: Ino80c siRNA: Ino80c_1, Ino80c_2 agent: Ino80e siRNA: Ino80e_1, Ino80e_2 cell line: mouse J1 ESC: Mock_1, Mock_2, Ino80a_1, Ino80a_2, Ino80b_1, Ino80b_2, Ino80c_1, Ino80c_2, Ino80e_1, Ino80e_2 time: 96 hours: Mock_1, Mock_2, Ino80a_1, Ino80a_2, Ino80b_1, Ino80b_2, Ino80c_1, Ino80c_2, Ino80e_1, Ino80e_2 biological replicate: Ino80a_1, Ino80a_2 biological replicate: Ino80b_1, Ino80b_2 biological replicate: Ino80c_1, Ino80c_2 biological replicate: Ino80e_1, Ino80e_2 biological replicate: Mock_1, Mock_2
2014-05-16 | E-GEOD-49251 | biostudies-arrayexpress
Project description:Embryonic stem cell (ESC) self-renewal and pluripotency is controlled by the coordinated action of transcription factors and chromatin regulators. Compared to the pluripotency transcription factors, the function of the chromatin regulators, especially the ATP-dependent chromatin remodelers, remains poorly understood in ESCs. Here, we show that INO80, a SWI/SNF family chromatin remodeling complex, is essential for ESC self-renewal, pluripotency, somatic cell reprogramming, and embryonic development. Ino80, the ATPase of the complex, forms an auto-regulatory loop with the ESC master transcription factors Oct4, Nanog, and Sox2. More importantly, it co-occupies the enhancer regions of most key pluripotency genes with the master transcription factors, and positively regulates their expression by maintaining an open chromatin structure. Our data suggests that INO80 is an integral component of the pluripotency transcription network, and plays a critical role in both the maintenance and establishment of pluripotency Mouse J1 cells were infected with lentiviral-shNT or lentiviral-Ino80, RNA was extracted at 2, 4 or 6 days after infection. agent: non-targeting shRNA: NS_Day_2_1, NS_Day_2_2, NS_Day_4_1, NS_Day_4_2, NS_Day_6_1, NS_Day_6_2 agent: Ino80 shRNA: shIno80_Day_2_1, shIno80_Day_2_2, shIno80_Day_4_1, shIno80_Day_4_2, shIno80_Day_6_1, shIno80_Day_6_2 time: 48 hours: NS_Day_2_1, NS_Day_2_2, shIno80_Day_2_1, shIno80_Day_2_2 time: 96 hours: NS_Day_4_1, NS_Day_4_2, shIno80_Day_4_1, shIno80_Day_4_2 time: 144 hours: NS_Day_6_1, NS_Day_6_2, shIno80_Day_6_1, shIno80_Day_6_2 cell line: mouse J1 ESC: NS_Day_2_1, NS_Day_2_2, shIno80_Day_2_1, shIno80_Day_2_2, NS_Day_4_1, NS_Day_4_2, shIno80_Day_4_1, shIno80_Day_4_2, NS_Day_6_1, NS_Day_6_2, shIno80_Day_6_1, shIno80_Day_6_2 biological replicate: shIno80_Day_2_1, shIno80_Day_2_2 biological replicate: shIno80_Day_4_1, shIno80_Day_4_2 biological replicate: shIno80_Day_6_1, shIno80_Day_6_2 biological replicate: NS_Day_2_1, NS_Day_2_2 biological replicate: NS_Day_4_1, NS_Day_4_2 biological replicate: NS_Day_6_1, NS_Day_6_2
2014-05-16 | E-GEOD-49250 | biostudies-arrayexpress