BCL11A promotes myeloid leukemogenesis by abrogating the transcriptional activity of PU.1 [array]
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ABSTRACT:
PROVIDER: PRJNA616393 | ENA |
REPOSITORIES: ENA
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Project description:The transcriptional repressor Bcl11a is involved in hematological malignancies, B-cell development and fetal to adult hemoglobin switching, however, the molecular mechanism how Bcl11a promotes development of myeloid leukemia remains largely unknown. We found that Bcl11a cooperates with the pseudokinase Trib1 in AML development. Bcl11a promotes proliferation of Trib1-expressing AML cells both in vitro and in vivo. ChIP-seq analysis showed that Bcl11a is significantly associated on DNA-binding with PU.1 that promotes myeloid differentiation, and Bcl11a represses a number of PU.1 target genes such as Clec5a, Fcgr3 and Csf1r. The repression of PU.1 target genes by Bcl11a is achieved by both sequence-specific DNA binding activity and recruitment of corepressors by Bcl11a, and suppression of corepressor components HDAC1 and LSD1 cancelled the repressive activity. Association of high level of expression of BCL11A and worse prognosis is observed in human AML patients, and blocking of BCL11A expression upregulates PU.1 target expression, inhibits engraftment to bone marrow, and enhances myeloid differentiation of HL-60 cells, suggesting that BCL11A is involved in human myeloid malignancies via the PU.1 transcriptional activity. We used microarrays to detail the global program of gene expression in mouse AML
2021-12-21 | GSE147797 | GEO
Project description:The transcriptional repressor Bcl11a is involved in hematological malignancies, B-cell development and fetal to adult hemoglobin switching, however, the molecular mechanism how Bcl11a promotes development of myeloid leukemia remains largely unknown. We found that Bcl11a cooperates with the pseudokinase Trib1 in AML development. Bcl11a promotes proliferation of Trib1-expressing AML cells both in vitro and in vivo. ChIP-seq analysis showed that Bcl11a is significantly associated on DNA-binding with PU.1 that promotes myeloid differentiation, and Bcl11a represses a number of PU.1 target genes such as Clec5a, Fcgr3 and Csf1r. The repression of PU.1 target genes by Bcl11a is achieved by both sequence-specific DNA binding activity and recruitment of corepressors by Bcl11a, and suppression of corepressor components HDAC1 and LSD1 cancelled the repressive activity. Association of high level of expression of BCL11A and worse prognosis is observed in human AML patients, and blocking of BCL11A expression upregulates PU.1 target expression, inhibits engraftment to bone marrow, and enhances myeloid differentiation of HL-60 cells, suggesting that BCL11A is involved in human myeloid malignancies via the PU.1 transcriptional activity.
2021-12-21 | GSE147787 | GEO
Project description:BCL11A promotes myeloid leukemogenesis by abrogating the transcriptional activity of PU.1
| PRJNA616392 | ENA
Project description:BCL11A promotes myeloid leukemogenesis by abrogating the transcriptional activity of PU.1 [ChIP-seq]
| PRJNA616362 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-12-21 | GSE147798 | GEO
Project description:Hematopoietic stem cells sustain life-long blood production. While they are the known cellular origin of aging-associated myeloid malignancies, such as acute myeloid leukemia (AML), mechanisms driving their malignant transformation have remained elusive. Epigenetic dysregulation following acquired loss-of-function mutations of DNA methyl-cytosine dioxygenase Ten-Eleven Translocation-2 (TET2) occurs frequently in the elderly leading to cytosine hypermethylation in and around DNA binding sites of master transcription factors, including PU.1. Here we show that Tet2 deficient hematopoietic stem and progenitor cells (HSPC) undergo malignant transformation upon compromised PU.1 gene regulation. Leukemic stem and progenitor cells show hypermethylation at PU.1 binding sites and fail to activate PU.1-depenent myeloid enhancers, and are hallmarked by a defined signature of impaired genes shared with human AML. Our study demonstrates that Tet2 and PU.1 cooperate in suppressing leukemogenesis in HSPC and establishes a methylation sensitive PU.1-dependent gene network as a unifying feature in acute myeloid leukemia.
2022-07-31 | GSE191052 | GEO
Project description:Hematopoietic stem cells sustain life-long blood production. While they are the known cellular origin of aging-associated myeloid malignancies, such as acute myeloid leukemia (AML), mechanisms driving their malignant transformation have remained elusive. Epigenetic dysregulation following acquired loss-of-function mutations of DNA methyl-cytosine dioxygenase Ten-Eleven Translocation-2 (TET2) occurs frequently in the elderly leading to cytosine hypermethylation in and around DNA binding sites of master transcription factors, including PU.1. Here we show that Tet2 deficient hematopoietic stem and progenitor cells (HSPC) undergo malignant transformation upon compromised PU.1 gene regulation. Leukemic stem and progenitor cells show hypermethylation at PU.1 binding sites and fail to activate PU.1-depenent myeloid enhancers, and are hallmarked by a defined signature of impaired genes shared with human AML. Our study demonstrates that Tet2 and PU.1 cooperate in suppressing leukemogenesis in HSPC and establishes a methylation sensitive PU.1-dependent gene network as a unifying feature in acute myeloid leukemia.
2022-07-31 | GSE186146 | GEO
Project description:Hematopoietic stem cells sustain life-long blood production. While they are the known cellular origin of aging-associated myeloid malignancies, such as acute myeloid leukemia (AML), mechanisms driving their malignant transformation have remained elusive. Epigenetic dysregulation following acquired loss-of-function mutations of DNA methyl-cytosine dioxygenase Ten-Eleven Translocation-2 (TET2) occurs frequently in the elderly leading to cytosine hypermethylation in and around DNA binding sites of master transcription factors, including PU.1. Here we show that Tet2 deficient hematopoietic stem and progenitor cells (HSPC) undergo malignant transformation upon compromised PU.1 gene regulation. Leukemic stem and progenitor cells show hypermethylation at PU.1 binding sites and fail to activate PU.1-depenent myeloid enhancers, and are hallmarked by a defined signature of impaired genes shared with human AML. Our study demonstrates that Tet2 and PU.1 cooperate in suppressing leukemogenesis in HSPC and establishes a methylation sensitive PU.1-dependent gene network as a unifying feature in acute myeloid leukemia.
2022-07-31 | GSE194170 | GEO
Project description:The plasmacytoid dendritic cell (pDC) is vital to the coordinated action of innate and adaptive immunity. pDC development has not been unequivocally traced, nor has its transcriptional regulatory network been fully clarified. Here we confirm an essential requirement for the BCL11A transcription factor in fetal pDC development, and demonstrate this lineage-specific requirement in the adult organism. Furthermore, we identify BCL11A gene targets and provide a molecular mechanism for its action in pDC commitment. Embryonic germ-line deletion of Bcl11a revealed an absolute cellular, molecular, and functional absence of pDCs in fetal mice. In adults, deletion of Bcl11a in hematopoietic stem cells resulted in perturbed yet continued generation of progenitors, loss of downstream pDC and B-cell lineages, and persisting myeloid, conventional dendritic, and T-cell lineages. Challenge with virus resulted in a marked reduction of antiviral response in conditionally deleted adults. Genome-wide analyses of BCL11A DNA binding and expression revealed that BCL11A regulates transcription of E2-2 and other pDC differentiation modulators, including ID2 and MTG16. Our results identify BCL11A as an essential, lineage- specific factor that regulates pDC development, supporting a model wherein differentiation into pDCs represents a primed "default" pathway for common dendritic cell progenitors. Raji cells were infected with retroviruses containing pXY-PURO (negative control vector) or pXY-BCL11A-XS. BJAB cells were infected with retroviruses containing pXY-PURO (negative control vector) or pXY-BCL11A-XL. Two arrays measured Raji BCL11A-XS expression and two arrays measured BJAB BCL11A-XL expression.
2015-02-01 | E-GEOD-55237 | biostudies-arrayexpress
Project description:Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the beta-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here we examine BCL11A as a potential regulator of HbF expression. The high HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the beta-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in beta-hemoglobin disorders. BCL11A siRNA label: B, NT siRNA label: N Experiment Overall Design: Microarray expression analysis from CD34-derived erythroid progenitors treated with either non-targeting (NT) control siRNAs or BCL11A targeting siRNAs. Six samples from the NT control and six samples from the BCL11A siRNA treatment are included. Cells were harvested on day 7 of erythroid differentiation after introduction of siRNAs on day 0 of the differentiation protocol. Experiment Overall Design: 6 BCL11A siRNA datasets, 6 control (NT) datasets
2009-01-13 | E-GEOD-13284 | biostudies-arrayexpress