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LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8;21) AML.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207234 | GEO | 2022/11/10

REPOSITORIES: GEO

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Similar Datasets

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8;21) AML.

Project description:Transcription factors (TFs) play critical roles in hematopoiesis, and their aberrant expression can lead to various types of leukemia. The t(8;21) leukemogenic fusion protein AML1-ETO (AE) is the most common fusion protein in acute myeloid leukemia and can enhance hematopoietic stem cell renewal while blocking differentiation. A key question in understanding AE-mediated leukemia is what determines the choice of AE to activate self-renewal genes or repress differentiation genes. Toward the resolution of this problem, we earlier showed that AE resides in the stable AETFC complex and that its components colocalize on up- or down-regulated target genes and are essential for leukemogenesis. In the current study, using biochemical and genomic approaches, we show that AE-containing complexes are heterogeneous, and that assembly of the larger AETFC (containing AE, CBFβ, HEB, E2A, LYL1, LMO2, and LDB1) requires LYL1. Furthermore, we provide strong evidence that the LYL1-containing AETFC preferentially binds to active enhancers and promotes AE-dependent gene activation. Moreover, we show that coactivator CARM1 interacts with AETFC and facilitates gene activation by AETFC. Collectively, this study describes a role of oncoprotein LYL1 in AETFC assembly and gene activation by recruiting CARM1 to chromatin for AML cell survival.

| S-EPMC9586329 | biostudies-literature

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8;21) AML [RNA-seq]

Project description:Transcription factors (TFs) play critical roles in hematopoiesis, and their aberrant expression can lead to various types of leukemia. The t(8;21) leukemogenic fusion protein AML1-ETO (AE) is the most common fusion protein in acute myeloid leukemia and can enhance hematopoietic stem cell renewal while blocking differentiation. A key question in understanding AE-mediated leukemia is what determines the choice of AE to activate self-renewal genes or repress differentiation genes. Toward the resolution of this problem, we earlier showed that AE resides in the stable AETFC complex and that its components co-localize on up- or down-regulated target genes and are essential for leukemogenesis. In the current study, using biochemical and genomic approaches, we show that AE-containing complexes are heterogeneous, and that assembly of the larger AETFC (containing AE, HEB, E2A, LYL1, LMO2 and LDB2) requires LYL1. Furthermore, we provide strong evidence that the LYL1-containing AETFC preferentially binds to active enhancers and promotes AE-dependent gene activation. Moreover, we show that coactivator CARM1 interacts with AETFC and facilitates gene activation by AETFC. Collectively, this study describes a novel role of oncoprotein LYL1 in AETFC assembly and gene activation by recruiting CARM1 to chromatin for AML cell survival.

2022-11-10 | GSE207233 | GEO

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8;21) AML [CHIP-seq]

Project description:Transcription factors (TFs) play critical roles in hematopoiesis, and their aberrant expression can lead to various types of leukemia. The t(8;21) leukemogenic fusion protein AML1-ETO (AE) is the most common fusion protein in acute myeloid leukemia and can enhance hematopoietic stem cell renewal while blocking differentiation. A key question in understanding AE-mediated leukemia is what determines the choice of AE to activate self-renewal genes or repress differentiation genes. Toward the resolution of this problem, we earlier showed that AE resides in the stable AETFC complex and that its components co-localize on up- or down-regulated target genes and are essential for leukemogenesis. In the current study, using biochemical and genomic approaches, we show that AE-containing complexes are heterogeneous, and that assembly of the larger AETFC (containing AE, HEB, E2A, LYL1, LMO2 and LDB2) requires LYL1. Furthermore, we provide strong evidence that the LYL1-containing AETFC preferentially binds to active enhancers and promotes AE-dependent gene activation. Moreover, we show that coactivator CARM1 interacts with AETFC and facilitates gene activation by AETFC. Collectively, this study describes a novel role of oncoprotein LYL1 in AETFC assembly and gene activation by recruiting CARM1 to chromatin for AML cell survival.

2022-11-10 | GSE207232 | GEO

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8 21) AML.

Project description:LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8 21) AML.

| PRJNA854203 | ENA

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8 21) AML [RNA-seq]

Project description:LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8 21) AML [RNA-seq]

| PRJNA854206 | ENA

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8 21) AML [CHIP-seq]

Project description:LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8 21) AML [CHIP-seq]

| PRJNA854207 | ENA

Destabilization of AETFC through C/EBPα-mediated repression of LYL1 contributes to t(8;21) leukemic cell differentiation.

Project description: Not available

| S-EPMC6880927 | biostudies-literature

Destabilization of AETFC through C/EBPalpha-mediated repression of LYL1 contributes to t(8;21) leukemic cell differentiation

Project description:In t(8;21) leukemic cells, the leukemogenic fusion protein AML1-ETO is stabilized and functions through the AML1-ETO-containing transcription factor complex (AETFC). Destabilization of AETFC thus provides a strategy to target AML1-ETO. In this study, we found that AETFC can be destabilized by a specific mechanism involving a direct repression of the core component LYL1 by C/EBPalpha at transcriptional level. We performed a ChIP-seq analysis of the genome-wide occupancy of C/EBPalpha and identifeid a -1 kb C/EBPalpha-binding site in the LYL1 locus that mediate this repression. As LYL1 acts as a linker between the AML1-ETO-E and LMO2-LDB1 parts of AETFC, depletion of LYL1 causes a destabilization of AETFC, which increases susceptibility of the leukemic cells to differentiation. Our results have provided a novel mechanism by which C/EBPalpha can directly destabilize AETFC, and have identified LYL1 as a new therapeutic target for treatment of t(8;21) leukemia.

2019-02-19 | GSE114642 | GEO

Different roles of E proteins in t(8;21) leukemia: E2-2 compromises the function of AETFC and negatively regulates leukemogenesis.

Project description:The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 20% of acute myeloid leukemia (AML) cases. In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AML1-ETO-containing transcription factor complex (AETFC), that contains multiple transcription (co)factors. Among these AETFC components, HEB and E2A, two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNA-binding capacity to AETFC, and are essential for leukemogenesis. However, the third E protein, E2-2, is specifically silenced in AML1-ETO-expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2-2 selectively inhibits the growth of AML1-ETO-expressing leukemic cells, and this inhibition requires the bHLH DNA-binding domain. RNA-seq and ChIP-seq analyses reveal that, despite some overlap, the three E proteins differentially regulate many target genes. In particular, studies show that E2-2 both redistributes AETFC to, and activates, some genes associated with dendritic cell differentiation and represses MYC target genes. In AML patients, the expression of E2-2 is relatively lower in the t(8;21) subtype, and an E2-2 target gene, THPO, is identified as a potential predictor of relapse. In a mouse model of human t(8;21) leukemia, E2-2 suppression accelerates leukemogenesis. Taken together, these results reveal that, in contrast to HEB and E2A, which facilitate AML1-ETO-mediated leukemogenesis, E2-2 compromises the function of AETFC and negatively regulates leukemogenesis. The three E proteins thus define a heterogeneity of AETFC, which improves our understanding of the precise mechanism of leukemogenesis and assists development of diagnostic/therapeutic strategies.

| S-EPMC6338862 | biostudies-literature

Addiction of t(8;21) and inv(16) AML to native RUNX1

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-08-17 | E-GEOD-45748 | biostudies-arrayexpress