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The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer

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

ORGANISM(S): Mus musculus

SUBMITTER: Jae Seok Roe

PROVIDER: E-GEOD-66234 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer [ChIP-Seq]

Project description:Most mammalian transcription factors and cofactors occupy thousands of genomic sites and modulate the expression of large gene networks to implement their biological functions. In this study, we describe an exception to this paradigm. TRIM33 is identified here as a lineage dependency in B cell neoplasms and is shown to perform this essential function by associating with a single cis element. ChIP-seq analysis of TRIM33 in murine B cell leukemia revealed a preferential association with two lineage-specific enhancers that harbor an exceptional density of motifs recognized by the PU.1 transcription factor. TRIM33 is recruited to these elements by PU.1, yet acts to antagonize PU.1 function. One of the PU.1/TRIM33 co-occupied enhancers is upstream of the pro-apoptotic gene Bim, and deleting this enhancer renders TRIM33 dispensable for leukemia cell survival. These findings reveal an essential role for TRIM33 in preventing apoptosis in B lymphoblastic leukemia by interfering with enhancer-mediated Bim activation. ChIP-Seq for Trim33, Pu.1 and histone modification marks in different types of leukemia cells

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Hematopoietic transcription factors and p300/CBP shape the effects of BET bromodomain inhibition in leukemia [ChIP-Seq]

Project description:The bromodomain and extraterminal (BET) protein Brd4 is a validated drug target in leukemia, yet its regulatory function in this disease is not well understood. Here, we show that Brd4 chromatin occupancy in acute myeloid leukemia closely correlates with the hematopoietic transcription factors (TFs) Pu.1, Fli1, Erg, C/EBPα, C/EBPβ, and Myb at nucleosome-depleted enhancer and promoter regions. We provide evidence that these TFs, in conjunction with the lysine acetyltransferase activity of p300/CBP, facilitate Brd4 recruitment to their occupied sites to promote transcriptional activation. Moreover, chemical inhibition of BET bromodomains is found to suppress the functional output each hematopoietic TF, thereby interfering with essential lineage-specific transcriptional circuits in this disease. These findings reveal a chromatin-based signaling cascade comprised of hematopoietic TFs, p300/CBP, and Brd4, which supports leukemia maintenance and is suppressed by BET bromodomain inhibition. ChIP-Seq for regulatory factors of Brd4 in MLL-AF9 transformed acute myeloid leukemia cells (RN2)

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The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer [RNA-Seq]

Project description:Most mammalian transcription factors and cofactors occupy thousands of genomic sites and modulate the expression of large gene networks to implement their biological functions. In this study, we describe an exception to this paradigm. TRIM33 is identified here as a lineage dependency in B cell neoplasms and is shown to perform this essential function by associating with a single cis element. ChIP-seq analysis of TRIM33 in murine B cell leukemia revealed a preferential association with two lineage-specific enhancers that harbor an exceptional density of motifs recognized by the PU.1 transcription factor. TRIM33 is recruited to these elements by PU.1, yet acts to antagonize PU.1 function. One of the PU.1/TRIM33 co-occupied enhancers is upstream of the pro-apoptotic gene Bim, and deleting this enhancer renders TRIM33 dispensable for leukemia cell survival. These findings reveal an essential role for TRIM33 in preventing apoptosis in B lymphoblastic leukemia by interfering with enhancer-mediated Bim activation. RNA-Seq for shRNAs targeting Trim33 expressing B-ALL

2015-04-06 | E-GEOD-66232 | biostudies-arrayexpress

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2016-03-01 | E-GEOD-74536 | biostudies-arrayexpress

BET inhibition releases the Mediator complex from specific cis elements in acute myeloid leukemia cells (ChIP-Seq II)

Project description:Genome occupancy profiling by high throughput sequencing ChIP-seq of Brd4 with or without Doxycycline treatment to induce Med12 or Med23 shRNAs in MLL-AF9 transformed acute myeloid leukemia cells (RN2)

2016-03-01 | E-GEOD-78221 | biostudies-arrayexpress

BET inhibition releases the Mediator complex from specific cis elements in acute myeloid leukemia cells

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

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The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer.

Project description:Most mammalian transcription factors (TFs) and cofactors occupy thousands of genomic sites and modulate the expression of large gene networks to implement their biological functions. In this study, we describe an exception to this paradigm. TRIM33 is identified here as a lineage dependency in B cell neoplasms and is shown to perform this essential function by associating with a single cis element. ChIP-seq analysis of TRIM33 in murine B cell leukemia revealed a preferential association with two lineage-specific enhancers that harbor an exceptional density of motifs recognized by the PU.1 TF. TRIM33 is recruited to these elements by PU.1, yet acts to antagonize PU.1 function. One of the PU.1/TRIM33 co-occupied enhancers is upstream of the pro-apoptotic gene Bim, and deleting this enhancer renders TRIM33 dispensable for leukemia cell survival. These findings reveal an essential role for TRIM33 in preventing apoptosis in B lymphoblastic leukemia by interfering with enhancer-mediated Bim activation.

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NSD3-short is an adaptor protein that couples BRD4 to the CHD8 chromatin remodeler (ChIP-Seq)

Project description:The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome, and each is released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription. ChIP-Seq for regulatory factors of BRD4, NSD3, CHD8 and histone modification H3K36me2 in MLL-AF9 transformed acute myeloid leukemia cells (RN2)

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NSD3-short is an adaptor protein that couples BRD4 to the CHD8 chromatin remodeler

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

2015-12-17 | E-GEOD-71186 | biostudies-arrayexpress