Key Super Enhancers Drive Tumor-Suppressing Transcription Feedback Programs in Mature B Cell Cancers (SNP array)
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ABSTRACT:
PROVIDER: PRJNA608515 | ENA |
REPOSITORIES: ENA
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Project description:Dynamic changes to the epigenome are essential regulators of B cell differentiation and, when perturbed, can lead to cancer. We compared three types of mature B cell lymphoma/leukemia (BCL) and normal lymphocytes to identify common and distinct epigenetic perturbations that promote oncogenesis. Purified malignant B cells from 52 patients (18 Follicular, 11 Diffuse Large B Cell, 23 Chronic Lymphocytic Lymphomas) and normal B cell subsets from 28 donor tonsils were subjected to chromatin immunoprecipitation and sequencing (ChIP-seq) for H3K4me1, H3K9/14ac, and H3K27ac; FAIRE-seq for open chromatin; RNA-seq; and genome copy number arrays. We identified a novel super enhancer (SE) connected to the aberrant expression of FCMR and PIGR in multiple BCL subtypes, which may drive the tissue-specific expression of the two immunoglobulin receptor genes. These integrative studies also revealed that loss of normal B cell SEs in BCL was associated with significant reduction in linked gene expression, the greatest impact among regulatory elements. Downregulation of crucial B cell transcription factors (TF) and tumor suppressors was consistent across BCL subtypes and linked to significantly diminished or absent active chromatin marks in adjacent SEs. These BCL-repressed SEs are enriched in binding sites for the same suppressed TFs that they regulate, suggesting transcriptional regulatory feedback loops for these key B cell identity genes. In sum, this study defined common alterations in the regulomes of mature B cell leukemias and lymphomas and implicate SEs as important hubs of tumor suppressing transcriptional feedback loops that are perturbed in B cell cancer.
2021-09-02 | GSE145846 | GEO
Project description:Key Super Enhancers Drive Tumor-Suppressing Transcription Feedback Programs in Mature B Cell Cancers
| PRJNA608506 | ENA
Project description:Dynamic changes to the epigenome are essential regulators of B cell differentiation and, when perturbed, can lead to cancer. We compared three types of mature B cell lymphoma/leukemia (BCL) and normal lymphocytes to identify common and distinct epigenetic perturbations that promote oncogenesis. Purified malignant B cells from 52 patients (18 Follicular, 11 Diffuse Large B Cell, 23 Chronic Lymphocytic Lymphomas) and normal B cell subsets from 28 donor tonsils were subjected to chromatin immunoprecipitation and sequencing (ChIP-seq) for H3K4me1, H3K9/14ac, and H3K27ac; FAIRE-seq for open chromatin; RNA-seq; and genome copy number arrays. We identified a novel super enhancer (SE) connected to the aberrant expression of FCMR and PIGR in multiple BCL subtypes, which may drive the tissue-specific expression of the two immunoglobulin receptor genes. These integrative studies also revealed that loss of normal B cell SEs in BCL was associated with significant reduction in linked gene expression, the greatest impact among regulatory elements. Downregulation of crucial B cell transcription factors (TF) and tumor suppressors was consistent across BCL subtypes and linked to significantly diminished or absent active chromatin marks in adjacent SEs. These BCL-repressed SEs are enriched in binding sites for the same suppressed TFs that they regulate, suggesting transcriptional regulatory feedback loops for these key B cell identity genes. In sum, this study defined common alterations in the regulomes of mature B cell leukemias and lymphomas and implicate SEs as important hubs of tumor suppressing transcriptional feedback loops that are perturbed in B cell cancer.
2021-09-02 | GSE145847 | GEO
Project description:Dynamic changes to the epigenome are essential regulators of B cell differentiation and, when perturbed, can lead to cancer. We compared three types of mature B cell lymphoma/leukemia (BCL) and normal lymphocytes to identify common and distinct epigenetic perturbations that promote oncogenesis. Purified malignant B cells from 52 patients (18 Follicular, 11 Diffuse Large B Cell, 23 Chronic Lymphocytic Lymphomas) and normal B cell subsets from 28 donor tonsils were subjected to chromatin immunoprecipitation and sequencing (ChIP-seq) for H3K4me1, H3K9/14ac, and H3K27ac; FAIRE-seq for open chromatin; RNA-seq; and genome copy number arrays. We identified a novel super enhancer (SE) connected to the aberrant expression of FCMR and PIGR in multiple BCL subtypes, which may drive the tissue-specific expression of the two immunoglobulin receptor genes. These integrative studies also revealed that loss of normal B cell SEs in BCL was associated with significant reduction in linked gene expression, the greatest impact among regulatory elements. Downregulation of crucial B cell transcription factors (TF) and tumor suppressors was consistent across BCL subtypes and linked to significantly diminished or absent active chromatin marks in adjacent SEs. These BCL-repressed SEs are enriched in binding sites for the same suppressed TFs that they regulate, suggesting transcriptional regulatory feedback loops for these key B cell identity genes. In sum, this study defined common alterations in the regulomes of mature B cell leukemias and lymphomas and implicate SEs as important hubs of tumor suppressing transcriptional feedback loops that are perturbed in B cell cancer.
2021-09-02 | GSE145842 | GEO
Project description:Dynamic changes to the epigenome are essential regulators of B cell differentiation and, when perturbed, can lead to cancer. We compared three types of mature B cell lymphoma/leukemia (BCL) and normal lymphocytes to identify common and distinct epigenetic perturbations that promote oncogenesis. Purified malignant B cells from 52 patients (18 Follicular, 11 Diffuse Large B Cell, 23 Chronic Lymphocytic Lymphomas) and normal B cell subsets from 28 donor tonsils were subjected to chromatin immunoprecipitation and sequencing (ChIP-seq) for H3K4me1, H3K9/14ac, and H3K27ac; FAIRE-seq for open chromatin; RNA-seq; and genome copy number arrays. We identified a novel super enhancer (SE) connected to the aberrant expression of FCMR and PIGR in multiple BCL subtypes, which may drive the tissue-specific expression of the two immunoglobulin receptor genes. These integrative studies also revealed that loss of normal B cell SEs in BCL was associated with significant reduction in linked gene expression, the greatest impact among regulatory elements. Downregulation of crucial B cell transcription factors (TF) and tumor suppressors was consistent across BCL subtypes and linked to significantly diminished or absent active chromatin marks in adjacent SEs. These BCL-repressed SEs are enriched in binding sites for the same suppressed TFs that they regulate, suggesting transcriptional regulatory feedback loops for these key B cell identity genes. In sum, this study defined common alterations in the regulomes of mature B cell leukemias and lymphomas and implicate SEs as important hubs of tumor suppressing transcriptional feedback loops that are perturbed in B cell cancer.
2021-09-02 | GSE145841 | GEO
Project description:Key Super Enhancers Drive Tumor-Suppressing Transcription Feedback Programs in Mature B Cell Cancers (RNA array)
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Project description:Key Super Enhancers Drive Tumor-Suppressing Transcription Feedback Programs in Mature B Cell Cancers (RNA-seq)
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Project description:Key Super Enhancers Drive Tumor-Suppressing Transcription Feedback Programs in Mature B Cell Cancers (ChIP-seq, FAIRE-seq)
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Project description:Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERα)-positive breast carcinogenesis. ERα-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERα-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERα-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERα-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERα-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERα phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERα-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERα-RET-ERα positive feedback loop in ERα-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
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