Project description:We confirmed that common CREBBP mutations in human FL result in reduced acetyltransferase activity of the protein, and modeled this loss of function by B-cell-specific deletion of one or both alleles of Crebbp in transgenic mouse models. We show that Crebbp deletion results in deficits in B-cell development, and provide the first evidence from transgenic mouse models that Crebbp inactivation can cooperate with Bcl2 over-expression to promote B-cell lymphoma. Through transcriptional and epigenetic profiling of these B-cells we found that Crebbp inactivation was associated with broad transcriptional alterations, but no changes in the patterns of histone acetylation at the regulatory regions of these genes. In contrast, B-cells with Crebbp inactivation showed high expression of Myc and patterns of altered histone acetylation that were localized to intragenic regions that were enriched for Myc DNA binding motifs and Myc binding. These transgenic models therefore provide important links between Crebbp inactivation and Bcl2 dependence, and a potential role for Crebbp inactivation in the induction of Myc expression.
Project description:The presence of unspliced transcripts in hematopoietic stem cells (HSCs) and the proposed association of CREBBP with the constitutive production of unspliced RNA and with pre-mRNA processing prompted us to examine more closely an anomaly we had noted in microarray-based gene expression studies but had previously attributed to experimental noise. We noticed that more than half of the probe sets down-regulated in Crebbp+/- fetal liver HSCs (FLHSCs) relative to wild-type (WT) mapped entirely within introns, rather than detecting exonic or spliced sequences. We therefore set out to test whether this might be evidence that reduced CREBBP levels selectively alter the generation of full-length, unspliced pre-mRNA. We also asked whether this process might be associated with differentiation since self-renewal and lineage commitment are the both responses for which HSCs are primed. Total RNA from wild-type, Crebbp+/-, Ep300+/-, Cdkn1a-/- FLHSCs and from wild type and Crebbp+/- mouse embryonic fibroblasts (MEFs) was isolated and hybridized to Affymetrix Mouse 430 2.0 expression microarrays. Fetal liver HSC RNA was amplified using the Ovation kit prior to hybridization. cell type comparison
Project description:This study assessed tumor suppressor roles of CREBBP in SCLC and other neuroendocrine tumors. Genetically engineered mouse models were used to determine the tumor suppressor role of Crebbp in SCLC and other neuroendocrine tumors.
Project description:This study assessed tumor suppressor roles of CREBBP in SCLC and other neuroendocrine tumors. Genetically engineered mouse models were used to determine the tumor suppressor role of Crebbp in SCLC and other neuroendocrine tumors.