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BRCA1 Mutations Attenuate Super-Enhancer Function and Chromatin Looping in Haploinsufficient Human Breast Epithelial Cells

ABSTRACT: BRCA1 Mutations Attenuate Super-Enhancer Function and Chromatin Looping in Haploinsufficient Human Breast Epithelial Cells

PROVIDER: PRJNA496412 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8054030.fastq.gz	Fastqsanger.gz
	SRR8054025.fastq.gz	Fastqsanger.gz
	SRR8054026.fastq.gz	Fastqsanger.gz
	SRR8054027.fastq.gz	Fastqsanger.gz
	SRR8054028.fastq.gz	Fastqsanger.gz

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BRCA1 Mutations Attenuate Super-Enhancer Function and Chromatin Looping in Haploinsufficient Human Breast Epithelial Cells

Project description:BRCA1 functions in multiple biological processes, including double-strand break repair, replication stress suppression, transcriptional regulation, and chromatin reorganization. While non-malignant cells carrying cancer-predisposing BRCA1 mutations exhibit increased genomic instability, it remains unclear whether BRCA1 haploinsufficiency affects transcription and chromatin dynamics. Here we show that primary mammary epithelial cells from women with BRCA1 mutations (BRCA1mut/+) display significant loss of H3K27ac-associated super-enhancers.

2019-04-19 | GSE121229 | GEO

BRCA1 mutations attenuate super-enhancer function and chromatin looping in haploinsufficient human breast epithelial cells.

Project description:BackgroundBRCA1-associated breast cancer originates from luminal progenitor cells. BRCA1 functions in multiple biological processes, including double-strand break repair, replication stress suppression, transcriptional regulation, and chromatin reorganization. While non-malignant cells carrying cancer-predisposing BRCA1 mutations exhibit increased genomic instability, it remains unclear whether BRCA1 haploinsufficiency affects transcription and chromatin dynamics in breast epithelial cells.MethodsH3K27ac-associated super-enhancers were compared in primary breast epithelial cells from BRCA1 mutation carriers (BRCA1mut/+) and non-carriers (BRCA1+/+). Non-tumorigenic MCF10A breast epithelial cells with engineered BRCA1 haploinsufficiency were used to confirm the H3K27ac changes. The impact of BRCA1 mutations on enhancer function and enhancer-promoter looping was assessed in MCF10A cells.ResultsHere, we show that primary mammary epithelial cells from women with BRCA1 mutations display significant loss of H3K27ac-associated super-enhancers. These BRCA1-dependent super-enhancers are enriched with binding motifs for the GATA family. Non-tumorigenic BRCA1mut/+ MCF10A cells recapitulate the H3K27ac loss. Attenuated histone mark and enhancer activity in these BRCA1mut/+ MCF10A cells can be partially restored with wild-type BRCA1. Furthermore, chromatin conformation analysis demonstrates impaired enhancer-promoter looping in BRCA1mut/+ MCF10A cells.ConclusionsH3K27ac-associated super-enhancer loss is a previously unappreciated functional deficiency in ostensibly normal BRCA1 mutation-carrying breast epithelium. Our findings offer new mechanistic insights into BRCA1 mutation-associated transcriptional and epigenetic abnormality in breast epithelial cells and tissue/cell lineage-specific tumorigenesis.

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BRCA1 haploinsufficient Mesenchyme Derived from human peripheral blood Induced Pluripotent Stem Cell

Project description:BRCA1 molecule, known to be implicated in DNA repair and its alterations were associated to familial breast cancer prediposition. Genome of the patients with familial breast cancer predispostion harbor some germinal alterations in BRCA1 locus. Cells from peripheral blood of human with haplodeficiency BRCA1 locus and also from comparative sample (BRCA1 unaffected) were collected to produce induced pluripotent stem cell by classical protocol (Yamanaka OKSM) and Sendai Stem cell reprogammation which was validated by expression assessment of pluripotent stem cell markers and induction of teratoma after xenotransplantation mice model. Induced pluripotent stem cell (IPSC) were differentiated in mesenchymal lineage in order to see influence of BRCA1 effects during developmental steps of the stroma: effectively microenvironment of breast tumor is infiltrate of mesenchymal stromal cell. Total RNA of the mesenchyme derived IPS from control and BRCA1 haploinsufficient were respectively collected to screen whole expression analysis by transcriptome microarray.

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Chromatin looping evidence between PAX3-FOXO1 bound super enhancer and MYOD1 promoter [4C-seq]

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Chromatin interactions involving super-enhancers associate with specific expression patterns of target genes

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Proteomic analysis of somatosensory cortex of Pten haploinsufficient mice

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Expression data from mammary epithelial cells from BRCA1 mutation carriers and non BRCA1 mutation carriers

Project description:Female BRCA1 mutation carriers have a nearly 80% probability of developing breast cancer during their life-time. We hypothesized that the breast epithelium at risk in BRCA1 mutation carriers harbors mammary epithelial cells (MECs) with altered proliferation and differentiation properties. Microarray studies revealed that PMEC colonies from BRCA1 mutation carriers anticipate expression profiles found in BRCA1-related tumors, and that the EGFR pathway is upregulated in BRCA1 mutation carriers compared ton non BRCA1 mutation carriers. Keywords: Class comparison and pathway analysis

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CGH profiles of BRCA1-mutated tumors

Project description:While new defects in BRCA1 are still being found, it is unclear whether current breast cancer diagnostics misses many BRCA1-associated cases. A reliable test that is able to indicate the involvement of BRCA1 deficiency in cancer genesis could support decision making in genetic counselling and clinical management. To find BRCA1-specific markers and explore the effectiveness of the current diagnostic strategy, we designed a classification method, validated it and examined whether we could find BRCA1-like breast tumours in a group of patients initially diagnosed as non-BRCA1/2 mutation carriers. A classifier was built based on array-CGH profiles of 18 BRCA1-related and 32 control breast tumours, and validated on independent sets of 16 BRCA1-related and 16 control breast carcinomas. Subsequently, we applied the classifier to 48 breast tumours of patients from Hereditary Breast and Ovarian Cancer (HBOC) families in whom no germ line BRCA1/BRCA2 mutations were identified. The classifier showed an accuracy of 91% when applied to the validation sets. In 48 non-BRCA1/2 patients, only two breast tumours presented a BRCA1-like CGH profile. Additional evidence for BRCA1 dysfunction was found in one of these tumours. We here describe the specific chromosomal aberrations in BRCA1-related breast carcinomas. We developed a predictive genetic test for BRCA1-association and show that BRCA1-related tumours can still be identified in HBOC families after routine DNA diagnostics.

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