Chromatin interactome mapping at 139 independent breast cancer risk signals

Funder: National Breast Cancer Foundation; doi: http://dx.doi.org/10.13039/501100001026Funder: University of Queensland; doi: http://dx.doi.org/10.13039/501100001794Abstract: Background: Genome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression. Results: We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers, and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals and explore the functional mechanism underlying altered risk at the 12q24 risk region. Conclusions: Our results demonstrate the power of combining genetics, computational genomics, and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals

Chromatin interactome mapping at 139 independent breast cancer risk signals

Funder: National Breast Cancer Foundation; doi: http://dx.doi.org/10.13039/501100001026Funder: University of Queensland; doi: http://dx.doi.org/10.13039/501100001794Abstract: Background: Genome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression. Results: We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers, and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals and explore the functional mechanism underlying altered risk at the 12q24 risk region. Conclusions: Our results demonstrate the power of combining genetics, computational genomics, and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals

Role of the lysine methyltransferase Set7 in smooth muscle gene expression and function

Histone methylation is controlled by lysine methyltransferase enzymes to regulate the expression of genes implicated in cellular differentiation and lineage specificity. The lysine methyltransferase Set7 was originally described to monomethylate histone H3 on lysine 4 (H3K4me1) and more recently non-histone proteins. Set7 has been implicated in regulating key genes involved in the maintenance of pluripotency and skeletal and cardiac muscle development. While the importance of epigenetic modifiers in cardiac and skeletal muscle gene program has been described, epigenetic regulation of smooth muscle genes is poorly understood. The aims of this thesis are to identify (i) how the Set7 gene is regulated in embryonic stem cells; (ii) investigate the role of Set7 in smooth muscle gene regulation utilizing an in vitro stem cell differentiation system; and (iii) investigate the role of Set7 using a knockout mouse model. Promoter analysis of Set7 in mouse embryonic stem cells (mESCs) show bivalency with active H3K4me3 and repressive H3K27me3 modifications. The Set7 promoter is suppressed by the pluripotent transcription factors, Oct4 and Sox2. Deletion of the Oct4/Sox2 binding site activates Set7 transcription. Differentiation of mESCs is associated with reduced H3K27me3 and reduced Oct4 and Sox2 binding. Transcriptional network analysis identifies genes associated with differentiation are broadly regulated. More specifically, smooth muscle (SM)-associated gene expression is reduced in Set7 knockdown (KD) Sca1+ cells. Pharmacological inhibition of Set7 activity also reduces the expression of SM-associated genes corresponding with the results derived from Set7 KD cells. Furthermore, SM-associated gene regulation is subject to Set7 mediated methylation of H3K4me1 as well as the interaction with the Serum Response Factor (SRF) protein. Investigation of a Set7 knockout (KO) mouse model showed reduced expression of canonical SM-related genes in the aorta. Morphological abnormalities within SM layer of Set7-/- mice aorta were observed correlating with reduced vessel wall thickness and reduced SM cell number. Taken together, the results presented in this thesis suggest a novel role for Set7 in SM gene regulation, smooth muscle architecture and function. <br> <br

Set7 mediated interactions regulate transcriptional networks in embryonic stem cells

Histone methylation by lysine methyltransferase enzymes regulate the expression of genes implicated in lineage specificity and cellular differentiation. While it is known that Set7 catalyzes mono-methylation of histone and non-histone proteins, the functional importance of this enzyme in stem cell differentiation remains poorly understood. We show Set7 expression is increased during mouse embryonic stem cell (mESC) differentiation and is regulated by the pluripotency factors, Oct4 and Sox2. Transcriptional network analyses reveal smooth muscle (SM) associated genes are subject to Set7-mediated regulation. Furthermore, pharmacological inhibition of Set7 activity confirms this regulation. We observe Set7-mediated modification of serum response factor (SRF) and mono-methylation of histone H4 lysine 4 (H3K4me1) regulate gene expression. We conclude the broad substrate specificity of Set7 serves to control key transcriptional networks in embryonic stem cells

Current perspectives in Set7 mediated stem cell differentiation

Set7 is a key regulatory enzyme involved in the methylation of lysine residues of histone and non-histone proteins. This lysine methyltransferase is induced during stem cell differentiation and regulates lineage specific gene transcription and cell fate. In this article we discuss recent experimental evidence identifying regulatory targets under the control of Set7 as well as emerging evidence of regulation in stem cell differentiation. Furthermore, we discuss the function of non-coding RNAs regulated by Set7 implicated in cell plasticity

CRISPRi enables isoform-specific loss-of-function screens and identification of gastric cancer-specific isoform dependencies

10.1186/s13059-021-02266-6Genome Biology2214

Author Correction: CRISPRi enables isoform-specific loss-of-function screens and identification of gastric cancer-specific isoform dependencies (Genome Biology, (2021), 22, 1, (47), 10.1186/s13059-021-02266-6)

10.1186/s13059-021-02314-1Genome Biology2218

Chromatin interactome mapping at 139 independent breast cancer risk signals.

BACKGROUND:Genome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression. RESULTS:We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers, and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals and explore the functional mechanism underlying altered risk at the 12q24 risk region. CONCLUSIONS:Our results demonstrate the power of combining genetics, computational genomics, and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals

Chromatin interactome mapping at 139 independent breast cancer risk signals

Funder: National Breast Cancer Foundation; doi: http://dx.doi.org/10.13039/501100001026Funder: University of Queensland; doi: http://dx.doi.org/10.13039/501100001794Abstract: Background: Genome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression. Results: We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers, and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals and explore the functional mechanism underlying altered risk at the 12q24 risk region. Conclusions: Our results demonstrate the power of combining genetics, computational genomics, and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals