Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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ATACseq of mouse hematopoietic stem cells after 4 hours of LPS/PBS treatment in vivo

ABSTRACT: To understand whether hematopoietic stem cells (HSCs) take part in emergency granulopoiesis, WT C57BL6 mice were treated intraperitoneally with 35 ug of lipopolysacharide (LPS) to induce emergency granulopoiesis, or PBS control. Mice were sacrificed 4 hours after the treatment and HSCs (Lin-c-Kit+Sca-1+CD48-CD150+) were sorted and subjected to bulk ATACseq.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Mus musculus

SUBMITTER: Jan Kubovčiak

PROVIDER: E-MTAB-12310 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Cholangiocarcinoma (CCA) is a devastating liver cancer characterized by high aggressiveness and resistance to therapy, which results to poor prognosis. Signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ) frequently contribute to CCA development. In this study, we explored novel effectors of the TGFβ pathway in CCA by gene expression profiling. We identified the long non-coding RNA LINC00313 as a novel target gene of TGFβ signalling in CCA cells. TGFβ induced LINC00313 expression in a TβRI/Smad-dependent manner. Subcellular fractionation showed that LINC00313 is a predominantly nuclear lncRNA. By integrating RNA-seq and ATAC-seq data from LINC00313 over-expressing cells, we observed that LINC00313 regulates the expression of several genes involved in the Wnt signalling pathway. As a proof of concept, we focused on the gene encoding transcription factor 7 (TCF7), a major effector that drives transcription of Wnt-target genes. LINC00313 gain of function resulted in increased TCF7 expression, while its loss of function diminished basal or TGFβ-induced TCF7 expression levels. Interestingly, LINC00313 enhanced basal or chemically induced TCF/LEF-dependent transcriptional responses, promoted colony-forming capacities of CCA cells in vitro and accelerated tumor growth in vivo. We also report that genes associated with LINC00313 over-expression recapitulate poor prognosis human CCA associated with a reduced overall survival and KRAS mutations. To decipher the underlying molecular functions of LINC00313, we identified its interacting proteins by performing an unbiased RNA pull-down assay followed by mass spectrometry. We demonstrated that actin-like 6A (ACTL6A), a subunit of the SWI/SNF chromatin remodelling complex specifically binds to LINC00313 and impacts TCF7 expression and TCF/LEF signalling output. Thus, we propose a model whereby TGFβ induces LINC00313, in order to regulate the expression of a subset of target genes, such as TCF7 possibly in co-operation with the SWI/SNF chromatin remodelling complex, via establishing direct interaction with ACTL6A. By regulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and boosts cholangiocarcinogenesis.

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ATACseq of mouse hematopoietic stem cells after 4 hours of LPS/PBS treatment in vivo

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