Dataset Information

LncRNA HOTAIRM1 promotes osteogenesis by controlling JNK/AP-1 signalling-mediated RUNX2 expression.

ABSTRACT: Mesenchymal stem cells (MSCs) have potential ability to differentiate into osteocytes in response to in vitro specific induction. However, the molecular basis underlying this biological process remains largely unclear. In this study, we identify lncRNA HOTAIRM1 as a critical regulator to promote osteogenesis of MSCs. Loss of HOTAIRM1 significantly inhibits the calcium deposition and alkaline phosphatase activity of MSCs. Mechanistically, we find that HOTAIRM1 positively modulates the activity of JNK and c-Jun, both of which are widely accepted as crucial regulators of osteogenic differentiation. More importantly, c-Jun is found to be functionally involved in the regulation of RUNX2 expression, a master transcription factor of osteogenesis. In detail, c-Jun can help recruit the acetyltransferase p300 to RUNX2 promoter, facilitating acetylation of histone 3 at K27 site, therefore epigenetically activating RUNX2 gene transcription. In summary, this study highlights the functional importance of HOTAIRM1 in regulation of osteogenesis, and we characterize HOTAIRM1 as a promising molecular target for bone tissue repair and regeneration.

SUBMITTER: Fu L

PROVIDER: S-EPMC6815819 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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LncRNA HOTAIRM1 promotes osteogenesis by controlling JNK/AP-1 signalling-mediated RUNX2 expression.

Fu Lei L Peng Shifang S Wu Wanfeng W Ouyang Yi Y Tan Deming D Fu Xiaoyu X

Journal of cellular and molecular medicine 20190911 11

Mesenchymal stem cells (MSCs) have potential ability to differentiate into osteocytes in response to in vitro specific induction. However, the molecular basis underlying this biological process remains largely unclear. In this study, we identify lncRNA HOTAIRM1 as a critical regulator to promote osteogenesis of MSCs. Loss of HOTAIRM1 significantly inhibits the calcium deposition and alkaline phosphatase activity of MSCs. Mechanistically, we find that HOTAIRM1 positively modulates the activity of ...[more]

PMID: 31512358

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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.

Dataset Information

LncRNA HOTAIRM1 promotes osteogenesis by controlling JNK/AP-1 signalling-mediated RUNX2 expression.

Publications

LncRNA HOTAIRM1 promotes osteogenesis by controlling JNK/AP-1 signalling-mediated RUNX2 expression.

Similar Datasets

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