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Transcriptome effects mediated by forced repression of LncRNA BACE1-AS in HAOEC cells

ABSTRACT: Recently, high-throughput studies identified tens of thousands of sites transcribed to produce transcripts with little protein-coding potential. The function of these transcripts remains largely obscure and their relevance to cardiovascular disease is mostly undefined. Many non-protein-coding transcripts belong to the group of Long non coding RNAs (LncRNAs), which are arbitrarily classified according to their length >200 nt. They control protein targeting to genomic loci, epigenetic silencing and serve as scaffolds for multiple proteins. We measured the expression of 83 diseases-related LncRNAs in biopsies from heart failure patients and in controls. We found 15 lncRNAs modulated in HF samples. To explore the functional relevance of BACE1-AS, we investigated the effects of its forced repression on transcriptome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE76768 | GEO | 2018/12/31

REPOSITORIES: GEO

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Project description:Activated brown adipose tissue contributes to control of energy and glucose homeostasis in rodents and humans. Defining cell-autonomous processes underlying BAT differentiation and activation may thus reveal novel therapeutic targets for obesity and type 2 diabetes mellitus intervention. Here we show that ageing- and obesity-associated demises in BAT function coincide with down-regulation of mature microRNAs in BAT in the presence of reduced expression of the critical microRNA processing enzyme Dicer1. To mimic this partial down-regulation of microRNA processing in obesity and ageing, we inactivated one allele of Dicer1 selectively in BAT of mice. BAT- restricted heterozygosity of Dicer1 caused glucose intolerance in lean mice and aggravated diet-induced-obesity (DIO)-evoked deterioration of glucose homeostasis. Using combinatorial analyses of altered microRNA-expression in BAT during in vitro preadipocyte commitment and mouse models of progeria, longevity and DIO, we identified 23 microRNAs dysregulated among these conditions. Of these, we identified miR-328 as a novel regulator of BAT differentiation. miR-328 over-expression promotes BAT-differentiation and impairs muscle progenitor commitment, while reducing miR-328 expression blocks BAT specification. We validated the ß-Secretase Bace1 as a target of miR-328, which is consequently over-expressed in BAT of obese and premature ageing mice. Reducing Bace1 expression enhances brown adipocyte, while impairing myogenic differentiation in vitro. In vivo small-molecule Bace1 inhibition in obese mice delayed DIO-induced weight gain, ameliorated obesity-associated deterioration of glucose metabolism and improved insulin sensitivity. Collectively, these experiments reveal reduced Dicer1-miR-328-Bace1 axis in presence of generalized impairment of microRNA processing in ageing and obesity as a novel determinant of ageing- and obesity-associated decline in BAT function. This may define in vivo Bace1-inhibition as an innovative therapeutic approach to not only target age-related neurodegenerative diseases but at the same time improving age-related impairment of BAT-function and metabolism. C57BL/6 mice ( 4 weeks of age) were treated with a calory-rich, high-sugar high-fat diet (HFD) for a course of 4 weeks. Then groups were stratified and one group continued to receive HFD (BAT13-15) or HFD supplemented with an experimental small-molecule Bace 1 inhibitor (BAT17, 33, 35).

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Transcriptome effects mediated by forced repression of LncRNA BACE1-AS in HAOEC cells

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