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Transcriptome effects mediated by forced overexpression of 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 failured patients and in controls. We found 15 lncRNAs modulated in HF samples. To explore the functional relevance of two of them, H19 and BACE1-AS, we investigated the effects of their forced overexpression on transcriptome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE85965 | GEO | 2019/08/23

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 overexpression of BACE1-AS in HAOEC cells

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