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Mutat Res. 2015 Jul;777:69-78. doi: 10.1016/j.mrfmmm.2015.04.010. Epub 2015 Apr 24.

MicroRNA transcriptome analysis identifies miR-365 as a novel negative regulator of cell proliferation in Zmpste24-deficient mouse embryonic fibroblasts.

Author information

1
Institute of Aging Research, Guangdong Medical College, Xin Cheng Avenue 1#, Songshan Lake, Dongguan, Guangdong 523808, PR China; Institute of Biochemistry & Molecular Biology, Guangdong Medical College, Zhanjiang 524023, PR China; Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan 523808, PR China; Institute of Laboratory Medicine, Guangdong Medical College, Dongguan, Guangdong 523808, PR China.
2
Departments of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
3
Departments of Systems Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
4
Institute of Aging Research, Guangdong Medical College, Xin Cheng Avenue 1#, Songshan Lake, Dongguan, Guangdong 523808, PR China; Institute of Biochemistry & Molecular Biology, Guangdong Medical College, Zhanjiang 524023, PR China; Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan 523808, PR China.
5
Institute of Aging Research, Guangdong Medical College, Xin Cheng Avenue 1#, Songshan Lake, Dongguan, Guangdong 523808, PR China; Department of Pathology, University of Washington, Seattle, WA 98195, USA.
6
Institute of Aging Research, Guangdong Medical College, Xin Cheng Avenue 1#, Songshan Lake, Dongguan, Guangdong 523808, PR China; The Buck Institute for Research on Aging, Novato, CA 94945, USA.
7
Institute of Aging Research, Guangdong Medical College, Xin Cheng Avenue 1#, Songshan Lake, Dongguan, Guangdong 523808, PR China; Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.
8
Institute of Aging Research, Guangdong Medical College, Xin Cheng Avenue 1#, Songshan Lake, Dongguan, Guangdong 523808, PR China; Institute of Biochemistry & Molecular Biology, Guangdong Medical College, Zhanjiang 524023, PR China; Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan 523808, PR China; Institute of Laboratory Medicine, Guangdong Medical College, Dongguan, Guangdong 523808, PR China. Electronic address: xgliu64@126.com.
9
Institute of Aging Research, Guangdong Medical College, Xin Cheng Avenue 1#, Songshan Lake, Dongguan, Guangdong 523808, PR China; Departments of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: yousin.suh@einstein.yu.edu.

Abstract

Zmpste24 is a metalloproteinase responsible for the posttranslational processing and cleavage of prelamin A into mature laminA. Zmpste24(-/-) mice display a range of progeroid phenotypes overlapping with mice expressing progerin, an altered version of lamin A associated with Hutchinson-Gilford progeria syndrome (HGPS). Increasing evidence has demonstrated that miRNAs contribute to the regulation of normal aging process, but their roles in progeroid disorders remain poorly understood. Here we report the miRNA transcriptomes of mouse embryonic fibroblasts (MEFs) established from wild type (WT) and Zmpste24(-/-) progeroid mice using a massively parallel sequencing technology. With data from 19.5 × 10(6) reads from WT MEFs and 16.5 × 10(6) reads from Zmpste24(-/-) MEFs, we discovered a total of 306 known miRNAs expressed in MEFs with a wide dynamic range of read counts ranging from 10 to over 1 million. A total of 8 miRNAs were found to be significantly down-regulated, with only 2 miRNAs upregulated, in Zmpste24(-/-) MEFs as compared to WT MEFs. Functional studies revealed that miR-365, a significantly down-regulated miRNA in Zmpste24(-/-) MEFs, modulates cellular growth phenotypes in MEFs. Overexpression of miR-365 in Zmpste24(-/-) MEFs increased cellular proliferation and decreased the percentage of SA-β-gal-positive cells, while inhibition of miR-365 function led to an increase of SA-β-gal-positive cells in WT MEFs. Furthermore, we identified Rasd1, a member of the Ras superfamily of small GTPases, as a functional target of miR-365. While expression of miR-365 suppressed Rasd1 3' UTR luciferase-reporter activity, this effect was lost with mutations in the putative 3' UTR target-site. Consistently, expression levels of miR-365 were found to inversely correlate with endogenous Rasd1 levels. These findings suggest that miR-365 is down-regulated in Zmpste24(-/-) MEFs and acts as a novel negative regulator of Rasd1. Our comprehensive miRNA data provide a resource to study gene regulatory networks in MEFs.

KEYWORDS:

HGPS; Premature senescence; Zmpste24; miR-365; miRNA

PMID:
25983189
PMCID:
PMC4654172
DOI:
10.1016/j.mrfmmm.2015.04.010
[Indexed for MEDLINE]
Free PMC Article

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