Functional analysis of Smg6/Est1 in stem cell maintenance and differentiation

• Applicant: Professor Dr. Zhao-Qi Wang
• Subject Area: General Genetics and Functional Genome Biology ; Developmental Biology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264350668

Est1, ever shorter telomere 1, is originally discovered as a co-factor of the telomerase machinery. Loss of Est1 in yeast causes telomere shortening and cell senescence. Vertebrate Est1, Smg6, is also involved in non-sense mediated mRNA decay (NMD) degrading aberrant mRNAs with premature termination codon (PTC), which may be produced by alternative splicing (AS). AS events have a profound role in various cellular processes, including cell proliferation and cell death as well as embryonic development. Over 90% of human multi-exonic genes are alternatively spliced; over 60% of human disease-causing mutations affect splicing rather than changing coding sequences. It is hypothesised that NMD balances the reservoir of gene isoforms, and contributes to the biological processes of development and tissue homeostasis. Our recent study shows that Smg6 deletion causes early embryonic lethality due to blocked differentiation of embryonic stem cells. How Smg6 regulates stem cell self-renewal and differentiation and development remains unknown. The objectives of the project: (1) To study the biological function of Smg6; (2) To characterize the Smg6-NMD specific targets in regulating stem cell maintenance and differentiation; (3) To understand the functions of Smg6 in stem cell maintenance and ageing using mouse and cellular models.This project will benefit the interesting preliminary results and the expertise of our lab in mouse model and stem cells. We will employ the following approaches: (1) The generation and characterization of mice, ES and somatic cells, with Smg6 knock-out alleles; (2) RNA-seq and PAR-CLIP sequencing to identify Smg6 specific targets; (3) in vitro and in vivo differentiation assays; (4) Deletion of Smg6 in specific stem cell compartment, i.e. central nervous system. This study will advance our understandings of the stem cell maintenance, tissue homeostasis, regeneration and healthy ageing.

• DFG Programme: Research Grants