The de novo design and synthesis of yeast chromosome XIII facilitates investigations on aging

Chun Zhou; Yun Wang; Yikun Huang; Yongpan An; Xian Fu; Daqian Yang; Yilin Wang; Jintao Zhang; Leslie A Mitchell; Joel S Bader; Yizhi Cai; Junbiao Dai; Jef D Boeke; Zhiming Cai; Zhengwei Xie; Yue Shen; Weiren Huang

doi:10.1038/s41467-024-54130-3

The de novo design and synthesis of yeast chromosome XIII facilitates investigations on aging

Nat Commun. 2024 Nov 22;15(1):10139. doi: 10.1038/s41467-024-54130-3.

Authors

Chun Zhou^#^{1

2

3

4}, Yun Wang^#^{2

5}, Yikun Huang^#¹, Yongpan An^#⁶, Xian Fu^#^{2

5}, Daqian Yang⁶, Yilin Wang¹, Jintao Zhang⁵, Leslie A Mitchell^{7

8}, Joel S Bader⁹, Yizhi Cai¹⁰, Junbiao Dai^{3

4

11}, Jef D Boeke^{7

12}, Zhiming Cai^{1

13}, Zhengwei Xie¹⁴, Yue Shen^{15

16

17}, Weiren Huang^{18

19

20

21}

Affiliations

¹ The First Affiliated Hospital of Shenzhen University; Shenzhen Second People's Hospital; Medical Innovation Technology Transformation Center of Shenzhen Second People's Hospital, Institute for Advanced Study, Synthetic Biology Research Center, International Cancer Center of Shenzhen University, Shenzhen, 518039, China.
² BGI Research, Changzhou, 213299, China.
³ Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
⁴ China College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
⁵ Guangdong Provincial Key Laboratory of Genome Read and Write, BGI Research, Shenzhen, 518083, China.
⁶ Peking University International Cancer Institute, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Peking University, Beijing, China.
⁷ Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York, NY, 10016, USA.
⁸ Neochromosome, Inc., Long Island City, NY, USA.
⁹ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
¹⁰ Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.
¹¹ Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Synthetic Biology, Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.
¹² Department of Biomedical Engineering, NYU Tandon School of Engineering, Brooklyn, NY, 11201, USA.
¹³ Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen, 518035, China.
¹⁴ Peking University International Cancer Institute, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Peking University, Beijing, China. xiezhengwei@hsc.pku.edu.cn.
¹⁵ BGI Research, Changzhou, 213299, China. shenyue@genomics.cn.
¹⁶ China College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. shenyue@genomics.cn.
¹⁷ Guangdong Provincial Key Laboratory of Genome Read and Write, BGI Research, Shenzhen, 518083, China. shenyue@genomics.cn.
¹⁸ The First Affiliated Hospital of Shenzhen University; Shenzhen Second People's Hospital; Medical Innovation Technology Transformation Center of Shenzhen Second People's Hospital, Institute for Advanced Study, Synthetic Biology Research Center, International Cancer Center of Shenzhen University, Shenzhen, 518039, China. wr.huang@siat.ac.cn.
¹⁹ Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. wr.huang@siat.ac.cn.
²⁰ Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen, 518035, China. wr.huang@siat.ac.cn.
²¹ Guangdong Engineering Technology Research Center for clinical application of cancer genome, Guangdong, China. wr.huang@siat.ac.cn.

^# Contributed equally.

PMID: 39578428
DOI: 10.1038/s41467-024-54130-3

Abstract

In the era of synthetic biology, design, construction, and utilization of synthetic chromosomes with unique features provide a strategy to study complex cellular processes such as aging. Herein, we successfully construct the 884 Kb synXIII of Saccharomyces cerevisiae to investigate replicative aging using these synthetic strains. We verify that up-regulation of a rRNA-related transcriptional factor, RRN9, positively influence replicative lifespan. Using SCRaMbLE system that enables inducible whole-genome rearrangement on synXIII, we obtain 20 SCRaMbLEd synXIII strains with extended lifespan. Transcriptome analysis reveal the expression of genes involve in global protein synthesis is up-regulated in longer-lived strains. We establish causal links between genotypic change and the long-lived phenotype via reconstruction of some key structural variations observed in post-SCRaMbLE strains and further demonstrate combinatorial effects of multiple aging regulators on lifespan extension. Our findings underscore the potential of synthetic yeasts in unveiling the function of aging-related genes.

MeSH terms

Aging / genetics
Chromosomes, Artificial, Yeast / genetics
Chromosomes, Fungal / genetics
Gene Expression Profiling
Gene Expression Regulation, Fungal
Saccharomyces cerevisiae Proteins* / genetics
Saccharomyces cerevisiae Proteins* / metabolism
Saccharomyces cerevisiae* / genetics
Saccharomyces cerevisiae* / metabolism
Synthetic Biology / methods
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Saccharomyces cerevisiae Proteins
Transcription Factors