An integrated systems biology approach identifies positive cofactor 4 as a factor that increases reprogramming efficiency

Junghyun Jo; Sohyun Hwang; Hyung Joon Kim; Soomin Hong; Jeoung Eun Lee; Sung-Geum Lee; Ahmi Baek; Heonjong Han; Jin Il Lee; Insuk Lee; Dong Ryul Lee

doi:10.1093/nar/gkv1468

An integrated systems biology approach identifies positive cofactor 4 as a factor that increases reprogramming efficiency

Nucleic Acids Res. 2016 Feb 18;44(3):1203-15. doi: 10.1093/nar/gkv1468. Epub 2016 Jan 5.

Authors

Affiliations

¹ Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea.
² Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
³ CHA Stem Cell Institute, CHA University, Seoul, Korea.
⁴ Fertility Center, CHA Gangnam Medical Center, College of Medicine, CHA University, Seoul, Korea.
⁵ Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea insuklee@yonsei.ac.kr.
⁶ Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea CHA Stem Cell Institute, CHA University, Seoul, Korea Fertility Center, CHA Gangnam Medical Center, College of Medicine, CHA University, Seoul, Korea drleedr@cha.ac.kr.

Abstract

Spermatogonial stem cells (SSCs) can spontaneously dedifferentiate into embryonic stem cell (ESC)-like cells, which are designated as multipotent SSCs (mSSCs), without ectopic expression of reprogramming factors. Interestingly, SSCs express key pluripotency genes such as Oct4, Sox2, Klf4 and Myc. Therefore, molecular dissection of mSSC reprogramming may provide clues about novel endogenous reprogramming or pluripotency regulatory factors. Our comparative transcriptome analysis of mSSCs and induced pluripotent stem cells (iPSCs) suggests that they have similar pluripotency states but are reprogrammed via different transcriptional pathways. We identified 53 genes as putative pluripotency regulatory factors using an integrated systems biology approach. We demonstrated a selected candidate, Positive cofactor 4 (Pc4), can enhance the efficiency of somatic cell reprogramming by promoting and maintaining transcriptional activity of the key reprograming factors. These results suggest that Pc4 has an important role in inducing spontaneous somatic cell reprogramming via up-regulation of key pluripotency genes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult Stem Cells / cytology
Adult Stem Cells / metabolism
Animals
Blotting, Western
Cells, Cultured
Cellular Reprogramming / genetics*
Cluster Analysis
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Gene Expression Profiling*
Induced Pluripotent Stem Cells / cytology
Induced Pluripotent Stem Cells / metabolism
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism
Mice
Mice, Inbred C57BL
Mouse Embryonic Stem Cells / cytology
Mouse Embryonic Stem Cells / metabolism
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / metabolism
Oligonucleotide Array Sequence Analysis
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Reverse Transcriptase Polymerase Chain Reaction
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism
Systems Biology / methods
Transcription Factors / genetics*
Transcription Factors / metabolism

Substances

DNA-Binding Proteins
Klf4 protein, mouse
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
Myc protein, mouse
Nuclear Proteins
Octamer Transcription Factor-3
Pou5f1 protein, mouse
Proto-Oncogene Proteins c-myc
Rpo2tc1 protein, mouse
SOXB1 Transcription Factors
Sox2 protein, mouse
Transcription Factors

Associated data

GEO/GSE74156