title: Transcription factors interfering with dedifferentiation induce cell type-specific transcriptional profiles.
abstract: Transcription factors (TFs) are able to regulate differentiation-related processes, including dedifferentiation and direct conversion, through the regulation of cell type-specific transcriptional profiles. However, the functional interactions between the TFs regulating different transcriptional profiles are not well understood. Here, we show that the TFs capable of inducing cell type-specific transcriptional profiles prevent the dedifferentiation induced by TFs for pluripotency. Of the large number of TFs expressed in a neural-lineage cell line, we identified a subset of TFs that, when overexpressed, strongly interfered with the dedifferentiation triggered by the procedure to generate induced pluripotent stem cells. This interference occurred through a maintenance mechanism of the cell type-specific transcriptional profile. Strikingly, the maintenance activity of the interfering TF set was strong enough to induce the cell line-specific transcriptional profile when overexpressed in a heterologous cell type. In addition, the TFs that interfered with dedifferentiation in hepatic-lineage cells involved TFs with known induction activity for hepatic-lineage cells. Our results suggest that dedifferentiation suppresses a cell type-specific transcriptional profile, which is primarily maintained by a small subset of TFs capable of inducing direct conversion. We anticipate that this functional correlation might be applicable in various cell types and might facilitate the identification of TFs with induction activity in efforts to understand differentiation.
authors.affiliation: Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Takafusa
authors.initials: T
authors.lastname: Hikichi
authors.forename: Ryo
authors.initials: R
authors.lastname: Matoba
authors.forename: Takashi
authors.initials: T
authors.lastname: Ikeda
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Satoko
authors.initials: S
authors.lastname: Yoshitake
authors.forename: Miwa
authors.initials: M
authors.lastname: Tamura-Nakano
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kimura
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kamon
authors.forename: Mari
authors.initials: M
authors.lastname: Shimura
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawakami
authors.forename: Akihiko
authors.initials: A
authors.lastname: Okuda
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okochi
authors.forename: Takafumi
authors.initials: T
authors.lastname: Inoue
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suzuki
authors.forename: Shinji
authors.initials: S
authors.lastname: Masui
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation / Q000502:physiology*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D034741:RNA, Small Interfering; D014157:Transcription Factors
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