title: The Krüppel-associated box repressor domain induces reversible and irreversible regulation of endogenous mouse genes by mediating different chromatin states.
abstract: The Krüppel-associated box (KRAB) domain is a transcription repression module from the largest family of transcriptional regulators encoded by higher vertebrates. We developed a drug-controllable regulation system based on an artificial KRAB-containing repressor (tTS) that targets the endogenous Hprt gene to explore the regulatory mechanism and molecular basis of KRAB-containing regulators within the context of an endogenous gene in vivo. We show that KRAB can mediate irreversible and reversible regulation of endogenous genes in mouse that is dependent on embryonic developmental stage. KRAB-induced stable DNA methylation within the KRAB binding region during the early embryonic stage, resulting in irreversible gene repression. In later stages, KRAB mainly induced de-acetylation and methylation of histone, resulting in reversible gene repression. Thus, we have characterized the KRAB-mediated regulation system within the context of an endogenous gene and multiple spatiotemporal ranges, thereby providing a basis for identifying the function of KRAB-containing regulators and aiding development of novel KRAB-based gene regulation tools in vivo.
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai 200072, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ying
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai 200072, China.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Yang
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai 200072, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Shanghai Research Center For Model Organisms, Shanghai 201210, China.
authors.forename: Jifang
authors.initials: J
authors.lastname: Mao
authors.affiliation: Shanghai Research Center For Model Organisms, Shanghai 201210, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Kuang
authors.affiliation: Shanghai Research Center For Model Organisms, Shanghai 201210, China.
authors.forename: Zhugang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Shanghai Research Center For Model Organisms, Shanghai 201210, China rlsun@sibs.ac.cn.
authors.forename: Ruilin
authors.initials: R
authors.lastname: Sun
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai 200072, China Shanghai Research Center For Model Organisms, Shanghai 201210, China jfei@tongji.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Fei
mesh_terms: D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D017931:DNA Primers; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; D017931:DNA Primers; D009687:Nuclear Proteins; D012097:Repressor Proteins; C486788:Zfp472 protein, mouse; D007041:Hypoxanthine Phosphoribosyltransferase