title: Reprogramming by De-bookmarking the Somatic Transcriptional Program through Targeting of BET Bromodomains.
abstract: One critical event in reprogramming to pluripotency is erasure of the somatic transcriptional program of starting cells. Here, we present the proof of principle of a strategy for reprogramming to pluripotency facilitated by small molecules that interfere with the somatic transcriptional memory. We show that mild chemical targeting of the acetyllysine-binding pockets of the BET bromodomains, the transcriptional bookmarking domains, robustly enhances reprogramming. Furthermore, we show that chemical targeting of the transcriptional bookmarking BET bromodomains downregulates or turns off the expression of somatic genes in both naive and reprogramming fibroblasts. Chemical blocking of the BET bromodomains also results in loss of fibroblast morphology early in reprogramming. We therefore experimentally demonstrate that cell fate conversion can be achieved by chemically targeting the transcriptional bookmarking BET bromodomains responsible for transcriptional memory.
authors.affiliation: Stem Cell Institute, Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024, USA.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Stem Cell Institute, Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024, USA; Department of Radiation Oncology, Shandong Cancer Hospital, Shandong University, Jinan, Shandong 250117, China.
authors.forename: Chunping
authors.initials: C
authors.lastname: Yao
authors.affiliation: Stem Cell Institute, Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024, USA.
authors.forename: Alireza
authors.initials: A
authors.lastname: Khodadadi-Jamayran
authors.affiliation: Longyan University, Fujian 364012, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Xu
authors.affiliation: Stem Cell Institute, Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024, USA.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Townes
authors.affiliation: Howell and Elizabeth Heflin Center for Genomic Science, Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Crowley
authors.affiliation: Stem Cell Institute, Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024, USA. Electronic address: hukejin@gmail.com.
authors.forename: Kejin
authors.initials: K
authors.lastname: Hu
mesh_terms: D001381:Azepines / Q000494:pharmacology*; D065150:Cellular Reprogramming / Q000187:drug effects* / Q000502:physiology*; D000067470:Cellular Reprogramming Techniques / Q000379:methods*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000502:physiology*; D011506:Proteins / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D011506:Proteins; D014230:Triazoles; C561695:(+)-JQ1 compound; C000624329:bromodomain and extra-terminal domain protein, human; D000092468:Bromodomain Containing Proteins