title: Histone chaperone ASF1B promotes human β-cell proliferation via recruitment of histone H3.3.
abstract: Anti-silencing function 1 (ASF1) is a histone H3-H4 chaperone involved in DNA replication and repair, and transcriptional regulation. Here, we identify ASF1B, the mammalian paralog to ASF1, as a proliferation-inducing histone chaperone in human β-cells. Overexpression of ASF1B led to distinct transcriptional signatures consistent with increased cellular proliferation and reduced cellular death. Using multiple methods of monitoring proliferation and mitotic progression, we show that overexpression of ASF1B is sufficient to induce human β-cell proliferation. Co-expression of histone H3.3 further augmented β-cell proliferation, whereas suppression of endogenous H3.3 attenuated the stimulatory effect of ASF1B. Using the histone binding-deficient mutant of ASF1B (V94R), we show that histone binding to ASF1B is required for the induction of β-cell proliferation. In contrast to H3.3, overexpression of histone H3 variants H3.1 and H3.2 did not have an impact on ASF1B-mediated induction of proliferation. Our findings reveal a novel role of ASF1B in human β-cell replication and show that ASF1B and histone H3.3A synergistically stimulate human β-cell proliferation.
authors.affiliation: a Department of Biochemistry , University of Wisconsin , Madison , WI , USA.
authors.forename: Pradyut K
authors.initials: PK
authors.lastname: Paul
authors.affiliation: a Department of Biochemistry , University of Wisconsin , Madison , WI , USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Rabaglia
authors.affiliation: a Department of Biochemistry , University of Wisconsin , Madison , WI , USA.
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Wang
authors.affiliation: a Department of Biochemistry , University of Wisconsin , Madison , WI , USA.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Stapleton
authors.affiliation: b Department of Statistics , University of Wisconsin , Madison , WI , USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Leng
authors.affiliation: c Department of Biostatistics and Medical Informatics , University of Wisconsin , Madison , WI , USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Kendziorski
authors.affiliation: d Department of Biomolecular Chemistry , University of Wisconsin , Madison , WI , USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Lewis
authors.affiliation: a Department of Biochemistry , University of Wisconsin , Madison , WI , USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Keller
authors.affiliation: a Department of Biochemistry , University of Wisconsin , Madison , WI , USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D004249:DNA Damage / Q000235:genetics; D005786:Gene Expression Regulation; D056488:Histone Chaperones / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: C491640:ASF1B protein, human; D018797:Cell Cycle Proteins; D056488:Histone Chaperones; D006657:Histones
keywords: ASF1B; cell cycle; histone H3.3; replication-independent histone deposition; β-cell proliferation