Loss of the histone chaperone ASF1B reduces female reproductive capacity in mice

Abstract

Laboratoire de Recherche sur la réparation et la transcription dans les cellules souches, 6 INSERM, UMR 967, Fontenay-aux-roses, F-92265, 7 Univ Paris Diderot, Sorbonne Paris cité, UMR S967, Fontenay-aux-roses, F-92265 and 8 Univ Paris-Sud, UMR S967, Fontenay-aux-roses, F-92265 Correspondence should be addressed to M Vernet; Email: muriel.vernet@cea.fr Abstract Anti-silencing function 1 (ASF1) is an evolutionarily conserved histone H3-H4 chaperone involved in the assembly/disassembly of nucleosome and histone modification. Two paralogous genes, Asf1a and Asf1b, exist in the mouse genome. Asf1a is ubiquitously expressed and its loss causes embryonic lethality. Conversely, Asf1b expression is more restricted and has been less studied. To determine the in vivo function of Asf1b, we generated a Asf1b-deficient mouse line (Asf1b GT(ROSA-bgeo)437) in which expression of the lacZ reporter gene is driven by the Asf1b promoter. Analysis of b-galactosidase activity at early embryonic stages indicated a correlation between Asf1b expression and cell differentiation potential. In the gonads of both male and female, Asf1b expression was specifically detected in the germ cell lineage with a peak expression correlated with meiosis. The viability of Asf1b-null mice suggests that Asf1b is dispensable for mouse development. However, these mice showed reduced reproductive capacity compared with wild-type controls. We present evidence that the timing of meiotic entry and the subsequent gonad development are affected more severely in Asf1b-null female mice than in male mice. In female mice, in addition to subfertility related to altered gamete formation, variable defects compromising the development and/or survival of their offspring were also observed. Altogether, our data indicate the importance of Asf1b expression at the time of meiotic entry, suggesting that chromatin modifications may play a central role in this process. [477][478][479][480][481][482][483][484][485][486][487][488][489] 478 S Messiaen and others Reproduction (2016) 151 [477][478][479][480][481][482][483][484][485][486][487][488][489] www.reproduction-online.org Reproduction (2016) 151In eukaryotes, Asf1 exists either as a single gene (e.g. in yeast) or as two paralogs (Abascal et al. 2013). In mammals, these paralogs are called Asf1a and Asf1b. Due to the high sequence identity of the two ASF1 proteins, their functional redundancy or specialization has been investigated in vitro in human cell lines. Based on these studies, human ASF1A is preferentially involved in DNA repair and cell senescence, while ASF1B primarily contributes to cell proliferation (Groth et al. 2005(Groth et al. , 2007. Moreover, Asf1a-knockout mouse embryos die at mid-gestation (E9.5) (Hartford et al. 2011), indicating that Asf1b cannot compensate for the loss of Asf1a in vivo. The lack of redundancy between the Asf1 paralogs might be partially explained by their different expression patterns. In both humans and mice, Asf1a is ubiquitously expressed, whereas Asf1b expression is ...

Differential requirements for Tousled-like kinases 1 and 2 in mammalian development

“…In contrast, ASF1b is dispensable for viability, although it affects fertility. 39 While mice lacking either TLK1 or TLK2 were fertile, we cannot rule out subtle or age-related differences in fertility from existing data. Future analysis of mice lacking combinations of both TLK and ASF1 alleles may be informative for identifying more specific functions and determining how much of the TLK-deficient phenotype relies on ASF1 regulation.…”

Histone chaperone ASF1B promotes humanβ-cell proliferation via recruitment of histone H3.3

“…43,49,61 Initially, ASF1 proteins were implicated in the formation of replication-coupling assembly factor (RCAF). 62 However, more recent reports show that ASF1B can directly interact with the B-domain of HIRA, suggesting that it may play a role in RI histone deposition.…”

Histone Chaperones Regulate Mammalian Gene Expression

“…Loss in maternal HIRA leads to complete inability to deposit the core histones on to the paternal genome thus resulting in a compromised maternal genome reactivation in mice [5]. Also, ASF1B has been found to be required for retaining the female reproductive capacity in mouse where in loss of ASF1B could introduce change in meiotic entry thereby resulting in a discrepancy in gonad development [6]. The development of morula to blastocyst occurs around E3.5 and E5.5 in mouse and human respectively ( Figure 2).…”