TIF1β association with HP1 is essential for post-gastrulation development, but not for Sertoli cell functions during spermatogenesis

Abstract

TIF1β is an essential mammalian transcriptional corepressor. It interacts with the heterochromatin proteins HP1 through a highly conserved motif, the HP1box, and we have previously shown that this interaction is essential for the differentiation of F9 cells to occur. Here we address the in vivo functions of the TIF1β-HP1 interaction, by generating mice in which the TIF1β HP1box is mutated, leading to the loss of TIF1β interaction with HP1. The effects of the mutation were monitored in two instances, where TIF1β is known to play key roles: early embryonic development and spermatogenesis. We find that mutating the HP1box of TIF1β disrupts embryonic development soon after gastrulation. This effect is likely caused by the misexpression of TIF1β targets that regulate mitotic progression and pluripotency. In contrast, in Sertoli cells, we found that the absence of TIF1β but not its mutation in the HP1box leads to a clear defect of spermatogenesis characterized by a failure of spermatid release and a testicular degeneration. These data show that the interaction between TIF1β and HP1 is essential for some but not all TIF1β functions in vivo. Furthermore, we observed that TIF1β is dispersed through the nucleoplasm of E7.0 embryos, whereas it is mainly associated with pericentromeric heterochromatin of E8.5 embryos and of Sertoli cells, an association that is lost upon TIF1β HP1box mutation. Altogether, these data provide strong evidence that nuclear organization plays key roles during early embryonic development.

Epigenetic tethering of AID to the donor switch region during immunoglobulin class switch recombination

“…Our results thus provide a mechanism linking AID to epigenetic modifications associated with the IgH locus during CSR. (Cammas et al, 2000), CD19 Cre/+ (provided by K. Rajewsky, Harvard Medical School, Boston, MA; Rickert et al, 1997), Kap1 V488A-L490A/+ (Herzog et al, 2011), and AID Cre/Cre (Robbiani et al, 2008) mice were on a C57BL/6 background and were bred and maintained under specific pathogen-free conditions. Age-matched littermates (8-12 wk old) were used in all experiments.…”

KAPtain in charge of multiple missions: Emerging roles of KAP1

“…The function of KAP1 in maintaining pluripotency of embryonic stem cells (ESCs) has been demonstrated [78,93] . In addition, KAP1 is also required for ESC differentiation [94][95][96][97] . Studies using conditional Kap1-knockout mice show that KAP1 plays pivotal roles in different cellular maturation processes such as spermatogenesis, erythropoiesis, and the development of T-cell and B-cell (Table 3) [71,94,[98][99][100][101] .…”

Expression of the Ubiquitin Proteasome System in Neonatal Rat Gonocytes and Spermatogonia: Role in Gonocyte Differentiation1

“…Among those, the E2 enzyme UBC2 is believed to regulate transcriptional activation by catalyzing the mono-ubiquitination of histones and to be an RA-responsive gene during rat embryo development [45], two important processes in gonocyte development. The E3 ligase Trim28 (TIF1b), abundant in germ and somatic cells, was also shown to affect chromatin structure [46] and to be a transcriptional corepressor required for proper spermatogenesis [47]. Similarly, HUWE1 (ARF-BP1; LASU1), corresponding to the most abundant E3 ligase transcript in gonocytes, is highly expressed in the nuclei of spermatogonia and spermatocytes and was shown to poly-ubiquitinate histones in vitro [28] and was proposed to play a role in histone removal during chromatin condensation in elongating spermatids [48].…”