Identification of Heat Shock Factor 1 Molecular and Cellular Targets during Embryonic and Adult Female Meiosis

Abstract

Heat shock factor 1 (HSF1), while recognized as the major regulator of the heat shock transcriptional response, also exerts important functions during mammalian embryonic development and gametogenesis. In particular, HSF1 is required for oocyte maturation, the adult phase of meiosis preceding fertilization. To identify HSF1 target genes implicated in this process, comparative transcriptomic analyses were performed with wild-type and HSF-deficient oocytes. This revealed a network of meiotic genes involved in cohesin and synaptonemal complex (SC) structures, DNA recombination, and the spindle assembly checkpoint (SAC). All of them were found to be regulated by HSF1 not only during adult but also in embryonic phases of female meiosis. Additional investigations showed that SC, recombination nodules, and DNA repair were affected in Hsf1 ؊/؊ oocytes during prenatal meiotic prophase I. However, targeting Hsf1 deletion to postnatal oocytes (using Zp3 Cre; Hsf1 loxP/loxP ) did not fully rescue the chromosomal anomalies identified during meiotic maturation, which possibly caused a persistent SAC activation. This would explain the metaphase I arrest previously described in HSF1-deficient oocytes since SAC inhibition circumvented this block. This work provides new insights into meiotic gene regulation and points out potential links between cellular stress and the meiotic anomalies frequently observed in humans.

Rethinking HSF1 in Stress, Development, and Organismal Health

“…However, there is now increasing evidence from a number of biological systems that HSF1 is important for diverse “non-stress” conditions including development [26, 40], energy metabolism [27], programmed cell death [41, 42] and carcinogenesis [28, 43]. For these non-heat shock conditions, the transcriptomes regulated by HSF1 are distinct from that of acute heat shock [26, 40]. It is, therefore, important to understand mechanistically how HSF1 regulates these alternative transcriptional programs to influence long-term cellular health.…”

HSF1 at a glance

“…This broad effect of HSF1 on transcription suggests that HSF1 is involved in balancing core cellular processes during stress and enables their rapid reestablishment once conditions suitable for proliferation have been restored. Importantly, HSF1 controls a distinct set of target genes in cell stress, development and cancer progression, and has radically limited capacity to bind to condensed chromatin (Å kerfelt et al, 2010b;Le Masson et al, 2011;Mendillo et al, 2012;Vihervaara et al, 2013). These recent findings highlight the plasticity of HSF1 as a transcriptional regulator, and imply that the HSF1-driven transcription strongly depends on the cell type, developmental state, metabolic conditions and the phase of the cell cycle (see poster).…”

“…In mice, HSF1 is a maternal factor that is required for gametogenesis and formation of sensory epithelium (Å kerfelt et al 2006). Importantly, the developmental functions of HSF1 are mainly executed through target genes that are unrelated to HSPs, and studies in Drosophila have shown that HSF1 is activated differently in development as compared to in stressed cells (Å kerfelt et al, 2010b;Fujimoto et al, 2004;Jedlicka et al, 1997;Le Masson et al, 2011;Takaki et al, 2006). In cultured cells, HSF1 is stably expressed but, in the context of entire animals, its expression level and subcellular localization vary depending on the tissue and the developmental state (Fiorenza et al, 1995;Å kerfelt et al, 2010b).…”

E2F coregulates an essential HSF developmental program that is distinct from the heat-shock response

“…However, these observations have not addressed whether the activation of chaperone gene expression by HSF1 during development corresponds to a distinct regulatory process or a variant of the HSR. Furthermore, genomic analyses in mouse oocytes and testes have identified HSF1 target genes unrelated to HSPs as executors of HSF1 developmental function (Akerfelt et al 2010b;Le Masson et al 2011). Similarly, many of the HSF2 and HSF4 target genes that are crucial for development of cortex and sensory organs, respectively, do not correspond to classical HSP genes (Chang et al 2006;Takaki et al 2006).…”