CDK2 regulates the NRF1/Ehmt1 axis during meiotic prophase I

CDK2 regulates the NRF1/Ehmt1 axis during meiotic prophase I
Title:
CDK2 regulates the NRF1/Ehmt1 axis during meiotic prophase I
Other Titles:
Journal of Cell Biology
Keywords:
Publication Date:
26 July 2019
Citation:
Nathan Palmer, S. Zakiah A. Talib, Chandrahas Koumar Ratnacaram, Diana Low, Xavier Bisteau, Joanna Hui Si Lee, Elisabeth Pfeiffenberger, Heike Wollmann, Joel Heng Loong Tan, Sheena Wee, Radoslaw Sobota, Jayantha Gunaratne, Daniel M. Messerschmidt, Ernesto Guccione, Philipp Kaldis; CDK2 regulates the NRF1/Ehmt1 axis during meiotic prophase I. J Cell Biol 2 September 2019; 218 (9): 2896–2918. doi: https://doi.org/10.1083/jcb.201903125
Abstract:
Prophase I is the longest and most complex stage of the first meiotic division, which can be further divided into five major sub-stages: leptotene, zygotene, pachytene, diplotene, and diakinesis (Cobb and Handel, 1998). Progression through meiotic prophase I is driven in part by histone tail modifications, which direct specific proteins to interact with meiotic chromatin (Nottke et al., 2009; Kota and Feil, 2010). Chromatin modifications have been shown to be widespread and dynamic during germ cell development (Hammoud et al., 2014). Perhaps the best-known example of this is the designation of recombination hotspots during leptotene stage by the PR-domain zinc finger protein 9 (PRDM9). This enzyme is able to directly bind DNA through its C-terminal zinc fingers and catalyses the trimethylation of histone H3 at K4 and K36 (H3K4me3 and H3K36me3; Hayashi et al., 2005; Eram et al., 2014; Powers et al., 2016). This epigenetic signature is then associated with the formation of meiotic double strand breaks by the DNA topoisomerase SPO11 (Bergerat et al., 1997; Keeney et al., 1997; de Massy, 2013; Lange et al., 2016). Another histone modification important for normal prophase I progression is the methylation of H3K9. The complex responsible for the establishment of dimethylated H3K9 is composed of the euchromatic histone methyltransferases (EHMT) EHMT1 and EHMT2 heterodimer (also known as GLP1 and G9a; Tachibana et al., 2005). During spermatogenesis, histone H3K9 dimethylation (H3K9me2) is established at specific sites in chromatin, as spermatogonia exit self-renewal and adopt a differentiating profile (Tachibana et al., 2007; Shirakawa et al., 2013). This persists throughout spermatogonial differentiation into primary spermatocytes and extends into the leptotene and zygotene sub-stages of prophase I, in which chromosomal homologues initiate pairing (also known as synapsis). During the pachytene stage, H3K9 becomes globally demethylated (H3K9me0; Tachibana et al., 2007), which occurs in tandem with the completion of chromosomal synapsis. The methylation status of H3K9 during this transitional period (especially in regard to di- and trimethylation) has been shown to be essential for normal synapsis of chromosomal homologues (Takada et al., 2011), but the upstream regulation of the epigenetic writers and erasers responsible for this transition is not known yet. Here we provide compelling insights into the upstream regulatory process of chromatin regulation. We identify Ehmt1, a crucial regulator of H3K9me2 during the meiotic prophase, to be a target of a novel transcriptional regulatory pathway mediated by nuclear respiratory factor 1 (NRF1). Phosphorylation of NRF1 by CDK2 negatively regulates its binding to DNA. Induced deletion of CDK2 in male germ cells leads to enhanced binding of NRF1 to many promoters including Ehmt1 and subsequently to inappropriately persisting levels of EHMT1 and its downstream histone mark (H3K9me2). We propose a regulatory role for CDK2 in negatively modulating NRF1 transcriptional activity during meiotic prophase. This allows NRF1 target genes such as Ehmt1 to be turned off in a stage-specific manner during meiotic prophase I. Therefore, we propose that CDK2 regulates meiosis not only by tethering telomeres to the nuclear envelope (Viera et al., 2009, 2015; Mikolcevic et al., 2016; Tu et al., 2017) but also through the transcriptional regulation of NRF1.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
This work is supported by the Biomedical Research Council, Agency for Science, Technology and Research (to P. Kaldis, E. Guccione, D.M. Messerschmidt, J. Gunaratne, and R. Sobota), by the Singapore International Graduate Award (to N. Palmer), by the Biomedical Research Council – Joint Council Office Grant (1231AFG031 to P. Kaldis), by the National Medical Research Council Singapore (NMRC/CBRG/0091/2015 to P. Kaldis), and by the National Research Foundation Singapore (NRF2016-CRP001-103 to E. Guccione and P. Kaldis).
Description:
ISSN:
0021-9525
1540-8140
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