Published On: Thu, Jan 17th, 2019

Maintenance of cell fates and regulation of the histone variant H3.3 by TLK kinase in Caenorhabditis elegans [RESEARCH ARTICLE]

INTRODUCTION

Defects in cell-fate maintenance cause aberrant cell-fate transformation, which can induce tumor formation and tissue malfunction. Conversely, suppression of the mechanisms that maintain cell fate is necessary for efficient reprogramming such as the generation of induced pluripotent stem (iPS) cells (Takahashi and Yamanaka, 2015). Aberrant activation of genes that induce specific cell fates causes abnormal cell-fate transformation (Riddle et al., 2013; Halder et al., 1995; Tursun et al., 2011). Thus, the repression of the genes that specify cell fate is critical for maintaining individual cell fate.

Epigenetic marks including histone modifications play important roles in transcriptional repression during development. For example, methylation on lysine 27 of histone H3 (H3K27me) is required to silence developmentally regulated genes such as Hox genes (Ringrose and Paro, 2004). In contrast, the roles of histone variants in transcriptional repression are poorly understood. We previously showed that a histone H2A variant, H2A.z, is required to maintain cell fate in multiple cell lineages in Caenorhabditis elegans (Shibata et al., 2014). Subnuclear localization of H2A.z is regulated by an acetylated histone-binding protein, BET-1, which is also required to maintain cell fate. BET-1 represses selector genes that encode DNA-binding transcription factors (TFs) such as LIM homeodomain protein MEC-3 and CEH-22/Nkx2.5, which induce specific cell fates (Shibata et al., 2014, 2010; Shibata and Nishiwaki, 2014). The selector gene activates transcription of itself and of genes that are required for the specific function of each cell type (Hobert, 2008). Thus, although many studies suggest a role for H2A.z in transcriptional activation, H2A.z also preserves transcriptional repression in the maintenance of cell fate.

In addition to the H2A variant, another major histone variant is the histone H3 variant H3.3, which is often observed on actively transcribed loci (Wirbelauer et al., 2005). Canonical histone H3 and H3 variant H3.3 are deposited by chromatin assembly factor 1 (CAF1) and histone regulator A (HIRA), respectively (Tagami et al., 2004). In cultured cells, CAF1 depletion causes alternative deposition of H3.3 to fill the nucleosome gap at the replication site by HIRA (Ray-Gallet et al., 2011). CAF1 deficiency promotes artificial trans-differentiation, such as induction of iPS cells and the generation of neurons from fibroblasts and of macrophages from pre-B cells (Cheloufi et al., 2015). However, the roles of CAF1 and H3.3 in cell-fate maintenance during development are not known.

Tousled-like kinases (TLKs) are conserved protein kinases in multicellular organisms. They phosphorylate anti-silencing factor 1 (ASF1), which interacts with CAF1 (Klimovskaia et al., 2014). Arabidopsis TLK, Tousled, acts in the maintenance of transcriptional gene silencing and is required for leaf and flower development (Roe et al., 1993; Wang et al., 2007). In C. elegans early embryos, the ortholog TLK-1 is required for chromosome segregation and cytokinesis and promotes transcription (Yeh et al., 2010; Han et al., 2003, 2005). The C. elegans CAF1 complex is required to establish bilateral asymmetry (Nakano et al., 2011), although the in vivo relationship between TLK and the CAF1 complex is not known. In addition, the role of TLK and the CAF1 complex in cell fate maintenance remains elusive. Our genetic screening for mutants that are defective in cell-fate maintenance resulted in the isolation of tlk-1 mutants. Here, we analyzed the roles of TLK-1 and CAF1 in cell-fate maintenance and the regulation of H3.3.

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