Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST -CNRS OPEN ACCESS JOURNAL Gene Section Review BYSL (Bystin-Like) Michiko N Fukuda, Kazuhiro Sugihara Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA (MNF), Department of Gynecology and Obstetrics, Hamamatsu University School of Medicine, Hamamatsu City, Shizuoka, Japan (KS) Published in Atlas Database: September 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/BYSLID857ch6p21.html DOI: 10.4267/2042/53636 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract DNA/RNA Review on BYSL, with data on DNA/RNA, on the Description protein encoded and where the gene is implicated. BYSL locates on 6 chromosome 6p21.1 (Pack et al., 1998). Identity It contains 8 exons spanning 10.7 kb of genomic Other names: BYSTIN DNA. HGNC (Hugo): BYSL Protein Location: 6p21.1 Local order: In human chromosome, BYSL gene Description localizes in chromosome 6, between TRFP Human bystin is a 49.6 kDa cytoplasmic protein encoding a transcription mediator, and CCND3 composed of 437 amino acid residues. encoding cyclin D3 (Figure 1). Bystin is a basic protein with isoelectric point 8.10. Figure 1. Genomic organization of BYSL. Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 293 BYSL (Bystin-Like) Fukuda MN, Sugihara K Figure 2. Blastocyst-dependent localization of bystin protein in the mouse endometrial epithelia. Above: mouse endometrium with implanting blastocyst (Bl) shows bystin protein (red) on the apical side of epithelia. below: mouse endometrium from pseudopregnant female shows bystin at abluminal side of epithelia. Glandular epithelia (ge); luminal epithelia (le). Bystin protein contains many potential protein proteins localized to the apical side of the epithelia, kinase phosphorylation sites, suggesting an active whereas in their absence bystin protein was role of bystin in signal transduction. localized to the abluminal or basal side of the However, no known structural motif is found in epithelia (Figure 2). This observation suggests the bystin protein. existence of an embryonic factor affecting in a way determining the localization of bystin in the Expression maternal epithelia. The molecular basis underlying BYSL is expressed in trophectoderm cells and apical or basal localization of bystin is presently endometrial epithelial cells during embryo unknown. implantation in human (Aoki and Fukuda, 2000; Bysl is strongly expressed in the adult rat brain Nakayama et al., 2003; Suzuki et al., 1999; Suzuki after injury (Ma et al., 2006; Sheng et al., 2004). et al., 1998). The expression pattern of mouse Bystin is expressed after optic nerve injury in zebra bystin at peri-implantation (Aoki et al., 2006) is fish (Neve et al., 2012). similar to that of mouse trophinin (Nadano et al., Bystin protein was found in mature sperm, of which 2002). function is implicated to sperm motility In the mouse, bystin protein was found in the (Hatakeyama et al., 2008). Bystin is overexpressed blastocyst embryo and endometrial epithelial cells in hepatocellular carcinoma, suggesting its function during peri-implantation period (Aoki et al., 2006). in cell proliferation in liver cancer (Wang et al., Bystin is expressed in mouse endometrial luminal 2009). and glandular epithelial cells throughout hormonal In the Drosophila embryo, bys expression is cycles (Aoki et al., 2006). Bystin in the luminal ubiquitous but relatively weak at early stages, but at epithelia showed a distinct blastocyst-dependent later stages bys expression is strong and specifically pattern: in the presence of blastocysts, bystin localized to larval imaginal discs, suggesting a role Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 294 BYSL (Bystin-Like) Fukuda MN, Sugihara K of bys in cell adhesion. In particular, bys expression suggesting that bystin is essential for mouse is strong in the region of the wing pouch giving rise embryo survival after implantation. However, as to two epithelial sheets of the adult wing that described below, Bysl gene knockdown adhere to one another after the disc everts (Stewart experiments show that bystin is also required for and Nordquist, 2005). survival of pre-implantation stage mouse embryos (Adachi et al., 2007). In the knockout mouse, it is Localisation likely that maternally derived Bysl mRNA masks In 6 weeks human placenta, bystin protein was loss of Bysl at pre-implantation stages. found in the cytoplasm of the syncytiotrophoblast When Bysl siRNAs were microinjected into and cytotrophoblast in the chorionic villi, and in fertilized eggs, compaction at the eight-cell stage endometrial decidual cells at the utero placental occurred normally in vitro (Adachi et al., 2007). interface. In 10 weeks placenta, bystin was Bysl siRNA-injected embryos showed slightly exclusively in the nucli of cytotrophoblast (Suzuki reduced expression of cytokeratin 8 (EndoA), an et al., 1999). In cultured cells, bystin localizes to early trophectoderm marker (Oshima et al., 1983). both the nucleus and cytoplasm (Aoki et al., 2006; While control blastocysts showed assembled Miyoshi et al., 2007). In the nucleus, bystin was cytokeratin structures in the trophectoderm layer, often found in the nucleoli. no organized structures were detected in Bysl siRNA-injected embryos. Consequently, blastocyst Function formation was completely inhibited. These embryos Bystin function in human embryo implantation: failed to hatch from the zona pellucida and could Bystin was originally identified as a cytoplasmic not outgrow in culture, suggesting that the bystin protein that forms a complex with trophinin and functions in trophectoderm differentiation. Bysl tastin in human trophoblastic embryonal carcinoma knockdown also inhibited embryonic stem cell HT-H cells (Fukuda and Nozawa, 1999; Suzuki et proliferation (Adachi et al., 2007). al., 1998). While genes encoding trophinin and Bystin function in stem cells: Mouse bystin gene tastin are only found in mammals, the bystin gene is Bysl has been identified as the stem cell marker conserved across a wide range of eukaryotes, commonly expressed in embryonal, neuronal and including yeast, nematodes, insects, snakes, and hematopoietic stem cells (Ramalho-Santos et al., mammals (Roos et al., 1997; Stewart and Denell, 2002). BYSL is also identified as the major target 1993; Stewart and Nordquist, 2005; Trachtulec and of MYC in B-cells (Basso et al., 2005). Since MYC Forejt, 2001). Trophinin is an intrinsic membrane is one of essential genes for converting somatic protein that mediates cell adhesion by homophilic cells into induced pluripotent stem cell (iPS) trophinin-trophinin binding (Fukuda et al., 1995). (Takahashi and Yamanaka, 2006), these Tastin and bystin are cytoplasmic proteins required observations suggest strongly an essential role of for trophinin to function efficiently as a cell bystin in pluripotent stem cells. Bysl is included in adhesion molecule. In humans, trophinin, tastin and a gene cluster of stem cell markers found on mouse bystin are expressed at the utero-placental interface chromosome 16 (Ramalho-Santos et al., 2002). or at implantation sites (Suzuki et al., 1999). These Bystin function in human sperm motility: Bystin proteins are expressed in human placenta at early regulates sperm motility (Hatakeyama et al., 2008). stages of pregnancy but disappear from the placenta Trophinin plays multiple roles in each cell type after 10 weeks of pregnancy (Aoki and Fukuda, under different conditions. 2000; Fukuda and Nozawa, 1999; Suzuki et al., Bystin function in ribosomal biogenesis: The 1999). yeast bystin homologue ENP1 is essential for In trophoblastic HT-H cells, bystin protein budding yeast to survive (Roos et al., 1997). A associates with trophinin and ErbB4 in the temperature-sensitive ENP1-null mutant showed cytoplasm (Sugihara et al., 2007). When trophinin- defective processing of ribosomal RNA (rRNA) mediated cell adhesion takes place on the cell (Chen et al., 2003). Studies of ribosomal biogenesis surface, bystin dissociates from trophinin and in yeast indicate that Enp1 is required to synthesize tyrosine phosphorylation of ErbB4 takes place, 40S ribosomal subunits by functioning in their suggesting the mechanism underlying the nuclear export (Schafer et al., 2003). trophectoderm cell activation upon human embryo Eukaryotic ribosome formation occurs implantation (Figure 3). Bystin functions as predominantly in nucleoli, but late maturation steps molecular switch in trophinin-mediated signal occur in both the nucleoplasm and cytoplasm. transduction in trophoblastic cells (Fukuda and Location of bystin in the cytoplasm during G1 and Sugihara, 2007; Fukuda and Sugihara,2008; Fukuda its nuclear localization prior to mitosis suggest that and Sugihara,2012). bystin plays dual roles in cell growth and Bystin function in mouse embryo: Bystin null proliferation in mammalian cells. mouse embryos implanted successfully but died Although bystin exhibits activities similar to Enp1, soon after implantation (Aoki et al., 2006), human bystin cannot rescue the lethal phenotype of Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 295 BYSL (Bystin-Like) Fukuda MN, Sugihara K Enp1-null yeast mutant, suggesting that ribosomal the 40S subunit before translation in human cells RNA processing pathways in multicellular (Miyoshi et al., 2007), bystin may also function