The PYGO2 gene (6828 bp) contains a total of 3 exons and the PYGO2 transcript is 3146 bp.

Genomic size: 6828 bp. Exons count: 3. This gene has 3 transcript (splice variants), 112 orthologues and 1 paralogue

3 transcript variants have been found for this gene (font. www.ensembl.org).
PYGO2-202 ENST00000368457.2 : mRNA 3146 bp, protein 406 aa
PYGO2-201 ENST00000368456.1 : mRNA 1306 bp, protein 369 aa
PYGO2-203 ENST00000483463.1 : mRNA 594 bp, no protein.

PYGO2 protein, composed by 406 aa with a molecular mass of 41244 Da, is one of mammalian homologs of Drosophila Pygopus, essential for early embryonic development, moreover is known to be co-activator of the Wnt/β-catenin pathway transcriptional complex.
PYGO2 has two conserved domains, an N-terminal homology domain (NHD) and a C-terminal PHD zinc finger motif. The NHD domain plays an important role in transcriptional activation, taking part in the recruitment of histone modification factors and being involved in histone methylation (Gu et al., 2009). Deletion of NHD domain has been associated with 50% reduction of transcriptional activity (Liang et al., 2018). Moreover, in the N-terminal region, there is its nuclear localization signal-NLS (from aa 41 to aa 47) and a NPF (asparagine-proline-phenylalanine) sequence, which takes part in interactions with several proteins involved in chromatin remodelling. PYGO2 contains a plant homeodomain (PHD) finger, from aa 327 to aa 385, composed by 60 aminoacids organized in C4HC3 motives, which is important for the PYGO2 PHD-BCL9-HD1 complex formation (Miller et al., 2010).

The first molecular cloning and expression analysis of a mouse pygopus gene, mpygo2, were described by Li et al. (2004). Its transcripts were expressed in various adult mouse tissues, such as brain, heart, kidney, liver, lung, skin, small intestine, spleen, stomach, testis tissue and thymus; at the same manner, mpygo2 transcripts were detected in all embryos stages examined. The majority of tissues in which mpygo2 is expressed requires Wnt signaling activation for development, morphogenesis and maintenance and this is in line with the involvement of this gene in the Wnt signaling. Interestingly, since the hair follicle development is a well-known system which involves Wnt signaling, mpygo2 expression was detected both in developing and adult hair follicle (Li et al; 2004). The homologous Drosophila pygo gene is necessary to the binding with Lgs (legless) and for this reason Drosophila embryos homozygous for a pygo mutation, with any Pygo activity, die with a severe segment polarity phenotype (Kramps et al., 2002); this lethality is not found in mice. Mammals have two Pygopus homologues, Pygo1 and Pygo2, and the latter seems to be dominant (Schwab et al., 2007). The hPygo is expressed in a Wnt-dependent manner, in tissues such as kidney (Schwab et al., 2007), pancreas (Jonckheere et al., 2008), brain (Lake and Kao, 2003) and mammary gland (Gu et al., 2012); while is expressed in a Wnt-independent fashion for eye development (Song et al., 2007), spermiogenesis (Nair et al., 2008) and embryonic brain patterning (Lake and Kao, 2003). hPYGO2 shows high expression levels also in several types of cancer, in particular in epithelial ovarian cancer cell lines (Popadiuk et al., 2006), in several breast malignant tumours (Andrews et al., 2007), in gliomas and glioblastoma cells (Wang et al., 2010 14; Chen et al., 2011); recently hPYGO2 has been associated also with adenomas and colon tumours (Brembeck et al., 2011) and esophageal squamous cell carcinoma (Moghbeli et al., 2013).

PYGO2 is localized in the nucleus (UniProt Pygo2)

PYGO2 protein is known to be implicated in chromatin remodelling and binding to methylated residues on lysine 4 of histone H3 (H3K4me), relevant for active transcription (Aasland et al., 1995). Has also been demonstrated that PYGO2 is involved in promoting trimethylation of the same residue (H3K4) and acetylation of H3K9/K14 (Gu et al., 2009; Chen et al., 2010). In addition, PYGO2 seems to act as scaffold protein between CTNNB1 (β-catenin), HNMT, TMPRSS11D (HAT) and the chromatin (Chen et al., 2010). This protein is also involved in signal transduction through the Wnt pathway and it showed a role in nuclear retention of β-catenin. Several studies reported that the NHD domain of Pygo regulates the transactivation activity, instead the PHD domain is responsible for the binding, through adaptor proteins, to the N-terminal domain of β-catenin (Townsley et al., 2004; Stadeli and Basler, 2005). Several studies reported not only the association with β-catenin to act as co-activators of the β-catenin/ LEF1/TCF complex (Kramps et al., 2002, Stadeli and Basler, 2005), but also the β-catenin independent association with LEF/TCF target genes (de la Roche and Bienz, 2007). In two of the most extensively characterized PYGO2-requiring tissues, testis and eye, its function is β-catenin independent. In the developing kidney PYGO2 shows wide expression in the ureteric bud and PYGO2 mutant phenotype resulted in reduced branching morphogenesis of this (Schwab et al., 2007). Similarly, a mutant phenotype has been observed also in pancreas, where lack of PYGO2 results in pancreas hypoplasia and defective endocrine cell differentiation (Jonckheere et al., 2008). PYGO2 demonstrated to play a role in development also in lung morphogenesis, because mpygo2^-/- showed lungs pale and smaller than the wild type and with airways defects (Boan et al., 2007). Concerning the tissues where PYGO2 is not linked to the Wnt signalling, it showed to play a role in lens development, because of its expression in tissues of early eye such as optic vesicle and presumptive lens (Song et al., 2007), and during spermatogenesis, as a matter of fact its block leads to spermiogenesis arrest and infertility (Nair et al., 2008).

PYGO2 is conserved in human, mouse, rat, chimpanzee, cattle, dog and chicken.

Some somatic mutations have been identified and described by COSMIC (Catalogue of Somatic Mutation In Cancer) and they are listed mostly as substitutions and frameshift insertion or deletions; their role in disease has not yet been clarified.