Alternative titles; symbols
HGNC Approved Gene Symbol: CDYL
Cytogenetic location: 6p25.1 Genomic coordinates (GRCh38) : 6:4,706,138-4,955,544 (from NCBI)
CDY family proteins, such as CDYL, each contain a chromodomain and catalytic domain that are highly conserved and implicated in histone modification and recognition. However, due to subtle amino acid changes in their chromodomains, CDY proteins display substantial differences in chromatin recognition and binding, thereby diversifying the epigenetic regulatory roles they play (Fischle et al., 2008).
Lahn and Page (1999) determined that there are at least 2 Y-linked CDY genes, CDY1 (400016) and CDY2 (400018), each of which may exist as multiple copies. By screening human and mouse testis libraries at low stringency with a CDY probe, these authors isolated cDNAs encoding an autosomal homolog, CDYL. Like CDY, the predicted CDYL protein contains an N-terminal chromodomain (see 603079) and a C-terminal catalytic domain. Human CDYL shares 93% and 63% protein sequence identity with mouse Cdyl and human CDY, respectively. Northern blot analysis revealed that human CDYL was expressed at moderate levels in all tissues examined, indicating that it may perform a housekeeping function.
Fischle et al. (2008) showed that FLAG-tagged human CDY and CDYL and mouse Cdyl2 (618816) localized exclusively in nuclei of mouse fibroblasts. Cdyl2 was found throughout nucleus in a punctate distribution pattern and colocalized with regions of trimethylated histone H3 (see 602810) lys9 (H3K9me3). CDY was excluded from nucleoli, but overlapped in chromatin with regions of H3K9me3. CDYL was also excluded from nucleoli, but it did not overlap with regions of H3K9me3.
By affinity purification of epitope-tagged CDYL from HeLa cell nuclear extracts, followed by mass spectrometry, Mulligan et al. (2008) identified 22 proteins that interacted with CDYL, the majority of which had roles in transcriptional repression. CDYL associated particularly with a complex containing REST (600571) and the histone H3K9 methylases G9A (EHMT2; 604599), EHMT1 (607001), and SETDB1 (604396), among others. CDYL bridged the interaction between REST and G9A/EHMT1 in vitro and in vivo and functioned as a REST corepressor that facilitated G9A recruitment to REST target genes. Knockdown of CDYL and G9A in immortalized human mammary epithelial cells led to oncogenic transformation in vitro. REST/CDYL/G9A directly repressed transcription of TRKC (NTRK3; 191316), whose overexpression was sufficient to cause cellular transformation. Knockdown of CDYL also augmented cellular transformation in a human cell culture model of cervical cancer.
Fischle et al. (2008) noted that the chromodomain of human CDY interacts with methylated H3K9. They found that, despite their high homology and similar tertiary structures, the chromodomains of CDY, CDYL, and CDYL2 displayed variability in binding to H3K9me3. Unlike the CDY and CDYL2 chromodomains, the CDYL chromodomain did not bind to the H3K9me3 peptide, but efficient binding could be established by point mutations in the chromodomain.
Lahn and Page (1999) determined that the mouse and human CDYL genes both contain 9 exons.
By analysis of radiation hybrids, Lahn and Page (1999) mapped the CDYL gene to regions of human chromosome 6 and mouse chromosome 13 that share homology of synteny.
Gross (2020) mapped the CDYL gene to chromosome 6p25.1 based on an alignment of the CDYL sequence (GenBank AF081258) with the genomic sequence (GRCh38).
Lahn and Page (1999) suggested that the CDY genes arose during primate evolution by retroposition of an mRNA from the CDYL gene, followed by amplification of the retroposed gene. In mouse, which has no Y-linked CDY homologs, Cdyl is expressed as 2 transcripts: a ubiquitous transcript, similar in length to the human CDYL mRNA, and a highly expressed testis-specific transcript, similar in length to the human CDY mRNA. The authors proposed that the expression pattern of mouse Cdyl represents the evolutionarily ancestral condition, and that a genomic partitioning of the housekeeping and testis-specific functions evolved in primates. Thus, in humans, CDYL produces only the ubiquitous transcript, while the testis-specific transcript is encoded by the Y-linked CDY genes.
Fischle, W., Franz, H., Jacobs, S. A., Allis, C. D., Khorasanizadeh, S. Specificity of the chromodomain Y chromosome family of chromodomains for lysine-methylated ARK(S/T) motifs. J. Biol. Chem. 283: 19626-19635, 2008. [PubMed: 18450745] [Full Text: https://doi.org/10.1074/jbc.M802655200]
Gross, M. B. Personal Communication. Baltimore, Md. 3/17/2020.
Lahn, B. T., Page, D. C. Retroposition of autosomal mRNA yielded testis-specific gene family on human Y chromosome. Nature Genet. 21: 429-433, 1999. Note: Erratum: Nature Genet. 22: 209 only, 1999. [PubMed: 10192397] [Full Text: https://doi.org/10.1038/7771]
Mulligan, P., Westbrook, T. F., Ottinger, M., Pavlova, N., Chang, B., Macia, E., Shi, Y.-J., Barretina, J., Liu, J., Howley, P. M., Elledge, S. J., Shi, Y. CDYL bridges REST and histone methyltransferases for gene repression and suppression of cellular transformation. Molec. Cell 32: 718-726, 2008. [PubMed: 19061646] [Full Text: https://doi.org/10.1016/j.molcel.2008.10.025]