Alternative titles; symbolsDPY30, C. ELEGANS, HOMOLOG OFHGNC Approved Gene Symbol: DPY30Cytogenetic location: 2p22.3 Genomic coordinates (GRCh38): 2:32,011,6...
Alternative titles; symbols
HGNC Approved Gene Symbol: DPY30
Cytogenetic location: 2p22.3 Genomic coordinates (GRCh38): 2:32,011,648-32,039,839 (from NCBI)
DPY30 is a component of a Set1-like multiprotein histone methyltransferase complex (Cho et al., 2007).
▼ Cloning and Expression
As part of a large scale sequencing project of a human brain cDNA library, Dong et al. (2005) cloned DPY30. Because they identified a peak just under 52 kD for soluble, recombinantly expressed DPY30, compared to the calculated molecular mass of 12.5 kD, they suggested that DPY30 may form a stable oligomer. CD spectroscopy of the purified protein showed that DPY30 contains an alpha-helical structure.
By affinity purification of PTIP (PAXIP1; 608254)-associated proteins in a HeLa cell line expressing mouse Ptip, followed by mass spectrometry, Cho et al. (2007) identified DPY30.
▼ Gene Function
Using mass spectrometry and protein purification, Cho et al. (2007) demonstrated that DPY30 is part of a larger complex of PTIP-associated proteins including ASH2L (604782), RBBP5 (600697), WDR5 (609012), NCOA6 (605299), MLL3 (606833), MLL4 (606834), and PA1 (C16ORF53; 612033). The protein complex is a Set1-like histone methyltransferase complex that displays histone H3 lysine-4 (H3K4) methyltransferase activity. Cho et al. (2007) showed that DPY30 is a common subunit of all human Set1-like histone methyltransferase complexes and directly interacts with ASH2L but not with RBBP5 or WDR4.
Jiang et al. (2011) showed that recombinant human DPY30 weakly stimulated methylation of H3K4 by the MLL2 complex. However, knockdown of DPY30 significantly decreased global methylation of H3K4 in human cell lines. Knockdown of Dpy30 in mouse embryonic stem cells (ESCs) reduced H3K4 trimethylation on all monitored genes. Knockdown of Dpy30 or Rbbp5 did not alter the expression of genes associated with ESC self-renewal or heat stress response, but it blocked retinoic acid (RA)-induced neural differentiation of ESCs and the accompanying upregulation of RA-induced neuronal marker genes. Knockdown of DPY30 also blocked RA-induced neural differentiation in the human embryonic carcinoma cell line NT2. Jiang et al. (2011) concluded that DPY30 is a core MLL subunit that is essential for neural specification of ESCs.
Gross (2011) mapped the DPY30 gene to chromosome 2p22.3 based on an alignment of the DPY30 sequence (GenBank AF226998) with the genomic sequence (GRCh37).
▼ Animal Model
In C. elegans, sex is determined by the ratio of X chromosomes to sets of autosomes (X:A), which directs X:2A animals to develop as males and 2X/2A animals to develop as hermaphrodites. XX hermaphrodites reduce the transcript levels produced by the X chromosomes to achieve the same levels produced by the single X in males. Hsu and Meyer (1994) identified Dpy30 as a component of the X chromosome dosage compensation machinery in C. elegans. Homozygous Dpy30-null XX offspring of Dpy30-null mothers were inviable, but homozygous Dpy30-null XX offspring of Dpy30+/- mothers showed temperature-sensitive abnormalities. The findings indicated that lack of Dpy30 resulted in overexpression of X-linked genes in XX animals, likely resulting from a disruption in the dosage compensation process. Loss of Dpy30 in XO animals also caused some developmental and behavioral abnormalities. Dpy30 acted downstream of sex-determining genes, and did not appear to directly affect sex determination, although it may be involved in masculinization or femininization depending on the genetic background.
Yang et al. (2016) found that mice lacking Dpy30 in adult hemopoietic stem cells (HSCs) had severe pancytopenia and a striking accumulation of HSCs and early hemopoietic progenitor cells defective in multilineage reconstitution, suggesting a differentiation block. In mixed bone marrow chimeric mice, Dpy30-deficient HSCs failed to differentiate or to efficiently upregulate lineage regulatory genes and ultimately were unable to sustain long-term transplantation. Chromatin immunoprecipitation analysis showed that loss of Dpy30 impaired H3K4 methylation. Yang et al. (2016) concluded that DPY30 has a critical and selective role in the H3K4 methylation activity of SET1/MLL complexes in maintaining the identity and function of adult HSCs.