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The DPY30 subunit in SET1/MLL complexes regulates the proliferation and differentiation of hematopoietic progenitor cells.

ABSTRACT: Epigenetic mechanisms including histone modifications have emerged as important factors influencing cell fate determination. The functional role of H3K4 methylation, however, remains largely unclear in the maintenance and differentiation of hematopoietic stem/progenitor cells (HSC/HPCs). Here we show that DPY30, a shared core subunit of the SET1/MLL family methyltransferase complexes and a facilitator of their H3K4 methylation activity, is important for ex vivo proliferation and differentiation of human CD34+ HPCs. DPY30 promotes HPC proliferation by directly regulating the expression of genes critical for cell proliferation. Interestingly, while DPY30 knockdown (KD) in HPCs impaired their differentiation into the myelomonocytic lineage, it potently promoted hemoglobin production and affected the kinetics of their differentiation into the erythroid lineage. In an in vivo model, we show that morpholino-mediated dpy30 KD resulted in severe defects in the development of the zebrafish hematopoietic system, which could be partially rescued by co-injection of dpy30 mRNA. Taken together, our results establish a critical role of DPY30 in the proliferation and appropriate differentiation of hematopoietic progenitor cells as well as in animal hematopoiesis. Finally, we also demonstrate a crucial role of DPY30 in the growth of several MLL1-fusion-mediated leukemia cell lines.

ORGANISM(S): Homo sapiens

PROVIDER: GSE59643 | GEO | 2014/09/01

SECONDARY ACCESSION(S): PRJNA255852

REPOSITORIES: GEO

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The DPY30 subunit in SET1/MLL complexes regulates the proliferation and differentiation of hematopoietic progenitor cells.

Project description:Epigenetic mechanisms including histone modifications have emerged as important factors influencing cell fate determination. The functional role of H3K4 methylation, however, remains largely unclear in the maintenance and differentiation of hematopoietic stem/progenitor cells (HSC/HPCs). Here we show that DPY30, a shared core subunit of the SET1/MLL family methyltransferase complexes and a facilitator of their H3K4 methylation activity, is important for ex vivo proliferation and differentiation of human CD34+ HPCs. DPY30 promotes HPC proliferation by directly regulating the expression of genes critical for cell proliferation. Interestingly, while DPY30 knockdown (KD) in HPCs impaired their differentiation into the myelomonocytic lineage, it potently promoted hemoglobin production and affected the kinetics of their differentiation into the erythroid lineage. In an in vivo model, we show that morpholino-mediated dpy30 KD resulted in severe defects in the development of the zebrafish hematopoietic system, which could be partially rescued by co-injection of dpy30 mRNA. Taken together, our results establish a critical role of DPY30 in the proliferation and appropriate differentiation of hematopoietic progenitor cells as well as in animal hematopoiesis. Finally, we also demonstrate a crucial role of DPY30 in the growth of several MLL1-fusion-mediated leukemia cell lines. Total RNAs from control (scr) or knockdown (hD2, hD5) cells before and after culturing under condition promoting myelomonocytic differentiation were subjected to Illumina microarray analyses.

2014-09-01 | E-GEOD-59643 | biostudies-arrayexpress

Dpy30 Is Critical for Maintaining the Identity and Function of Adult Hematopoietic Stem Cells

Project description:As the major histone H3K4 methyltransferases in mammals, the Set1/Mll complexes play important roles in animal development and are increasingly associated with diseases including hematological malignancies. The role of H3K4 methylation activity of these complexes, however, remains elusive in fate determination of hematopoietic stem and progenitor cells (HSCs and HPCs). Here we address this question by generating a conditional knockout mouse for Dpy30, which is a common core subunit of all Set1/Mll complexes and facilitates genome-wide H3K4 methylation in cells. Dpy30 loss in the adult hematopoietic system results in severe pancytopenia but striking accumulation of HSCs and early HPCs that are defective in multilineage reconstitution, suggesting a differentiation block. In mixed bone marrow chimeras, Dpy30-deficient HSCs cannot differentiate or efficiently upregulate lineage-regulatory genes, and eventually fail to sustain for long term with significant loss of HSC signature gene expression. Our molecular analyses reveal that Dpy30 directly regulates H3K4 methylation and expression of key transcriptional factors, cofactors, and chromatin modulators involved in HSC function. Collectively, our results establish a critical role of Dpy30 and the H3K4 methylation activity of the Set1/Mll complexes for maintaining the identity and function of adult hematopoietic stem cells.

2016-09-08 | GSE81390 | GEO

Effects of Dpy30 loss on gene expression in mouse fetal liver HSCs

Project description:Profound distinctions exist between fetal liver (FL) and adult bone marrow (BM) hematopoietic stem cells (HSCs) in many aspects. Previously we showed that efficient H3K4 methylation plays an essential role in the differentiation and long-term maintenance of adult hematopoietic stem cell. However, its role in fetal hematopoiesis is unknown. Here, we show that loss of Dpy30, a core subunit of Set1/Mll complexes that responsible for efficient global H3K4 methylation, in FL results in embryonic anemia as well as the accumulation of HSCs that are defective in multiple lineage reconstitution as shown in mixed chimera assays. Global gene expression analyses identified 21 genes co-downregulated by Dpy30 loss in FL and BM HSCs, among which we further demonstrate that Igdcc4 and Ntpcr are important for efficient colony formation capacity of both FL and BM HSCs in vitro. This study suggests that Dpy30 and certain Dpy30 targets are fundamentally important in regulating HSCs regardless of developmental stages, and that the identified common target genes may provide new insight into the molecular regulation of hematopoiesis.

2019-03-01 | GSE101856 | GEO

Gene expression changes during hematopoietic cell differentiation

Project description:Gene expression analyses of hematopoietic stem cells (HSCs), progenitor cells (HPCs), and differentiated cell. Gene expressions of long-term HSCs (CD34-ckit+Sca1+Lineage-), short term HSCs (CD34+ckit+Sca1+Lineage-), Progenitor cells (ckit+Sca1- Lineage-), and differentiated cels (Lineage+) were examined by microarray. Results provide insight into the mechanism of hematopoietic cell differentiation. Long-term HSCs (CD34-ckit+Sca1+Lineage-), Short term-HSCs (CD34+ckit+Sca1+Lineage-), Progenitor cells (ckit+Sca1- Lineage-, and Lineage+), and differentiated cell (Lineage+) were sorted from mouse bone marraw and were examined by microarray. Results provide insight into the mechanism of hematopoietic cell differentiation.

2013-11-06 | E-GEOD-48986 | biostudies-arrayexpress

Specific inhibition of DPY30 activity by peptides suppresses blood cancer cell growth

Project description:Epigenetic modulators are being recognized as attractive targets for potential cancer treatment. SET1/MLL complexes are the major H3K4 methyltransferase complexes in mammals. The DPY30 subunit is associated with these complexes by forming a dimer that directly binds to the ASH2L subunit in the complexes and facilitates methylation. We have previously established an important role of DPY30 in certain hematologic malignancies including MLL-rearranged leukemia and Burkitt’s lymphoma, but the domain on DPY30 that regulates cancer growth is not evident. Moreover, the potential of pharmacologically targeting this chromatin modulator to inhibit cancer has not been explored. Here we have developed a peptide-based strategy to specifically target DPY30 activity. We have designed cell-penetrating peptides that can either bind to DPY30 or show defective or enhanced binding to DPY30. The DPY30-binding peptides, but not the non-binding peptide, inhibit DPY30’s activity in interacting with ASH2L and in enhancing H3K4 methylation. Treatment with the DPY30-binding, but not the non-binding, peptide significantly inhibited the growth of MLL-rearranged leukemia and other MYC-dependent hematologic cancer cells including Burkitt’s lymphoma cells. These results strongly support a critical role of the ASH2L-binding groove of DPY30 in promoting the growth of certain blood cancers, and also demonstrate a proof-of-principle for the feasibility of pharmacologically targeting the ASH2L-binding groove of DPY30 for potential cancer inhibition.

2019-03-01 | GSE115988 | GEO

Gene expression changes during hematopoietic cell differentiation

2013-11-06 | GSE48986 | GEO

A chromatin modulator sustains self-renewal and enables differentiation of postnatal neural stem cells

Project description:It remains largely unclear if efficient H3K4 methylation, an epigenetic modification associated with gene activation, regulates fate determination of the postnatal neural stem cells (NSCs). By inactivating the Dpy30 subunit of the major mammalian H3K4 methyltransferase complexes in specific regions of mouse brain, we demonstrate a crucial role of efficient H3K4 methylation in maintaining both the self-renewal and differentiation capacity of postnatal NSCs. Loss Dpy30 disrupts the development of dentate gyrus and subventricular zone, the major regions for postnatal NSC activities. Dpy30 is indispensable for sustaining the self-renewal of NSCs in a cell-intrinsic manner. Dpy30 also enables the differentiation of mouse and human neural progenitor cells to neuronal and glial lineages. Dpy30 directly regulates H3K4 methylation and the induction of several genes critical in neurogenesis. These findings link a prominent epigenetic mechanism of gene expression to the fundamental properties of NSCs, and may have implications in neurodevelopmental disorders.

2019-03-01 | GSE114091 | GEO

Dpy30 regulates Myc binding to targets and Myc-driven tumorigenesis (ChIP-seq, RNA-seq)

Project description:It remains unclear how epigenetic modulators impact the tumorigenic potential of Myc. Here we show that the core subunits, including Dpy30, of the major H3K4 methyltransferase complexes are selectively upregulated in Burkitt lymphoma, and Dpy30 is important for efficient genomic binding of Myc. Dpy30 heterozygosity does not affect normal animal physiology, but significantly suppressed lymphomagenesis and reduced expression of a subset of key pro-survival genes when Myc is hyper-activated. Dpy30 heterozygosity also impedes cellular transformation without affecting normal cell growth. These results suggest that Myc hijacks this chromatin modulator to coordinate its oncogenic program for efficient tumorigenesis, meanwhile creating “epigenetic vulnerability”, which we then exploited by specifically targeting Dpy30’s activity to inhibit growth of the Burkitt lymphoma cell model.

2018-08-01 | GSE101853 | GEO

Dpy30 regulates Myc binding to targets and Myc-driven tumorigenesis (Illumina HumanHT-12 V4.0 expression)

2018-08-01 | GSE101852 | GEO

TrxG complex catalytic and non-catalytic activity play distinct roles in pancreas progenitor specification and differentiation (E13.5 Dpy30∆P pancreas scRNA-Seq)

Project description:Purpose: To investigate whether pancreas progenitor specification may be altered, we performed single-cell RNA-sequencing (scRNA-seq) using E13.5 control and Dpy30∆P pancreas. To determine whether Dpy30∆P cells have a different developmental trajectory than control cells, we performed pseudo-temporal analysis (Trapnell et al., 2014). Methods: Floxed Dpy30 mice were crossed to Pdx1-Cre driver mice to obtain conditional deletion of Dpy30 exon 4 in the pancreas. In all studies, knockout mice (Dpy30∆P, Pdx1-Cre; Dpy30flox/flox) were compared to littermate controls (Dpy30flox/flox or Dpy30flox/wt). Results: In total, we sequenced 3,900 control and 3,044 Dpy30∆P cells from which 786 control and 477 Dpy30∆P epithelial cells were identified for further analysis. As expected, control progenitor cells gave rise to cells in two distinct branches corresponding to the acinar and endocrine lineages, with terminal markers upregulated in cells at the ends of these branches. Dpy30∆P progenitors differentiated along these same trajectories; however, relatively few Dpy30∆P cells were found at the ends of these branches, and acinar and endocrine terminal marker expression was reduced in Dpy30∆P cells. Interestingly, a higher fraction of Dpy30∆P cells were found within the MPC/BPC and acinar clusters, predominantly at the expense of endocrine cells. Analyzing the fraction of cells in G1 phase across pseudo-time showed that a higher fraction of Dpy30∆P acinar lineage cells were in G1 phase. Conclusions: Overall, this suggests that MPC/BPCs and acinar cells may have a prolonged G1 phase due to a failure to appropriately induce genes essential for progression through G2M or S phase.

2019-07-12 | GSE134179 | GEO

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