Murine Histone Methyltransferase Mll5, is involved in Male Gametogenesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE19648 | GEO | 2010/09/30
SECONDARY ACCESSION(S): PRJNA122541
REPOSITORIES: GEO
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Project description:Male mice but not female Mll5 -/- mice are infertile. This study showed that post-meiotic spermatogenic maturation is impaired in Mll5 -/- mice. In order to investigate the role of Mll5 in spermatogenesis, a transcriptome analysis of whole testes from Mll5 knock out and wildtype mice was performed. Affymetrix Mouse Exon chips were hybridized with testes material from three individual male mice from each wild-type or Mll5 -/- genotype, in order to identify gene regulation differences attributed to the loss of Mll5. One-way ANOVA: wildtype vs. Mll5-/-
2010-09-30 | E-GEOD-19648 | biostudies-arrayexpress
Project description:MLL5 is a novel trithorax group gene and a candidate tumor suppressor gene located within a 2.5 Mb interval of chromosome band 7q22 that is frequently deleted in human myeloid malignancy. Here we show that Mll5 is required for normal hematopoietic stem cell (HSC) homeostasis. Inactivation of the Mll5 gene in mice results in reduced cellularity of the long-term HSC compartment, which correlates with functional impairment of long-term repopulation potential under competitive conditions. Bone marrow cells from Mll5-deficient mice were defective in spleen colony-forming assays, and the mutant mice showed enhanced susceptibility to 5-Fluorouracil-induced myelosuppression. Heterozygous and homozygous Mll5 mutant mice did not spontaneously develop hematologic cancers, and loss of Mll5 did not alter the phenotype of a fatal myeloprolferative disorder induced by oncogenic Kras in vivo. Collectively, the data reveal an important role for Mll5 in HSC homeostasis, and provide a basis for further studies to explore its role in leukemogenesis. Keywords: Cell type comparision.
2008-05-22 | GSE10817 | GEO
Project description:Expression profiling of mouse ing2 -/- testis vs WT reveals gene expression differences consistent with spermatogenic arrest and infertility. Ing2 is indispensable for male germ cell development in mice. While mice deficient for Ing2 were born and grew without apparent abnormalities, male, but not female, were infertile, consistent with the highest expression of Ing2 in testes in wild-type mice and in humans. Histological and DNA content analyses in Ing2-/- testes revealed a spermatogenesis arrest at meiotic phase and enhanced apoptosis associated with increased p53, resulting in a decline in mature spermatozoa, which became more severe in older age. HDAC1 accumulation and core histone deacetylation at pachytene stage were impaired in Ing2-/- testes, suggesting that the recruitment of HDAC1 by Ing2 plays a critical role in spermatogenesis. This study establishes Ing2 as a novel mammalian regulator of spermatocyte differentiation, which coordinates spermatogenesis stage-specific histone modifications. This study has implications in understanding human male infertility. Testis from WT and Ing2 KO mice at 2-3 months of age where analyzed for differences in gene expression.
2010-11-19 | E-GEOD-18610 | biostudies-arrayexpress
Project description:Expression profiling of mouse ing2 -/- testis vs WT reveals gene expression differences consistent with spermatogenic arrest and infertility. Ing2 is indispensable for male germ cell development in mice. While mice deficient for Ing2 were born and grew without apparent abnormalities, male, but not female, were infertile, consistent with the highest expression of Ing2 in testes in wild-type mice and in humans. Histological and DNA content analyses in Ing2-/- testes revealed a spermatogenesis arrest at meiotic phase and enhanced apoptosis associated with increased p53, resulting in a decline in mature spermatozoa, which became more severe in older age. HDAC1 accumulation and core histone deacetylation at pachytene stage were impaired in Ing2-/- testes, suggesting that the recruitment of HDAC1 by Ing2 plays a critical role in spermatogenesis. This study establishes Ing2 as a novel mammalian regulator of spermatocyte differentiation, which coordinates spermatogenesis stage-specific histone modifications. This study has implications in understanding human male infertility.
2010-11-19 | GSE18610 | GEO
Project description:The human mixed lineage leukemia 5 (MLL5) protein mediates hematopoietic cell homeostasis, cell cycle and survival, however, the molecular basis underlying MLL5 activities remains unknown. Here, we show that MLL5 is recruited to gene-rich euchromatic regions via the interaction of its PHD finger with the histone mark H3K4me3. The 1.48 Å resolution crystal structure of the MLL5 PHD finger in complex with the H3K4me3 peptide reveals a non-canonical binding mechanism, whereby K4me3 is recognized through a single aromatic residue and an aspartate. The binding induces a His-Asp swapping rearrangement mediated by a C-terminal α-helix. Phosphorylation of H3T3 and H3T6 abrogates the association with H3K4me3 in vitro and in vivo, releasing MLL5 from chromatin in mitosis. This regulatory switch is conserved in the Drosophila ortholog of MLL5, MLL5, and suggests the developmental control for targeting of H3K4me3. Together, our findings provide insight into the molecular basis for the recruitment, exclusion and regulation of MLL5 at chromatin.
2013-07-01 | GSE47100 | GEO
Project description:The human mixed lineage leukemia 5 (MLL5) protein mediates hematopoietic cell homeostasis, cell cycle and survival, however, the molecular basis underlying MLL5 activities remains unknown. Here, we show that MLL5 is recruited to gene-rich euchromatic regions via the interaction of its PHD finger with the histone mark H3K4me3. The 1.48 Ã
resolution crystal structure of the MLL5 PHD finger in complex with the H3K4me3 peptide reveals a non-canonical binding mechanism, whereby K4me3 is recognized through a single aromatic residue and an aspartate. The binding induces a His-Asp swapping rearrangement mediated by a C-terminal α-helix. Phosphorylation of H3T3 and H3T6 abrogates the association with H3K4me3 in vitro and in vivo, releasing MLL5 from chromatin in mitosis. This regulatory switch is conserved in the Drosophila ortholog of MLL5, MLL5, and suggests the developmental control for targeting of H3K4me3. Together, our findings provide insight into the molecular basis for the recruitment, exclusion and regulation of MLL5 at chromatin. For determaning MLL5 chromatin profile, DamID-MLL5 chromatin profiling was determined in C2C12 cells . Three biological replicates were performed. Normalized data was averaged and HMM approach was applied to establish the bound regions (Straub, T., Grimaud, C., Gilfillan, G. D., Mitterweger, A., and Becker, P. B. (2008). PLoS Genet 4, e1000302)
2013-07-01 | E-GEOD-47100 | biostudies-arrayexpress
Project description:Analysis of differential gene expression in wild type vs Mll5-/- Retinal Transcriptomes. The aim is to identify potential genes that are regulated by MLL5.
2022-02-20 | GSE196935 | GEO
Project description:Ip6k1 knockout male mice are infertile and display a delay in the first wave of spermatogenesis. To understand the underlying basis of this delay, we compared the gene expression profiles of whole testes from 17 days postpartum (17dpp) and 26 days postpartum (26dpp) Ip6k1 wild type (Ip6k1+/+) and Ip6k1 knockout (Ip6k1-/-) mice. We observed deregulation of several biological processes in Ip6k1-/- testes compared with Ip6k1+/+ testes.
2021-06-20 | GSE153500 | GEO
Project description:Luteinising hormone (LH) is a key regulator of male fertility through its effects on testosterone secretion by Leydig cells. Mice in which the LH receptor is knocked out (LuRKO) show reduced testicular size, reduced testosterone, elevated serum LH, and a spermatogenic arrest that can be rescued by administration of testosterone. This study examines the onset of spermatogenic arrest in LuRKO males using transcriptional profiling of developing mutant and control testes. We also examine the initial stages of testosterone rescue of the phenotype, in order to identify key upstream regulators of testosterone-dependent spermatogenesis.
2009-12-14 | GSE19453 | GEO
Project description:We found previously that the effect of decitabine (DAC) on hematopoietic stem cell viability differed between Mll5 wildtype and null cells. We therefore investigated the role of MLL5 expression levels on outcome of AML patients who were treated with decitabine. High MLL5 expressing AML patients have improved overall survival when treated with decitabine. In transformed murine cells, loss of Mll5 was associated with resistance to low-dose decitabine, less frequent promoter methylation, and reduced demethylation upon decitabine treatment. These data suggest a biological link between MLL5 expression and decitabine response involving regulation of DNA methylation. Leukemia cell model was generated by co-transfer of HOXA9 and MEIS1 into Mll5 wildtype or knockout mouse bone marrow cells. MeDIP was performed in Mll5+/+ HOXA9/MEIS1 and Mll5-/- HOXA9/MEIS1 leukemic cells, untreated or treated with 3-day exposure of 20 nM decitabine, triplicate for each condition. MeDIP-enriched DNA was amplified with the GenomePlex Complete Whole Genome Amplification (WGA) Kit (Sigma-Aldrich). DNA from three MeDIP and WGA of each cell type and treatment was pooled for subsequent microarray analysis. The enriched DNA and corresponding input genomic DNA was labeled, hybridized and scanned on Agilent custom mouse promoter microarrays (Agilent-025976 AP_1M_Custom_CH3, assembly build mm9). The methylation value of individual probes was defined by the signal intensity ratio of MeDIP DNA (Cy3) compared to input DNA (Cy5) .
2014-07-01 | GSE52199 | GEO