Investigation of MYST4 histone acetyltransferase and its involvement in mammalian gametogenesis

<p>Abstract</p> <p>Background</p> <p>Various histone acetylases (HATs) play a critical role in the regulation of gene expression, but the precise functions of many of those HATs are still unknown. Here we provide evidence that MYST4, a known HAT, may be involved in early mammalian gametogenesis.</p> <p>Results</p> <p>Although <it>MYST4 </it>mRNA transcripts are ubiquitous, protein expression was restricted to select extracts (including ovary and testis). Immunohistochemistry experiments performed on ovary sections revealed that the MYST4 protein is confined to oocytes, granulosa and theca cells, as well as to cells composing the blood vessels. The transcripts for <it>MYST4 </it>and all-<it>MYST4</it>-isoforms were present in oocytes and in <it>in vitro </it>produced embryos. In oocytes and embryos the MYST4 protein was localized in both the cytoplasm and nucleus. Within testis sections, the MYST4 protein was specific to only one cell type, the elongating spermatids, where it was exclusively nuclear.</p> <p>Conclusion</p> <p>We established that MYST4 is localized into specialized cells of the ovary and testis. Because the majority of these cells are involved in male and female gametogenesis, MYST4 may contribute to important and specific acetylation events occurring during gametes and embryo development.</p

Clearance of defective muscle stem cells by senolytics reduces the expression of senescence-associated secretory phenotype and restores myogenesis in myotonic dystrophy type 1

Muscle weakness and atrophy are clinical hallmarks of myotonic dystrophy type 1 (DM1). Muscle stem cells, which contribute to skeletal muscle growth and repair, are also affected in this disease. However, the molecular mechanisms leading to this defective activity and the impact on the disease severity are still elusive. Here, we explored through an unbiased approach the molecular signature leading to myogenic cell defects in DM1. Single cell RNAseq data revealed the presence of a specific subset of DM1 myogenic cells expressing a senescence signature, characterized by the high expression of genes related to senescence-associated secretory phenotype (SASP). This profile was confirmed using different senescence markers in vitro and in situ. Accumulation of intranuclear RNA foci in senescent cells, suggest that RNA-mediated toxicity contribute to senescence induction. High expression of IL-6, a prominent SASP cytokine, in the serum of DM1 patients was identified as a biomarker correlating with muscle weakness and functional capacity limitations. Drug screening revealed that the BCL-XL inhibitor (A1155463), a senolytic drug, can specifically target senescent DM1 myoblasts to induce their apoptosis and reduce their SASP. Removal of senescent cells re-established the myogenic function of the non-senescent DM1 myoblasts, which displayed improved proliferation and differentiation capacity in vitro; and enhanced engraftment following transplantation in vivo. Altogether this study presents a well-defined senescent molecular signature in DM1 untangling part of the pathological mechanisms observed in the disease; additionally, we demonstrate the therapeutic potential of targeting these defective cells with senolytics to restore myogenesis

Loss of DNMT1o Disrupts Imprinted X Chromosome Inactivation and Accentuates Placental Defects in Females

The maintenance of key germline derived DNA methylation patterns during preimplantation development depends on stores of DNA cytosine methyltransferase-1o (DNMT1o) provided by the oocyte. Dnmt1omat-/- mouse embryos born to Dnmt1Δ1o/Δ1o female mice lack DNMT1o protein and have disrupted genomic imprinting and associated phenotypic abnormalities. Here, we describe additional female-specific morphological abnormalities and DNA hypomethylation defects outside imprinted loci, restricted to extraembryonic tissue. Compared to male offspring, the placentae of female offspring of Dnmt1Δ1o/Δ1o mothers displayed a higher incidence of genic and intergenic hypomethylation and more frequent and extreme placental dysmorphology. The majority of the affected loci were concentrated on the X chromosome and associated with aberrant biallelic expression, indicating that imprinted X-inactivation was perturbed. Hypomethylation of a key regulatory region of Xite within the X-inactivation center was present in female blastocysts shortly after the absence of methylation maintenance by DNMT1o at the 8-cell stage. The female preponderance of placental DNA hypomethylation associated with maternal DNMT1o deficiency provides evidence of additional roles beyond the maintenance of genomic imprints for DNA methylation events in the preimplantation embryo, including a role in imprinted X chromosome inactivation. © 2013 McGraw et al

Études de facteurs impliqués dans le remodelage de la chromatine chez les gamètes et les embryons bovins

Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2007-2008

Preimplantation alcohol exposure and developmental programming of FASD: An epigenetic perspective.

Alcohol exposure during in utero development can permanently change the developmental programming of physiological responses, thereby increasing the risk of childhood neurological illnesses and later adverse health outcomes associated with fetal alcohol spectrum disorders (FASD). There is an increasing body of evidence indicating that alcohol exposure during gestation triggers lasting epigenetic alterations in offspring long after the initial insult; together, these studies support the role of epigenetics in FASD etiology. However, we still have little information about how ethanol interferes with the fundamental epigenetic reprogramming wave (e.g., erasure and re-establishment of DNA methylation marks) that characterizes preimplantation embryo development. This article will review key epigenetic processes occurring during preimplantation development and especially focus on the current knowledge regarding how a prenatal alcohol exposure during this period could affect the developmental programming of the early stage preimplantation embryo. We will also outline current limitations of studies examining the in vivo and in vitro effects of alcohol exposure on embryos as well as underline the next critical steps to be taken if we want to better understand the implicated mechanisms in order to strengthen the translational potential for non-invasive epigenetic diagnosis markers and the treatment of newborns that have higher risks of developing FASD.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Investigation of MYST4 histone acetyltransferase and its involvement in mammalian gametogenesis-7

<p><b>Copyright information:</b></p><p>Taken from "Investigation of MYST4 histone acetyltransferase and its involvement in mammalian gametogenesis"</p><p>http://www.biomedcentral.com/1471-213X/7/123</p><p>BMC Developmental Biology 2007;7():123-123.</p><p>Published online 2 Nov 2007</p><p>PMCID:PMC2190771.</p><p></p>main zinc finger; C2HC, zinc finger; MYST HAT, conserved HAT domain characteristic of MYST family members; Acidic, glutamate/aspartate-rich region; SM-rich, serine/methionine-rich domain. MYST4 is composed of 2054 residues in which the N-terminal region and the SM-rich domain encode transcriptional repression and activation domains respectively. B) Schematic illustration of MYST4 showing the alternative MYST4 splicing variants MORF and MORFα. Conserved regions between either 2 or 3 sequences are highlighted in gray and black respectively. Regions used for primer designs are underlined in blue (forward) and in red (reverse). The number of residues in each sequence is indicated on the right. (Accession numbers: MYST4; [GenBank; ], MORF; [GenBank; ], MORFα; [GenBank; ]

Investigation of MYST4 histone acetyltransferase and its involvement in mammalian gametogenesis-5

<p><b>Copyright information:</b></p><p>Taken from "Investigation of MYST4 histone acetyltransferase and its involvement in mammalian gametogenesis"</p><p>http://www.biomedcentral.com/1471-213X/7/123</p><p>BMC Developmental Biology 2007;7():123-123.</p><p>Published online 2 Nov 2007</p><p>PMCID:PMC2190771.</p><p></p>ly blastocyst and blastocyst) stained with an anti-MYST4 antibody (green signal) and with propidium iodide (red signal) to visualize the DNA. Original magnification 600×

Investigation of MYST4 histone acetyltransferase and its involvement in mammalian gametogenesis-4

<p><b>Copyright information:</b></p><p>Taken from "Investigation of MYST4 histone acetyltransferase and its involvement in mammalian gametogenesis"</p><p>http://www.biomedcentral.com/1471-213X/7/123</p><p>BMC Developmental Biology 2007;7():123-123.</p><p>Published online 2 Nov 2007</p><p>PMCID:PMC2190771.</p><p></p> relative mRNA levels shown represent the quantity of transcript corrected for the value obtained for each pool. The highest level was attributed the relative value of 100. Shown is the relative mRNA abundance (mean ± SEM). Different letters indicate a significant difference of relative mRNA abundance (P < 0.05)

Investigation of MYST4 histone acetyltransferase and its involvement in mammalian gametogenesis-6

<p><b>Copyright information:</b></p><p>Taken from "Investigation of MYST4 histone acetyltransferase and its involvement in mammalian gametogenesis"</p><p>http://www.biomedcentral.com/1471-213X/7/123</p><p>BMC Developmental Biology 2007;7():123-123.</p><p>Published online 2 Nov 2007</p><p>PMCID:PMC2190771.</p><p></p>s and round spermatids (C, D, E), round spermatids and elongating spermatids (F, G, H), round spermatids and elongated spermatids (I, J, K). Images D, G, K are enlargements of boxed sections in C, F, I respectively. In magnified sections, arrowheads indicate: round spermatocyte (D), nucleus (left) and tail (up) of an elongating spermatid (G) and nuclei of elongated spermatids located in inner (up) wall and inside (left) of the lumen (J). Positive sections were incubated with anti-MYST4 (A, C, D, F, G, I, J) and negatives were prepared by peptide-blocking assay (B, E, H, K). Original magnification 1000× (A, B)