ABSTRACT
Cancer cells frequently express genes normally active in male germ cells. ATAD2 is one of them encoding a conserved factor harbouring an AAA type ATPase domain and a bromodomain. We show here that ATAD2 is highly expressed in testis as well as in many cancers of different origins and that its high expression is a strong predictor of rapid mortality in lung and breast cancers. These observations suggest that ATAD2 acts on upstream and basic cellular processes to enhance oncogenesis in a variety of unrelated cell types. Accordingly, our functional studies show that ATAD2 controls chromatin dynamics, genome transcriptional activities and apoptotic cell response. We could also highlight some of the important intrinsic properties of its two regulatory domains, including a functional cross-talk between the AAA ATPase domain and the bromodomain. Altogether, these data indicate that ATAD2 overexpression in somatic cells, by acting on basic properties of chromatin, may contribute to malignant transformation.
Subject(s)
Adenosine Triphosphatases/physiology , Breast Neoplasms/physiopathology , DNA-Binding Proteins/physiology , Lung Neoplasms/physiopathology , Testis/metabolism , ATPases Associated with Diverse Cellular Activities , Acetylation , Adenosine Triphosphatases/chemistry , Adenosine Triphosphatases/genetics , Adenosine Triphosphatases/metabolism , Amino Acid Sequence , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Male , Molecular Sequence Data , Prognosis , Sequence Homology, Amino AcidABSTRACT
In addition to genetic information, the spermatozoon carries another type of information, named epigenetic, which is not associated with variations of the DNA sequence. In somatic cells, it is now generally admitted that epigenetic information is not only regulated by DNA methylation but also involves modifications of the genome structure, or epigenome. During male germ cell maturation, the epigenome is globally re-organized, since most histones, which are associated to DNA in somatic cells, are removed and replaced by sperm specific nuclear proteins, the protamines, responsible for the tight compaction of the sperm DNA. However, a small proportion of histones, and probably other proteins, are retained within the sperm nucleus, and the structure of the sperm genome is actually heterogeneous. This heterogeneity of the sperm epigenome could support an epigenetic information, transmitted to the embryo, which could be crucial for its development. Although it is nowadays possible to appreciate the global structure of the sperm genome, the precise constitution of the sperm epigenome remains unknown. In particular, very recent data suggest that specific regions of the genome could be associated with particular proteins and define specific structures. This structural partitioning of the sperm genome could convey important epigenetic information, crucial for the embryo development.
Subject(s)
Epigenesis, Genetic , Spermatozoa , DNA/genetics , Humans , Infertility, Male/genetics , Male , Meiosis , Mutation , Reproduction , Spermatogenesis/genetics , Spermatozoa/chemistryABSTRACT
One of the most dramatic chromatin remodelling events takes place during mammalian spermatogenesis involving massive incorporation of somatic and testis-specific histone variants, as well as generalized histone modifications before their replacement by new DNA packaging proteins. Our data suggest that the induced histone acetylation occurring after meiosis may direct the first steps of genome compaction. Indeed, a double bromodomain-containing protein expressed in postmeiotic cells, Brdt, shows the extraordinary capacity to specifically condense acetylated chromatin in vivo and in vitro. In elongating spermatids, Brdt widely co-localizes with acetylated histones before accumulating in condensed chromatin domains. These domains preferentially maintain their acetylation status until late spermatogenesis. Based on these data, we propose that Brdt mediates a general histone acetylation-induced chromatin compaction and also maintains differential acetylation of specific regions, and is therefore involved in organizing the spermatozoon's genome.
Subject(s)
Chromatin Assembly and Disassembly/physiology , Chromatin/metabolism , Histones/metabolism , Spermatogenesis/physiology , Testis/metabolism , Acetylation , Animals , COS Cells , Cells, Cultured , Chlorocebus aethiops , Chromatin/genetics , Histones/genetics , Male , Mice , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Spermatids/metabolism , Testis/cytologyABSTRACT
Thanks to the success of new assisted reproductive technology, including sperm microinjection (i.c.s.i.), men with severe spermatogenesis impairments can now become biological fathers. Whether the germinal cell used for i.c.s.i. is conveying appropriate genetic and epigenetic information is an important concern. However, to date, there is a huge lack of data on which information is epigenetically conveyed to the offspring and how. The basic support for epigenetic marks is the nucleus structure. During spermatogenesis, a major re-organization of the male germ cells nucleus structure occurs, which includes a global condensation associated with a removal of most core somatic histones and their replacement by sperm-specific nuclear proteins. The available data on the molecular mechanisms involved in this process and how it could relate to the setting of male-specific epigenetic information is reviewed and discussed in light of our current knowledge about nuclear structure and functions.
