dSETDB1 and SU(VAR)3–9 Sequentially Function during Germline-Stem Cell Differentiation in Drosophila melanogaster
et al. (2008) dSETDB1 and SU(VAR)3-9 Sequentially Function during Germline-Stem Cell Differentiation in
Drosophila melanogaster. PLoS ONE 3(5): e2234. doi:10.1371/journal.pone.0002234
dSETDB1 and SU(VAR)3-9 Sequentially Function during Germline-Stem Cell Differentiation in Drosophila melanogaster
Jeongheon Yoon 0
Kyu-Sun Lee 0
Jung Sun Park 0
Kweon Yu 0
Sang-Gi Paik 0
Yong-Kook Kang 0
Axel Imhof, University of Munich and Center of Integrated Protein Science, Germany
0 1 Center for Regenerative Medicine, Korean Research Institute of Bioscience and Biotechnology (KRIBB) , Daejeon , Korea , 2 Department of Biology, Chungnam National University , Daejon , Korea
Germline-stem cells (GSCs) produce gametes and are thus true ''immortal stem cells''. In Drosophila ovaries, GSCs divide asymmetrically to produce daughter GSCs and cystoblasts, and the latter differentiate into germline cysts. Here we show that the histone-lysine methyltransferase dSETDB1, located in pericentric heterochromatin, catalyzes H3-K9 trimethylation in GSCs and their immediate descendants. As germline cysts differentiate into egg chambers, the dSETDB1 function is gradually taken over by another H3-K9-specific methyltransferase, SU(VAR)3-9. Loss-of-function mutations in dsetdb1 or Su(var)3-9 abolish both H3K9me3 and heterochromatin protein-1 (HP1) signals from the anterior germarium and the developing egg chambers, respectively, and cause localization of H3K9me3 away from DNA-dense regions in most posterior germarium cells. These results indicate that dSETDB1 and SU(VAR)3-9 act together with distinct roles during oogenesis, with dsetdb1 being of particular importance due to its GSC-specific function and more severe mutant phenotype.
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Drosophila oogenesis is a complex developmental process
involving the coordinated differentiation of germline and somatic
cells, and begins with asymmetric division of a single germline
stem cell (GSC) [1,2]. This GSC is located at the tip of each
ovariole in the germarium, which is a generative region that is
divided into sub-regions such as region-1, -2a, -2b and -3. After
each GSC division, the posterior daughter cell becomes a
cystoblast, leaves region-1, undergoes four synchronous,
incomplete divisions to form a 16-cell germline cyst [3,4], and steadily
moves in a posterior direction through the germarium. Of the 16
interconnected cells, one cell develops into the oocyte whereas the
other 15 develop into polyploid nurse cells [5]. This 16-cell cyst
becomes surrounded by a monolayer of follicle cells and buds off
from the posterior germarium to form an egg chamber [6,7],
which ultimately gives rise to a single mature oocyte ready for
fertilization.
The germline cells, including the GSCs are the only population
from which both parental epigenetic information and
genetic information can be transferred to progeny. This
indicates that, other than the known pluripotency [8], the
germline cells possess another important property - an exceptional
capacity for epigenetic modifications of the genome [9]. In
fact, germ-cell development is associated with a dynamic process
of epigenetic reprogramming, leading to re-construction of the
whole genome-level epigenetic state [9,10,11,12,13]. The
developmental significance of this has driven studies to
investigate the epigenetic changes occurring in the germline
cells. Therefore, germ-cell development is an excellent
system to study how the epigenetic system involving
DNA methylation and histone lysine methylation is erased,
reestablished, and maintained in the germ cells at the genome-wide
level.
Histone-lysine methylation, which mainly occurs in the tails of
histones H3 and H4, plays a pivotal role in cellular processes
including heterochromatin formation, X-chromosome
inactivation, and transcription regulation [14]. Lysine methylation is of
particular interest because it can modulate the chromatin structure
to a compacted state or a relaxed one, depending on which lysine
residues are methylated. With regard to heterochromatin
formation, histone H3 trimethylated at lysine 9 (H3K9me3) is
enriched in pericentric heterochromatin and thereby recognized
as typical of a heterochromatin marker [15,16,17,18,19]. Correct
formation of heterochromatin is essential for chromosome stability
and integrity, and is required for the proper segregation of
chromosomes during mitosis [20] and the recombination events in
fission yeast [21], which further demonstrates the biological
significance of H3K9me3 that participates in heterochromatin
formation. So far, several histone-lysine methyltransferases
(HKMTases) with specificity to H3-K9 residues have been
identified [14]. Some of them are implicated in germ-cell
development. Male germ cells in mice lacking suv39h, which
synthesizes H3K9me3 in pericentric heterochromatin, display
severely impaired viability and chromosomal instability [22].
Mutant mice in which G9a is specifically inactivated in the
germcell lineage exhibited a marked lo (...truncated)