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BigH1 is the key histone in male fertility
All cells of an organism derive from differentiating stem cells. Histones in many species are known to play a crucial role in this process. In a study from the Institute for Research in Biomedicine (IRB), Barcelona, Spain, action and inhibition exerted by histone BigH1 regulates spermatogenesis in Drosophila and may also work similarly in other species - like humans. The work appears in Cell Magazine.
Depending on the stage in adult sex cell making, histone BigH1 is either present and repressing specific genes — or inhibited and allowing genes to function. BigH1 promotes the differentiation process in stem cells as well. When the delicate balance between repressing and/or allowing gene function is out of balance, male Drosophila melanogaster (fruit flies) show gonadal malformations accompanied by infertility. All animals have histones specific to their own germ (sex cell) line. In Drosophila, BigH1 is the histone expressed in both male and female germ lines, while variants of histone H1 also appears in humans.
"We hypothesize that BigH1 represses genes that are not specific to the germ line (when stem cells give rise to sex cells). But, we now have to unravel how it does this and how it is activated and silenced."
Explains Albert Carbonell, postdoctoral fellow and first author on the paper: "The histone BigH1, which we studied in Drosophila melanogaster, most resembles the germ line variant found in human females. But, it can also show similarities to variants of the human male germ line. Because of these similarities, our work can contribute to our understanding of sex cell diferentiation in humans, and help explain some infertility."
The germline linker histone dBigH1 and the translational regulator, Bam, form a repressor loop essential for male germ stem cell lineage differentiation?
The lab is now focusing on BigH1 during the differentiation of female sex cells. "We know that this histone is essential, but we assume it will have a distinct role since the process involving female sex cells is considerably different from that of male ones," says Paula Climent, a PhD student in the lab and one of the authors of the article.
• The linker histone dBigH1 is essential for male GSC maintenance and differentiation
• dBigH1 is on in GSC and spermatocytes but off in spermatogonia when Bam is on
• Bam represses dBigH1 in spermatogonia, while dBigH1 represses Bam in spermatocytes
• This double-repressor loop is crucial for spermatocyte differentiation
Drosophila spermatogenesis constitutes a paradigmatic system to study maintenance, proliferation, and differentiation of adult stem cell lineages. Each Drosophila testis contains 6–12 germ stem cells (GSCs) that divide asymmetrically to produce gonialblast cells that undergo four transit-amplifying (TA) spermatogonial divisions before entering spermatocyte differentiation. Mechanisms governing these crucial transitions are not fully understood. Here, we report the essential role of the germline linker histone dBigH1 during early spermatogenesis. Our results suggest that dBigH1 is a general silencing factor that represses Bam, a key regulator of spermatogonia proliferation that is silenced in spermatocytes. Reciprocally, Bam represses dBigH1 during TA divisions. This double-repressor mechanism switches dBigH1/Bam expression from off/on in spermatogonia to on/off in spermatocytes, regulating progression into spermatocyte differentiation. dBigH1 is also required for GSC maintenance and differentiation. These results show the critical importance of germline H1s for male GSC lineage differentiation, unveiling a regulatory interaction that couples transcriptional and translational repression.
Authors: Albert Carbonell, Salvador Pérez-Montero, Paula Climent-Cantó, Oscar Reina, Fernando Azorín
The research was supported by funding from MINECO, through ERDF, and from the Catalan Government.
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Tip region of a wild-type Drosophila melanogaster testis
with aBigH1 antibodies (red) and avasa (green), the cell nuclei in blue.
Image credit: Albert Carbonell, IRB Barcelona.