Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013:102:293-326.
doi: 10.1016/B978-0-12-416024-8.00011-8.

The role of the double bromodomain-containing BET genes during mammalian spermatogenesis

Binyamin D Berkovits  1 , Debra J Wolgemuth
Affiliations
Review

The role of the double bromodomain-containing BET genes during mammalian spermatogenesis

Binyamin D Berkovits et al. Curr Top Dev Biol. 2013.

Abstract

The double bromodomain-containing BET (bromodomain and extra terminal) family of proteins is highly conserved from yeast to humans and consists not just of transcriptional regulators but also histone-interacting chromatin remodelers. The four mammalian BET genes are each expressed at unique times during spermatogenesis, and the testis-specific gene Brdt is essential for spermatogenesis. Loss of the first bromodomain of BRDT results in improper/incomplete spermatid elongation and severely morphologically defective sperm. The elongation defects observed in mutant spermatids can be directly tied to altered postmeiotic chromatin architecture. BRDT is required for creation/maintenance of the chromocenter of round spermatids, a structure that forms just after completion of meiosis. The chromocenter creates a defined topology in spermatids, and the presence of multiple chromocenters rather than a single intact chromocenter correlates with loss of spermatid polarity, loss of heterochromatin foci at the nuclear envelope, and loss of proper spermatid elongation. BRDT is not only essential for proper chromatin organization but also involved in regulation of transcription and in cotranscriptional processing. That is, transcription and alternative splicing are altered in spermatocytes and spermatids that lack full-length BRDT. Additionally, the transcription of mRNAs with short 3' UTRs, which is characteristic of round spermatids, is also altered. Examination of the genes regulated by BRDT yields many possible targets that could in part explain the morphologically abnormal sperm produced by the BRDT mutant testes. Thus, BRDT and possibly the other BET genes are required for proper spermatogenesis, which opens up the possibility that the recently discovered small molecule inhibitors of the BET family could be useful as reversible male contraceptives.

PubMed Disclaimer

Figures

Figure 11.1
Figure 11.1
Structural comparison of the BET family members in S. cerevisiae, D. melanogaster, and M. musculus. The percentages under each bromodomain and the ET domain indicate the percentage of identical amino acid residues in the domain as compared to the corresponding domain in mBRD2, the founding member of the mouse BET family. The percentages under the CTD are compared to mBRD4.
Figure 11.2
Figure 11.2
Expression patterns of the BET family in the adult mouse testis. Expression depicted for BRD2, BRD4, and BRDT is at the protein level, and for Brd3, it is at the mRNA level. Solid bars represent high levels of expression and dashed bars represent less abundant but detectable expression. The figure is adapted from Shang et al. (2004).
Figure 11.3
Figure 11.3
Cartoon depicting chromocenter formation and function in control and BrdtΔBD1 spermatids. BRDT protein is found throughout the nucleus (dark red) but is excluded from the chromocenter (black). In control spermatids, BRDT is more densely localized around the chromocenter (bright red), but this localization is lost in mutant spermatids. SUV39H1/2 (green) is located exclusively in the heterochromatin of the chromocenter both in control and mutant spermatids. SIRT1 (blue) is located throughout the nucleus except in the chromocenter and in the region of high BRDT localization. In control spermatids, the high localization of BRDT around the chromocenter might function to separate SIRT1 and SUV39H1/2. In mutant spermatids, the loss of BRDT localization allows overlap of SIRT1 and SUV39H1/2 which may cause ectopic heterochromatin.
Figure 11.4
Figure 11.4
Model for how the presence of multiple chromocenters correlates with aberrant localization of H1FNT, loss of heterochromatin foci lining the nuclear membrane, and defective spermatid elongation. In control spermatids, an intact chromocenter (black circle) is present starting in step 1 spermatids. Starting in step 4 spermatids, H1FNT expression (red) begins and is restricted to a subacrosomal chromatin domain. In step 7 spermatids, heterochromatin foci (small black dots) begin to appear at the nuclear membrane in regions where H1FNT is not present. Nuclear elongation occurs in steps 9–11 spermatids, and chromatin condensation begins in step 12 spermatids and is completed in step 13 spermatids. In the BrdtΔBD1 mutant, the majority of spermatids do not have a single intact chromocenter (large black spots). Although H1FNT is initially localized in the subacrosomal region, ectopic localization appears in late mutant round spermatids. In step 9 spermatids, H1FNT is abnormally localized just inside the entire nuclear membrane and blocks the localization of heterochromatin foci in this region. Mutant spermatid nuclei do not fully elongate or take on a normal hook shape. However, chromatin condensation still occurs in steps 12 and 13 spermatids. Heterochromatin is shown in black.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Agricola E, Randall RA, Gaarenstroom T, Dupont S, Hill CS. Recruitment of TIF1gamma to chromatin via its PHD finger-bromodomain activates its ubiquitin ligase and transcriptional repressor activities. Molecular Cell. 2011;43:85–96. - PubMed
    1. Ai N, Hu X, Ding F, Yu B, Wang H, Lu X, et al. Signal-induced Brd4 release from chromatin is essential for its role transition from chromatin targeting to transcriptional regulation. Nucleic Acids Research. 2011;39:9592–9604. - PMC - PubMed
    1. Allton K, Jain AK, Herz HM, Tsai WW, Jung SY, Qin J, et al. Trim24 targets endogenous p53 for degradation. Proceedings of the National Academy of Sciences of the United States of America. 2009;106:11612–11616. - PMC - PubMed
    1. Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M. Epigenetic protein families: A new frontier for drug discovery. Nature Reviews. Drug Discovery. 2012;11:384–400. - PubMed
    1. Barboric M, Lenasi T, Chen H, Johansen EB, Guo S, Peterlin BM. 7SK snRNP/P-TEFb couples transcription elongation with alternative splicing and is essential for vertebrate development. Proceedings of the National Academy of Sciences of the United States of America. 2009;106:7798–7803. - PMC - PubMed

Publication types

MeSH terms