The first bromodomain of the testis-specific double bromodomain protein Brdt is required for chromocenter organization that is modulated by genetic background.
The first bromodomain of the testis-specific double bromodomain protein Brdt is required for chromocenter organization that is modulated by genetic background.
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DOI：
10.1016/j.ydbio.2011.10.005
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发表时间：
2011-12-15
影响因子：
2.7
通讯作者：
Wolgemuth DJ
中科院分区：
文献类型：
--
作者：
Berkovits BD;Wolgemuth DJ
缺乏Brdt的第一个溴结构域（含双溴结构域蛋白质的BET家族的睾丸特异性成员）的突变（BrdtΔ BD 1/Δ BD 1）的纯合子小鼠是不育的，并且在精子发生期间表现出染色质重塑的严重缺陷。我们现在已经观察到异常精子细胞核的一个显著特征是一个碎片化的染色中心，一种由着丝粒周围异染色质组成的结构。异染色质蛋白1 α（Hp 1 α）水平也随之增加，表明多个染色中心的存在与异染色质扩散到正常着丝粒区域之外相关。Brdt蛋白通常存在于整个细胞核，但被排除在染色中心。Brdt蛋白质的更密集染色区域似乎将sirtuin 1（Sirt 1）蛋白与染色中心接触分开。虽然Brdt蛋白仍在细胞核内，但在BrdtΔ BD 1/Δ BD 1突变精子细胞中Brdt蛋白的这种独特定位丢失，Brdt和Sirt 1在染色中心周围重叠。在BrdtΔ BD 1/Δ BD 1圆形精子细胞中还存在H1组蛋白家族成员N睾丸特异性（H1 fnt）蛋白的异位定位，这可能与先前报道的核周异染色质灶极化定位丢失有关。与纯C57 Bl/6背景相比，纯129 Sv/Ev突变体睾丸中染色中心断裂的程度更严重，并且更明显。事实上，在129 Sv/Ev背景下，突变表型的所有方面都更严重。与先前在精子细胞中观察到片段化染色中心的遗传模型研究相反，BrdtΔ BD 1/Δ BD 1突变精子细胞不发生凋亡（在任一背景下）。这些观察结果表明，Brdt的第一溴结构域在完整的染色中心的形成和/或维持中是至关重要的，并暗示该结构在精子头部的染色质结构的适当重塑中。
Mice homozygous for a mutation (BrdtΔBD1/ΔBD1) lacking the first bromodomain of Brdt, a testis-specific member of the BET family of double-bromodomain containing proteins, are sterile and exhibit profound defects in chromatin remodeling during spermiogenesis. We have now observed that a prominent feature of the aberrant spermatid nuclei is a fragmented chromocenter, a structure comprised of peri-centromeric heterochromatin. There was a concomitant increase in the levels of heterochromatin protein 1 alpha (Hp1α), suggesting that the presence of multiple chromocenters was correlated with a spread of heterochromatin beyond the normal centromeric region. Brdt protein was normally present throughout the nucleus but was excluded from the chromocenter. A more densely staining region of Brdt protein appeared to separate sirtuin 1 (Sirt1) protein from contact with the chromocenter. Although still nuclear, this unique localization of Brdt protein was lost in BrdtΔBD1/ΔBD1 mutant spermatids and Brdt and Sirt1 overlapped around the chromocenters. There was also ectopic localization of the H1 histone family, member N, testis-specific (H1fnt) protein in BrdtΔBD1/ΔBD1 round spermatids, which may be linked to the previously reported loss of polarized localization of peri-nuclear heterochromatin foci. The extent of chromocenter fragmentation was more severe and penetrant in mutant testes on a pure 129Sv/Ev as compared to a pure C57Bl/6 background. Indeed, all aspects of the mutant phenotype were more severe on the 129Sv/Ev background. Contrary to previous studies in genetic models where fragmented chromocenters were observed in spermatids, the BrdtΔBD1/ΔBD1 mutant spermatids do not undergo apoptosis (on either background). These observations suggest that the first bromodomain of Brdt is critical in the formation and/or maintenance of an intact chromocenter and implicate this structure in proper remodeling of the chromatin architecture of the sperm head.
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影响因子：
5.3
作者：
O'Carroll, D;Scherthan, H;Jenuwein, T
通讯作者：
Jenuwein, T
影响因子：
3.7
作者：
HAAF, T;WARD, DC
通讯作者：
WARD, DC
影响因子：
1.6
作者：
Horakova, Andrea Harnicarova;Bartova, Eva;Kozubek, Stanislav
通讯作者：
Kozubek, Stanislav
影响因子：
4.8
作者：
Chung, Sanny S. W.;Wang, Xiangyuan;Wolgemuth, Debra J.
通讯作者：
Wolgemuth, Debra J.
DOI：
10.1073/pnas.0406060102
发表时间：
2005-02-22
影响因子：
11.1
作者：
Martianov, I;Brancorsini, S;Davidson, I
通讯作者：
Davidson, I