Turnover of histones and histone variants in postnatal rat brain: effects of alcohol exposure.
Turnover of histones and histone variants in postnatal rat brain: effects of alcohol exposure.
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DOI：
10.1186/s13148-017-0416-5
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发表时间：
2017
影响因子：
5.7
通讯作者：
Sarkar D
中科院分区：
文献类型：
--
作者：
Rachdaoui N;Li L;Willard B;Kasumov T;Previs S;Sarkar D
怀孕期间饮酒是一个重大的公共健康问题，可能会导致胎儿一系列不良后果，称为胎儿酒精谱系障碍(FASD)。FASD受试者表现出明显的神经缺陷，从小脑、神经行为和精神健康问题到不良的社会适应和压力耐受性。神经元对酒精暴露特别敏感。酒精的神经毒性作用，即通过产生ROS，导致DNA损伤和神经细胞凋亡。此外，表观遗传学，包括DNA甲基化、组蛋白翻译后修饰(PTM)和非编码RNA，在FASD的神经病理学中发挥着重要作用。然而，对FASD中组蛋白及其PTM的时间动力学和动力学知之甚少。我们研究了出生后酒精暴露(PAE)，一个相当于人类晚期妊娠的动物模型，在两个不同的大脑区域，额叶皮质和下丘脑，各种组蛋白蛋白的动力学的影响，使用体内2H2O标记结合基于质谱学的蛋白质组学。我们证明了组蛋白有很长的半衰期，大约是几天。我们还表明，H3.3和H2 Az组蛋白变体比标准组蛋白有更快的周转，一般来说，乙酰化组蛋白比未修饰和甲基化的组蛋白有更快的周转。我们的工作首次表明，PAE在所研究的两个大脑区域诱导组蛋白周转率的不同降低。这些组蛋白更替的改变与出生后大鼠脑内DNA损伤增加和细胞增殖减少有关。组蛋白转化的改变可能干扰组蛋白沉积和染色质稳定性，导致细胞特异性基因表达的失控，从而导致与FASD相关的神经疾病的发展。使用体内2H2O标记和基于质谱学的蛋白质组学可能有助于了解酒精暴露后组蛋白的转换，并可能对研究人员识别预防和管理胎儿酒精谱障碍的新靶点和/或生物标志物具有重要意义。本文的在线版本(10.1186/s131480170416-5)包含补充材料，可供授权用户使用。
Alcohol consumption during pregnancy is a significant public health problem and can result in a continuum of adverse outcomes to the fetus known as fetal alcohol spectrum disorders (FASD). Subjects with FASD show significant neurological deficits, ranging from microencephaly, neurobehavioral, and mental health problems to poor social adjustment and stress tolerance. Neurons are particularly sensitive to alcohol exposure. The neurotoxic action of alcohol, i.e., through ROS production, induces DNA damage and neuronal cell death by apoptosis. In addition, epigenetics, including DNA methylation, histone posttranslational modifications (PTMs), and non-coding RNA, play an important role in the neuropathology of FASD. However, little is known about the temporal dynamics and kinetics of histones and their PTMs in FASD. We examined the effects of postnatal alcohol exposure (PAE), an animal model of human third-trimester equivalent, on the kinetics of various histone proteins in two distinct brain regions, the frontal cortex, and the hypothalamus, using in vivo 2H2O-labeling combined with mass spectrometry-based proteomics. We show that histones have long half-lives that are in the order of days. We also show that H3.3 and H2Az histone variants have faster turnovers than canonical histones and that acetylated histones, in general, have a faster turnover than unmodified and methylated histones. Our work is the first to show that PAE induces a differential reduction in turnover rates of histones in both brain regions studied. These alterations in histone turnover were associated with increased DNA damage and decreased cell proliferation in postnatal rat brain. Alterations in histone turnover might interfere with histone deposition and chromatin stability, resulting in deregulated cell-specific gene expression and therefore contribute to the development of the neurological disorders associated with FASD. Using in vivo 2H2O-labeling and mass spectrometry-based proteomics might help in the understanding of histone turnover following alcohol exposure and could be of great importance in enabling researchers to identify novel targets and/or biomarkers for the prevention and management of fetal alcohol spectrum disorders. The online version of this article (10.1186/s13148-017-0416-5) contains supplementary material, which is available to authorized users.
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影响因子：
56.9
作者：
Celeste, A;Petersen, S;Nussenzweig, A
通讯作者：
Nussenzweig, A
影响因子：
3.7
作者：
Gangisetty O;Bekdash R;Maglakelidze G;Sarkar DK
通讯作者：
Sarkar DK
影响因子：
4.2
作者：
Brooks, PJ
通讯作者：
Brooks, PJ
影响因子：
2.8
作者：
Anthony, Bruce;Zhou, Feng C.;Ruiz, Joseph
通讯作者：
Ruiz, Joseph
DOI：
10.1111/acer.12082
发表时间：
2013-07
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Bekdash RA;Zhang C;Sarkar DK
通讯作者：
Sarkar DK