Developmental Iron Deficiency Dysregulates TET Activity and DNA Hydroxymethylation in the Rat Hippocampus and Cerebellum.
Developmental Iron Deficiency Dysregulates TET Activity and DNA Hydroxymethylation in the Rat Hippocampus and Cerebellum.
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DOI：
10.1159/000521704
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发表时间：
2022
影响因子：
2.9
通讯作者：
Tran PV
中科院分区：
文献类型：
--
作者：
Barks A;Beeson MM;Hallstrom TC;Georgieff MK;Tran PV
神经发育期间的缺铁（ID）与持久的认知和社会情感缺陷有关，并增加了整个生命周期中神经精神疾病的风险。这些神经表型变化的基础是在大脑中的基因失调，持续时间超过ID的时期;然而，ID建立和维持基因表达变化的机制还不完全清楚。表观遗传修饰5-羟甲基胞嘧啶（5 hmC）或DNA羟甲基化是一种候选机制，因为它依赖于含铁的泰特酶。本研究的目的是确定胎儿-新生儿ID对区域脑泰特活性，泰特表达和5 hmC在发育中的大鼠海马和小脑的影响，并确定是否与膳食铁治疗的变化是可逆的。定时妊娠的Sprague-Dawley大鼠从妊娠第（G）2天开始饲喂缺铁饮食（ID; 4 mg/kg Fe）以产生缺铁性贫血（IDA）后代。对照组母鼠饲喂铁充足的饲料（IS; 200 mg/kg Fe）。在出生后第7天（P），将ID喂养的窝仔的一个子集随机分配至IS饮食，产生经处理的IDA（TIDA）后代。在P15，分离海马和小脑用于后续分析。通过ELISA从核蛋白定量泰特活性。通过qPCR从总RNA定量Tet 1、Tet 2和Tet 3的表达。通过ELISA从基因组DNA定量全局%5hmC。ID增加了DNA羟甲基化（p=0.0105），在P15海马中泰特活性（p<0.0001）和Tet 3表达（p<0.0001）相应增加。相反，ID降低P15小脑中的泰特活性（p=0.0016），对DNA羟甲基化的影响极小。新生儿膳食铁治疗导致这些变化在两个大脑区域的部分正常化。这些结果表明，发育ID以大脑区域特异性的方式破坏了泰特/DNA羟甲基化系统。这种表观遗传系统的差异性区域破坏可能导致与发育性ID相关的持久的神经回路功能障碍和神经行为功能障碍。
Iron deficiency (ID) during neurodevelopment is associated with lasting cognitive and socioemotional deficits, and increased risk for neuropsychiatric disease throughout the lifespan. These neurophenotypical changes are underlain by gene dysregulation in the brain that outlasts the period of ID; however, the mechanisms by which ID establishes and maintains gene expression changes are incompletely understood. The epigenetic modification 5-hydroxymethylcytosine (5hmC), or DNA hydroxymethylation, is one candidate mechanism because of its dependence on iron-containing TET enzymes. The aim of the present study was to determine the effect of fetal-neonatal ID on regional brain TET activity, Tet expression, and 5hmC in the developing rat hippocampus and cerebellum, and to determine whether changes are reversible with dietary iron treatment. Timed pregnant Sprague-Dawley rats were fed iron deficient diet (ID; 4 mg/kg Fe) from gestational day (G)2 to generate iron deficient anemic (IDA) offspring. Control dams were fed iron sufficient diet (IS; 200 mg/kg Fe). At postnatal day (P)7, a subset of ID-fed litters was randomized to IS diet, generating treated IDA (TIDA) offspring. At P15, hippocampus and cerebellum were isolated for subsequent analysis. TET activity was quantified by ELISA from nuclear proteins. Expression of Tet1, Tet2, and Tet3 was quantified by qPCR from total RNA. Global %5hmC was quantified by ELISA from genomic DNA. ID increased DNA hydroxymethylation (p=0.0105), with a corresponding increase in TET activity (p<0.0001) and Tet3 expression (p<0.0001) in the P15 hippocampus. In contrast, ID reduced TET activity (p=0.0016) in the P15 cerebellum, with minimal effect on DNA hydroxymethylation. Neonatal dietary iron treatment resulted in partial normalization of these changes in both brain regions. These results demonstrate that the TET/DNA hydroxymethylation system is disrupted by developmental ID in a brain region-specific manner. Differential regional disruption of this epigenetic system may contribute to the lasting neural circuit dysfunction and neurobehavioral dysfunction associated with developmental ID.
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影响因子：
3.6
作者：
Lukowski AF;Koss M;Burden MJ;Jonides J;Nelson CA;Kaciroti N;Jimenez E;Lozoff B
通讯作者：
Lozoff B
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作者：
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Barks, Amanda;Fretham, Stephanie J. B.;Tran, Phu, V
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作者：
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通讯作者：
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作者：
Insel, Beverly J.;Schaefer, Catherine A.;McKeague, Ian W.;Susser, Ezra S.;Brown, Alan S.
通讯作者：
Brown, Alan S.