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Chromatin and transcriptomic profiling uncover dysregulation of the Tip60 HAT/HDAC2 epigenomic landscape in the neurodegenerative brain
Epigenetics ( IF 2.9 ) Pub Date : 2021-08-09 , DOI: 10.1080/15592294.2021.1959742
Mariah Beaver 1 , Bhanu Chandra Karisetty , Haolin Zhang 1 , Akanksha Bhatnagar 1 , Ellen Armour 1 , Visha Parmar 1 , Reshma Brown 1 , Merry Xiang 1 , Felice Elefant 1
Affiliation  

ABSTRACT

Disruption of histone acetylation-mediated gene control is a critical step in Alzheimer’s Disease (AD), yet chromatin analysis of antagonistic histone acetyltransferases (HATs) and histone deacetylases (HDACs) causing these alterations remains uncharacterized. We report the first Tip60 HAT versus HDAC2 chromatin (ChIP-seq) and transcriptional (RNA-seq) profiling study in Drosophila melanogaster brains that model early human AD. We find Tip60 and HDAC2 predominantly recruited to identical neuronal genes. Moreover, AD brains exhibit robust genome-wide early alterations that include enhanced HDAC2 and reduced Tip60 binding and transcriptional dysregulation. Orthologous human genes to co-Tip60/HDAC2 D. melanogaster neural targets exhibit conserved disruption patterns in AD patient hippocampi. Notably, we discovered distinct transcription factor binding sites close or within Tip60/HDAC2 co-peaks in neuronal genes, implicating them in coenzyme recruitment. Increased Tip60 protects against transcriptional dysregulation and enhanced HDAC2 enrichment genome-wide. We advocate Tip60 HAT/HDAC2 mediated epigenetic neuronal gene disruption as a genome-wide initial causal event in AD.



中文翻译:

染色质和转录组分析揭示了神经退行性大脑中 Tip60 HAT/HDAC2 表观基因组景观的失调

摘要

破坏组蛋白乙酰化介导的基因控制是阿尔茨海默病 (AD) 的关键步骤,但对引起这些改变的拮抗组蛋白乙酰转移酶 (HAT) 和组蛋白去乙酰化酶 (HDAC) 的染色质分析仍未确定。我们报告了在模拟早期人类 AD 的黑腹果蝇大脑中的第一个 Tip60 HAT 与 HDAC2 染色质 (ChIP-seq) 和转录 (RNA-seq) 分析研究。我们发现 Tip60 和 HDAC2 主要招募到相同的神经元基因。此外,AD 大脑表现出强大的全基因组早期改变,包括增强的 HDAC2 和减少的 Tip60 结合和转录失调。co-Tip60/HDAC2黑腹果蝇的直系同源人类基因神经靶点在 AD 患者海马体中表现出保守的破坏模式。值得注意的是,我们在神经元基因中发现接近或位于 Tip60/HDAC2 共峰内的不同转录因子结合位点,表明它们与辅酶募集有关。增加的 Tip60 可防止转录失调并增强全基因组的 HDAC2 富集。我们提倡将 Tip60 HAT/HDAC2 介导的表观遗传神经元基因破坏作为 AD 中的全基因组初始因果事件。

更新日期:2021-08-09
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