Bermick Jennifer R, Lambrecht Nathalie J, denDekker Aaron D, Kunkel Steven L, Lukacs Nicholas W, Hogaboam Cory M, Schaller Matthew A
Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of Michigan Medical Center, 1540 E. Medical Center Drive, C.S. Mott Children's Hospital Room 8-621, Ann Arbor, MI 48109 USA.
Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI 48109 USA.
Clin Epigenetics. 2016 Sep 20;8:99. doi: 10.1186/s13148-016-0265-7. eCollection 2016.
Neonates have dampened expression of pro-inflammatory cytokines and difficulty clearing pathogens. This makes them uniquely susceptible to infections, but the factors regulating neonatal-specific immune responses are poorly understood. Epigenetics, including histone modifications, can activate or silence gene transcription by modulating chromatin structure and stability without affecting the DNA sequence itself and are potentially modifiable. Histone modifications are known to regulate immune cell differentiation and function in adults but have not been well studied in neonates.
To elucidate the role of histone modifications in neonatal immune function, we performed chromatin immunoprecipitation on mononuclear cells from 45 healthy neonates (gestational ages 23-40 weeks). As gestation approached term, there was increased activating H3K4me3 on the pro-inflammatory , , , and cytokine promoters ( < 0.01) with no change in repressive H3K27me3, suggesting that these promoters in preterm neonates are less open and accessible to transcription factors than in term neonates. Chromatin immunoprecipitation with massively parallel DNA sequencing (ChIP-seq) was then performed to establish the H3K4me3, H3K9me3, H3K27me3, H3K4me1, H3K27ac, and H3K36me3 landscapes in neonatal and adult CD14+ monocytes. As development progressed from neonate to adult, monocytes lost the poised enhancer mark H3K4me1 and gained the activating mark H3K4me3, without a change in additional histone modifications. This decreased H3K4me3 abundance at immunologically important neonatal monocyte gene promoters, including , , , , and was associated with reduced gene expression.
These results provide evidence that neonatal immune cells exist in an epigenetic state that is distinctly different from adults and that this state contributes to neonatal-specific immune responses that leaves them particularly vulnerable to infections.
新生儿促炎细胞因子表达减弱，清除病原体存在困难。这使得他们极易受到感染，但调节新生儿特异性免疫反应的因素却知之甚少。表观遗传学，包括组蛋白修饰，可以通过调节染色质结构和稳定性来激活或沉默基因转录，而不影响DNA序列本身，并且具有潜在的可修饰性。已知组蛋白修饰在成体中调节免疫细胞分化和功能，但在新生儿中尚未得到充分研究。
为了阐明组蛋白修饰在新生儿免疫功能中的作用，我们对45名健康新生儿（胎龄23 - 40周）的单核细胞进行了染色质免疫沉淀。随着孕周接近足月，促炎细胞因子启动子上的激活型H3K4me3增加（P < 0.01），而抑制型H3K27me3无变化，这表明与足月新生儿相比，早产新生儿的这些启动子对转录因子的开放性和可及性较低。随后进行了大规模平行DNA测序染色质免疫沉淀（ChIP-seq），以确定新生儿和成人CD14 +单核细胞中的H3K4me3、H3K9me3、H3K27me3、H3K4me1、H3K27ac和H3K36me3图谱。随着发育从新生儿进展到成人，单核细胞失去了平衡增强子标记H3K4me1并获得了激活标记H3K4me3，而其他组蛋白修饰没有变化。免疫重要的新生儿单核细胞基因启动子处H3K4me3丰度降低，包括IL1B、IL6、IL8、TNF和IFNG，这与基因表达降低相关。
这些结果提供了证据，表明新生儿免疫细胞存在一种与成人明显不同的表观遗传状态，并且这种状态促成了新生儿特异性免疫反应，使他们特别容易受到感染。
