A genome-wide study identified de novo DNA methylation alterations in leukocytes of children at paediatric intensive care unit (PICU) discharge, offering a biological basis for their impaired long-term development. Early parenteral nutrition (early-PN) in PICU, compared with omitting PN in the first week (late-PN), explained differential methylation of 23% of the affected CpG-sites. We documented the time course of altered DNA methylation in PICU and the impact hereon of early nutritional management. We selected 36 early-PN and 36 late-PN matched patients, and 42 matched healthy children. We quantified DNA methylation on days 3, 5 and 7 for the 147 CpG-sites of which methylation was normal upon PICU admission in this subset and altered by critical illness at PICU discharge. Methylation in patients differed from healthy children for 64.6% of the 147 CpG-sites on day 3, for 72.8% on day 5 and for 90.5% on day 7 as revealed by ANOVA at each time point. Within-patients methylation time course analyses for each CpG-site identified different patterns based on paired t test p value and direction of change. Rapid demethylation from admission to day 3 occurred for 76.2% of the CpG-sites, of which 67.9% remained equally demethylated or partially remethylated and 32.1% further demethylated beyond day 3. From admission to day 3, 19.7% of the CpG-sites became hypermethylated, of which, beyond day 3, 34.5% remained equally hypermethylated or partially demethylated again and 65.5% further hypermethylated. For 4.1% of the CpG-sites, changes only appeared beyond day 3. Finally, for the CpG-sites affected by early-PN on the last PICU day, earlier changes in DNA methylation were compared for early-PN and late-PN patients, revealing that 38.9% were already differentially methylated by day 3, another 25.0% by day 5 and another 13.9% by day 7. Critical illness- and early-PN-induced changes in DNA methylation occurred mainly within 3 days. Most abnormalities were at least partially maintained or got worse with longer time in PICU. Interventions targeting aberrant DNA methylation changes should be initiated early.

中文翻译：

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危重疾病和儿科 ICU 早期肠外营养引起的 DNA 甲基化改变的时间过程

一项全基因组研究确定了儿科重症监护病房 (PICU) 出院儿童白细胞的从头 DNA 甲基化改变，为他们的长期发育受损提供了生物学基础。与第一周省略 PN（晚期 PN）相比，PICU 中的早期肠外营养（早期 PN）解释了 23% 受影响 CpG 位点的差异甲基化。我们记录了 PICU 中 DNA 甲基化改变的时间过程以及早期营养管理对此的影响。我们选择了 36 名早期 PN 和 36 名晚期 PN 匹配的患者，以及 42 名匹配的健康儿童。我们在第 3、5 和 7 天量化了 147 个 CpG 位点的 DNA 甲基化，这些位点的甲基化在该亚组中在 PICU 入院时是正常的，并在 PICU 出院时因危重疾病而改变。患者的甲基化与健康儿童有 64 年的差异。ANOVA 在每个时间点显示 147 个 CpG 位点的 6%，第 5 天的 72.8% 和第 7 天的 90.5%。基于配对 t 检验 p 值和变化方向，针对每个 CpG 位点的患者体内甲基化时间进程分析确定了不同的模式。从入院到第 3 天，76.2% 的 CpG 位点发生快速去甲基化，其中 67.9% 保持同等去甲基化或部分再甲基化，32.1% 在第 3 天后进一步去甲基化。从入院到第 3 天，19.7% 的 CpG 位点变为高甲基化，其中，在第 3 天之后，34.5% 仍然同样高甲基化或部分去甲基化，65.5% 进一步高甲基化。对于 4.1% 的 CpG 位点，仅在第 3 天后才出现变化。最后，对于在 PICU 的最后一天受早期 PN 影响的 CpG 位点，比较早期 PN 和晚期 PN 患者 DNA 甲基化的早期变化，显示 38.9% 的患者在第 3 天已发生差异甲基化，第 5 天为 25.0%，第 7 天为 13.9%。 - 诱导的 DNA 甲基化变化主要发生在 3 天内。大多数异常至少部分维持或随着在 PICU 中的时间延长而恶化。应尽早启动针对异常 DNA 甲基化变化的干预措施。