Globally elevated levels of histone H3 lysine 9 trimethylation in early infancy are associated with poor growth trajectory in Bangladeshi children.

IF 5.7 2区 医学 Q1 Medicine Clinical Epigenetics Pub Date : 2023-08-11 DOI:10.1186/s13148-023-01548-z
Kristyna Kupkova, Savera J Shetty, Marilyn G Pray-Grant, Patrick A Grant, Rashidul Haque, William A Petri, David T Auble
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Abstract

Background: Stunting is a global health problem affecting hundreds of millions of children worldwide and contributing to 45% of deaths in children under the age of five. Current therapeutic interventions have limited efficacy. Understanding the epigenetic changes underlying stunting will elucidate molecular mechanisms and likely lead to new therapies.

Results: We profiled the repressive mark histone H3 lysine 9 trimethylation (H3K9me3) genome-wide in peripheral blood mononuclear cells (PBMCs) from 18-week-old infants (n = 15) and mothers (n = 14) enrolled in the PROVIDE study established in an urban slum in Bangladesh. We associated H3K9me3 levels within individual loci as well as genome-wide with anthropometric measurements and other biomarkers of stunting and performed functional annotation of differentially affected regions. Despite the relatively small number of samples from this vulnerable population, we observed globally elevated H3K9me3 levels were associated with poor linear growth between birth and one year of age. A large proportion of the differentially methylated genes code for proteins targeting viral mRNA and highly significant regions were enriched in transposon elements with potential regulatory roles in immune system activation and cytokine production. Maternal data show a similar trend with child's anthropometry; however, these trends lack statistical significance to infer an intergenerational relationship.

Conclusions: We speculate that high H3K9me3 levels may result in poor linear growth by repressing genes involved in immune system activation. Importantly, changes to H3K9me3 were detectable before the overt manifestation of stunting and therefore may be valuable as new biomarkers of stunting.

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全球范围内婴儿早期组蛋白H3赖氨酸9三甲基化水平升高与孟加拉国儿童生长轨迹不良有关。
背景:发育迟缓是一个全球性的健康问题,影响着全世界数亿儿童,造成了45%的5岁以下儿童死亡。目前的治疗干预措施效果有限。了解发育迟缓背后的表观遗传变化将阐明分子机制,并可能导致新的治疗方法。结果:我们分析了18周大的婴儿(n = 15)和母亲(n = 14)外周血单个核细胞(PBMCs)中抑制标记组蛋白H3赖氨酸9三甲基化(H3K9me3)的全基因组图谱,这些婴儿(n = 15)和母亲(n = 14)参加了在孟加拉国城市贫民窟建立的提供研究。我们将个体基因座内的H3K9me3水平以及全基因组与人体测量和其他发育迟缓的生物标志物联系起来,并对差异影响区域进行了功能注释。尽管来自这一脆弱人群的样本数量相对较少,但我们观察到,全球范围内H3K9me3水平升高与出生至1岁之间的不良线性增长有关。大量编码病毒mRNA蛋白的差异甲基化基因和高度显著区域在转座子元件中富集,这些转座子元件在免疫系统激活和细胞因子产生中具有潜在的调节作用。母亲的数据与儿童的人体测量数据显示出类似的趋势;然而,这些趋势缺乏统计意义来推断代际关系。结论:我们推测高H3K9me3水平可能通过抑制参与免疫系统激活的基因导致线性生长不良。重要的是,H3K9me3的变化在发育迟缓的明显表现之前就被检测到,因此可能作为发育迟缓的新生物标志物而有价值。
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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
期刊最新文献
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