MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, , Edinburgh, EH4 2XU, UK.
Epigenetics Chromatin. 2012 May 19;5(1):6. doi: 10.1186/1756-8935-5-6.
Chromatin structure at a given site can differ between chromosome copies in a cell, and such imbalances in chromatin structure have been shown to be important in understanding the molecular mechanisms controlling several disease loci. Human genetic variation, DNA methylation, and disease have been intensely studied, uncovering many sites of allele-specific DNA methylation (ASM). However, little is known about the genome-wide occurrence of sites of allele-specific histone modification (ASHM) and their relationship to human disease. The aim of this study was to investigate the extent and characteristics of sites of ASHM in human embryonic stem cells (hESCs).
Using a statistically rigorous protocol, we investigated the genomic distribution of ASHM in hESCs, and their relationship to sites of allele-specific expression (ASE) and DNA methylation. We found that, although they were rare, sites of ASHM were substantially enriched at loci displaying ASE. Many were also found at known imprinted regions, hence sites of ASHM are likely to be better markers of imprinted regions than sites of ASM. We also found that sites of ASHM and ASE in hESCs colocalize at risk loci for developmental syndromes mediated by deletions, providing insights into the etiology of these disorders.
These results demonstrate the potential importance of ASHM patterns in the interpretation of disease loci, and the protocol described provides a basis for similar studies of ASHM in other cell types to further our understanding of human disease susceptibility.
在细胞内的染色体拷贝之间，特定位置的染色质结构可能存在差异，并且已经证明这种染色质结构的不平衡在理解控制多个疾病位点的分子机制方面非常重要。人类遗传变异、DNA 甲基化和疾病已经得到了深入研究，揭示了许多等位基因特异性 DNA 甲基化（ASM）的位点。然而，关于等位基因特异性组蛋白修饰（ASHM）的全基因组发生位点及其与人类疾病的关系知之甚少。本研究旨在调查人类胚胎干细胞（hESC）中 ASHM 位点的程度和特征。
我们使用统计学上严格的方案，研究了 hESC 中 ASHM 的基因组分布及其与等位基因特异性表达（ASE）和 DNA 甲基化的关系。我们发现，尽管它们很少见，但 ASHM 位点在显示 ASE 的基因座上明显富集。许多位点也存在于已知的印迹区域，因此 ASHM 位点可能比 ASM 位点更好地标记印迹区域。我们还发现 hESC 中的 ASHM 位点和 ASE 与由缺失介导的发育综合征的风险基因座共定位，为这些疾病的病因学提供了新的见解。
这些结果表明 ASHM 模式在疾病位点解释中的潜在重要性，所描述的方案为在其他细胞类型中进行 ASHM 的类似研究提供了基础，以进一步了解人类疾病易感性。
