Xu Jin, Carter Ava C, Gendrel Anne-Valerie, Attia Mikael, Loftus Joshua, Greenleaf William J, Tibshirani Robert, Heard Edith, Chang Howard Y
Center for Personal Dynamic Regulomes, Stanford University, Stanford, California, USA.
Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, Paris, France.
Nat Genet. 2017 Mar;49(3):377-386. doi: 10.1038/ng.3769. Epub 2017 Jan 23.
We developed an allele-specific assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) to genotype and profile active regulatory DNA across the genome. Using a mouse hybrid F system, we found that monoallelic DNA accessibility across autosomes was pervasive, developmentally programmed and composed of several patterns. Genetically determined accessibility was enriched at distal enhancers, but random monoallelically accessible (RAMA) elements were enriched at promoters and may act as gatekeepers of monoallelic mRNA expression. Allelic choice at RAMA elements was stable across cell generations and bookmarked through mitosis. RAMA elements in neural progenitor cells were biallelically accessible in embryonic stem cells but premarked with bivalent histone modifications; one allele was silenced during differentiation. Quantitative analysis indicated that allelic choice at the majority of RAMA elements is consistent with a stochastic process; however, up to 30% of RAMA elements may deviate from the expected pattern, suggesting a regulated or counting mechanism.
我们开发了一种用于转座酶可及染色质高通量测序（ATAC-seq）的等位基因特异性检测方法，以对全基因组中的活性调控DNA进行基因分型和分析。利用小鼠杂交F系统，我们发现常染色体上的单等位基因DNA可及性普遍存在、受发育程序调控且由几种模式组成。遗传决定的可及性在远端增强子处富集，但随机单等位基因可及（RAMA）元件在启动子处富集，可能充当单等位基因mRNA表达的守门人。RAMA元件处的等位基因选择在细胞世代间稳定，并通过有丝分裂进行标记。神经祖细胞中的RAMA元件在胚胎干细胞中是双等位基因可及的，但预先带有二价组蛋白修饰；一个等位基因在分化过程中沉默。定量分析表明，大多数RAMA元件处的等位基因选择与随机过程一致；然而，高达30%的RAMA元件可能偏离预期模式，提示存在一种调控或计数机制。
