Widespread allele-specific topological domains in the human genome are not confined to imprinted gene clusters.
Widespread allele-specific topological domains in the human genome are not confined to imprinted gene clusters.
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DOI：
10.1186/s13059-023-02876-2
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发表时间：
2023-03-03
期刊：
影响因子：
12.3
通讯作者：
中科院分区：
文献类型：
--
作者：
人们对基因组的三维染色质构象及其对基因表达的影响广泛感兴趣。然而，这些研究经常不考虑亲本差异，例如导致单等位基因表达的基因组印记。此外，全基因组等位基因特异性染色质构象关联尚未得到广泛探索。用于研究等位基因构象差异的可用生物信息学工作流程很少，并且这些工作流程需要预先定相的单倍型，而这些单倍型尚未广泛使用。我们开发了一个生物信息学管道“HiCFlow”，它可以执行单倍型组装和亲本染色质结构的可视化。我们使用来自 GM12878 细胞的三个疾病相关印记基因簇的原型单倍型定相 Hi-C 数据对管道进行了基准测试。使用来自人类细胞系（1-7HB2、IMR-90 和 H1-hESC）的区域捕获 Hi-C 和 Hi-C 数据，我们可以可靠地识别 IGF2-H19 基因座上已知的稳定等位基因特异性相互作用。其他印记基因座（DLK1 和 SNRPN）变化更大，并且没有“规范的印记 3D 结构”，但我们可以检测 A/B 区室化中等位基因特异性的差异。在基因组范围内，当拓扑关联域 (TAD) 根据其等位基因特异性接触频率进行无偏排序时，可以定义一组等位基因特异性 TAD。这些发生在高序列变异的基因组区域。除了印记基因之外，等位基因特异性 TAD 还富集了等位基因特异性表达基因。我们发现了以前未被鉴定为等位基因特异性表达基因的位点，例如苦味受体（TAS2R）。这项研究强调了杂合位点之间染色质构象的广泛差异，并为理解等位基因特异性表达基因提供了新的框架。在线版本包含可在 10.1186/s13059-023-02876-2 获取的补充材料。
There is widespread interest in the three-dimensional chromatin conformation of the genome and its impact on gene expression. However, these studies frequently do not consider parent-of-origin differences, such as genomic imprinting, which result in monoallelic expression. In addition, genome-wide allele-specific chromatin conformation associations have not been extensively explored. There are few accessible bioinformatic workflows for investigating allelic conformation differences and these require pre-phased haplotypes which are not widely available. We developed a bioinformatic pipeline, “HiCFlow,” that performs haplotype assembly and visualization of parental chromatin architecture. We benchmarked the pipeline using prototype haplotype phased Hi-C data from GM12878 cells at three disease-associated imprinted gene clusters. Using Region Capture Hi-C and Hi-C data from human cell lines (1-7HB2, IMR-90, and H1-hESCs), we can robustly identify the known stable allele-specific interactions at the IGF2-H19 locus. Other imprinted loci (DLK1 and SNRPN) are more variable and there is no “canonical imprinted 3D structure,” but we could detect allele-specific differences in A/B compartmentalization. Genome-wide, when topologically associating domains (TADs) are unbiasedly ranked according to their allele-specific contact frequencies, a set of allele-specific TADs could be defined. These occur in genomic regions of high sequence variation. In addition to imprinted genes, allele-specific TADs are also enriched for allele-specific expressed genes. We find loci that have not previously been identified as allele-specific expressed genes such as the bitter taste receptors (TAS2Rs). This study highlights the widespread differences in chromatin conformation between heterozygous loci and provides a new framework for understanding allele-specific expressed genes. The online version contains supplementary material available at 10.1186/s13059-023-02876-2.
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