Diploid genome architecture revealed by multi-omic data of hybrid mice

While mammalian genomes are diploid, previous studies extensively investigated the average chromatin architectures without considering the differences between homologous chromosomes. Here we generated Hi-C, ChIP-seq and RNA-seq datasets from CD4 T cells of B6, Cast and hybrid mice, to investigate the diploid chromatin organization and epigenetic regulation. Our data indicate that inter-chromosomal interaction patterns between homologous chromosomes are similar and the similarity is highly correlated with their allelic co-expression levels. Reconstruction of 3D nucleus revealed that distances of the homologous chromosomes to the center of nucleus are almost the same. The inter-chromosomal interactions at centromere-ends are significantly weaker than those at telomere-ends, suggesting that they are located in different regions within the chromosome territories. The majority of A|B compartments or topologically associated domains (TADs) are consistent between B6 and Cast. We found 58% of the haploids in hybrids maintain their parental compartment status at B6/Cast divergent compartments due to cis-effect. About 95% of the trans-effected B6/Cast divergent compartments converge to the same compartment status potentially due to a shared cellular environment. We showed the differentially expressed genes between the two haploids in hybrid were associated with either genetic or epigenetic effects. In summary, our multi-omics data from the hybrid mice provided haploid-specific information on the 3D nuclear architecture and a rich resource for further understanding the epigenetic regulation of haploid-specific gene expression. Two Hi-C replicates for hybrid mouse, four Hi-C replicates for male B6 and two Hi-C replicates for female Cast. Three RNA-seq replicates for hybrid, B6 and Cast. H3K4me2, H3K4me3, H3K27me3, CTCF and PolII ChIP-seq samples for hybrid mouse.尽管哺乳动物基因组为二倍体，但既往研究多系统探究了染色质的平均架构，却未兼顾同源染色体之间的差异。本研究从B6、Cast及杂交小鼠的CD4阳性T细胞中获取了Hi-C实验、染色质免疫沉淀测序（ChIP-seq）与RNA测序（RNA-seq）数据集，旨在探究二倍体染色质组织与表观遗传调控机制。本研究数据显示，同源染色体间的染色质间相互作用模式具有相似性，且该相似性与其等位基因共表达水平显著相关。三维细胞核重构分析表明，同源染色体到细胞核中心的距离几乎一致。着丝粒端的染色质间相互作用显著弱于端粒端，提示二者在染色体领地（chromosome territory）内分布于不同区域。绝大多数A/B区室（A/B compartments）或拓扑关联结构域（TADs）在B6与Cast品系小鼠间保持一致。我们发现，在B6与Cast存在差异的区室中，杂交小鼠体内58%的单倍型保留了其亲本的区室状态，这一现象源于顺式作用（cis-effect）。约95%受反式作用（trans-effect）影响的B6/Cast差异区室收敛至相同的区室状态，这可能源于共享的细胞微环境。本研究证实，杂交小鼠体内两种单倍型间的差异表达基因与遗传效应或表观遗传效应均存在关联。综上，本研究获取的杂交小鼠多组学数据为解析三维细胞核架构提供了单倍型特异性信息，同时也为进一步探究单倍型特异性基因表达的表观遗传调控机制提供了宝贵的研究资源。杂交小鼠的Hi-C实验设置2次生物学重复，雄性B6小鼠与雌性Cast小鼠的Hi-C实验分别设置4次与2次生物学重复；杂交小鼠、B6小鼠及Cast小鼠的RNA-seq实验均设置3次生物学重复；杂交小鼠的ChIP-seq样本涵盖H3K4me2、H3K4me3、H3K27me3、CTCF及PolII靶标。