Science for Life Laboratory, Department of Environmental Science, Stockholm University, Stockholm, Sweden.
AVIAN Behavioural Genomics and Physiology Group, Linköping University, Linköping, Sweden.
PLoS Genet. 2024 Mar 8;20(3):e1010719. doi: 10.1371/journal.pgen.1010719. eCollection 2024 Mar.
DNA methylation is a key regulator of eukaryote genomes, and is of particular relevance in the regulation of gene expression on the sex chromosomes, with a key role in dosage compensation in mammalian XY systems. In the case of birds, dosage compensation is largely absent, with it being restricted to two small Male Hyper-Methylated (MHM) regions on the Z chromosome. To investigate how variation in DNA methylation is regulated on the Z chromosome we utilised a wild x domestic advanced intercross in the chicken, with both hypothalamic methylomes and transcriptomes assayed in 124 individuals. The relatively large numbers of individuals allowed us to identify additional genomic MHM regions on the Z chromosome that were significantly differentially methylated between the sexes. These regions appear to down-regulate local gene expression in males, but not remove it entirely (unlike the lncRNAs identified in the initial MHM regions). These MHM regions were further tested and the most balanced genes appear to show decreased expression in males, whilst methylation appeared to be far more correlated with gene expression in the less balanced, as compared to the most balanced genes. In addition, quantitative trait loci (QTL) that regulate variation in methylation on the Z chromosome, and those loci that regulate methylation on the autosomes that derive from the Z chromosome were mapped. Trans-effect hotspots were also identified that were based on the autosomes but affected the Z, and also one that was based on the Z chromosome but that affected both autosomal and sex chromosome DNA methylation regulation. We show that both cis and trans loci that originate from the Z chromosome never exhibit an interaction with sex, whereas trans loci originating from the autosomes but affecting the Z chromosome always display such an interaction. Our results highlight how additional MHM regions are actually present on the Z chromosome, and they appear to have smaller-scale effects on gene expression in males. Quantitative variation in methylation is also regulated both from the autosomes to the Z chromosome, and from the Z chromosome to the autosomes.
DNA 甲基化是真核生物基因组的关键调节因子，在性染色体上的基因表达调控中尤为重要，在哺乳动物 XY 系统的剂量补偿中起着关键作用。在鸟类中，剂量补偿在很大程度上不存在，仅限于 Z 染色体上的两个小的雄性超甲基化（MHM）区域。为了研究 Z 染色体上的 DNA 甲基化如何受到调节，我们利用了鸡的野生 x 家养先进杂交群体，在 124 只个体中检测了下丘脑的甲基组和转录组。相对较大的个体数量使我们能够在 Z 染色体上识别出更多的性别差异甲基化的基因组 MHM 区域。这些区域似乎在雄性中下调了局部基因表达，但并未完全去除（与最初的 MHM 区域中鉴定的 lncRNA 不同）。这些 MHM 区域进一步进行了测试，最平衡的基因似乎在雄性中表达降低，而与不太平衡的基因相比，甲基化似乎与基因表达的相关性更高。此外，还绘制了调节 Z 染色体上甲基化变异的数量性状位点（QTL），以及调节来自 Z 染色体的常染色体上甲基化的那些位点。还确定了基于常染色体但影响 Z 染色体的 Trans-effect 热点，以及一个基于 Z 染色体但影响常染色体和性染色体 DNA 甲基化调节的热点。我们表明，来自 Z 染色体的顺式和反式基因座都从未表现出与性别的相互作用，而来自常染色体但影响 Z 染色体的反式基因座总是表现出这种相互作用。我们的研究结果强调了 Z 染色体上实际上存在更多的 MHM 区域，它们似乎对雄性中的基因表达有较小的影响。甲基化的定量变化也受到来自常染色体到 Z 染色体的调节，以及来自 Z 染色体到常染色体的调节。
