性染色体非整倍体(SCA)引起广泛的表型性状和疾病。先前基于外周血样本的研究表明存在连锁反应,由X染色体数目改变引起的,影响甲基化组和转录组。这些改变是否可以与疾病特异性组织有关,从而对表型有临床意义,还有待阐明。
我们对血液中的转录组和甲基组进行了X染色体数目的综合分析,脂肪,和来自45,X,46,XX,46,XY,和47,XXY。
X染色体数量以组织特异性方式影响所有染色体的转录组和甲基化组。此外,45,X和47,XXY显示了基因表达和甲基化的不同模式,在45,X中具有整体基因下调和低甲基化,在47,XXY中具有基因上调和高甲基化。在脂肪和肌肉中,观察到明显的性别效应。我们鉴定了X染色体基因,其表达模式与基于X和Y染色体数量的预期不同。我们的数据还表明Y染色体基因对X染色体基因的调节功能。14个X染色体基因在45,X中下调,在47,XXY中上调,分别,在所有三种组织中(AKAP17A,CD99,DHRSX,EIF2S3,GTPBP6,JPX,KDM6A,PP2R3B,PUDP,SLC25A6,TSIX,XIST,ZBED1,ZFX)。这些基因可能是性染色体非整倍体的表观遗传和基因组调控的核心。
我们强调了X染色体数目对转录组和甲基化组的组织特异性和复杂效应,阐明SCAs之间共享和非共享的基因调控机制。
Sex chromosome aneuploidies (SCAs) give rise to a broad range of phenotypic traits and diseases. Previous studies based on peripheral blood samples have suggested the presence of ripple effects, caused by altered X chromosome number, affecting the methylome and transcriptome. Whether these alterations can be connected to disease-specific tissues, and thereby having clinical implication for the phenotype, remains to be elucidated.
We performed a comprehensive analysis of X chromosome number on the transcriptome and methylome in blood, fat, and muscle tissue from individuals with 45,X, 46,XX, 46,XY, and 47,XXY.
X chromosome number affected the transcriptome and methylome globally across all chromosomes in a tissue-specific manner. Furthermore, 45,X and 47,XXY demonstrated a divergent pattern of gene expression and methylation, with overall gene downregulation and hypomethylation in 45,X and gene upregulation and hypermethylation in 47,XXY. In fat and muscle, a pronounced effect of sex was observed. We identified X chromosomal genes with an expression pattern different from what would be expected based on the number of X and Y chromosomes. Our data also indicate a regulatory function of Y chromosomal genes on X chromosomal genes. Fourteen X chromosomal genes were downregulated in 45,X and upregulated in 47,XXY, respectively, in all three tissues (AKAP17A, CD99, DHRSX, EIF2S3, GTPBP6, JPX, KDM6A, PP2R3B, PUDP, SLC25A6, TSIX, XIST, ZBED1, ZFX). These genes may be central in the epigenetic and genomic regulation of sex chromosome aneuploidies.
We highlight a tissue-specific and complex effect of X chromosome number on the transcriptome and methylome, elucidating both shared and non-shared gene-regulatory mechanism between SCAs.