Large parental differences in chromatin organization in pancreatic beta cell line explaining diabetes susceptibility effects.
Large parental differences in chromatin organization in pancreatic beta cell line explaining diabetes susceptibility effects.
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DOI：
10.1038/s41467-021-24635-2
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发表时间：
2021-07-15
影响因子：
16.6
通讯作者：
Felsenfeld G
中科院分区：
文献类型：
--
作者：
Jian X;Felsenfeld G
先前的GWAS研究发现了双亲起源特异性影响2型糖尿病易感性的非编码位点。在这里，我们报道了11号染色体上KRTAP5-6基因附近的一个这样的位点的分子基础。在人类胰腺β细胞系EndoC-βH1中，我们确定了该基因座上的一个增强子与460 kb外的人类INS启动子之间的远程接触模式。3C远程接触实验区分两个姐妹染色体上的接触。与等位基因特异性SNPs的耦合允许构建揭示KRTAP5-6和INS之间整个区域的两个姐妹染色体组织的显着差异的图谱。进一步的定位区分了母系和父系等位基因。这揭示了一个从INS基因座向端粒方向延伸的亲本起源特异性染色质结构域。这更普遍地表明，印迹基因座可以通过长距离染色质结构将其对基因表达的影响扩展到这些基因座之外，从而导致远距离的亲本起源偏倚表达模式。一个远离KRTAP5-6基因附近的人类胰岛素（INS）基因的SNP，当出现在父系等位基因上时，对2型糖尿病的易感性增加，而出现在母系等位基因上时，易感性降低。本研究表明，INS基因座与KRTAP5-6基因座之间的远距离接触区分了父系和母系等位基因。
Previous GWAS studies identified non-coding loci with parent-of-origin-specific effects on Type 2 diabetes susceptibility. Here we report the molecular basis for one such locus near the KRTAP5-6 gene on chromosome 11. We determine the pattern of long-range contacts between an enhancer in this locus and the human INS promoter 460 kb away, in the human pancreatic β-cell line, EndoC-βH1. 3C long range contact experiments distinguish contacts on the two sister chromosomes. Coupling with allele-specific SNPs allows construction of maps revealing marked differences in organization of the two sister chromosomes in the entire region between KRTAP5-6 and INS. Further mapping distinguishes maternal and paternal alleles. This reveals a domain of parent-of-origin-specific chromatin structure extending in the telomeric direction from the INS locus. This suggests more generally that imprinted loci may extend their influence over gene expression beyond those loci through long range chromatin structure, resulting in parent-of-origin-biased expression patterns over great distances. A SNP distant from the human insulin (INS) gene near the KRTAP5-6 gene confers increased susceptibility to type 2 diabetes when present on the paternal allele while decreased susceptibility when on the maternal allele. Here the authors show that long-range contacts between the INS locus and the KRTAP5-6 gene locus distinguish paternal and maternal alleles.
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影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
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Tilghman, SM
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通讯作者：
Lernmark, Ake
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64.8
作者：
BARTOLOMEI, MS;ZEMEL, S;TILGHMAN, SM
通讯作者：
TILGHMAN, SM