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改变的染色质状态驱动衰老哺乳动物干细胞中的隐匿转录。

Altered Chromatin States Drive Cryptic Transcription in Aging Mammalian Stem Cells.

机构信息

Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.

Center for Epigenetics & Disease Prevention, Institute of Bioscience and Technology, Texas A&M University, Houston, TX 77030, USA.

出版信息

Nat Aging. 2021 Aug;1(8):684-697. doi: 10.1038/s43587-021-00091-x. Epub 2021 Aug 2.

DOI:10.1038/s43587-021-00091-x
PMID:34746802
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8570536/
Abstract

A repressive chromatin state featuring trimethylated lysine 36 on histone H3 (H3K36me3) and DNA methylation suppresses cryptic transcription in embryonic stem cells. Cryptic transcription is elevated with age in yeast and nematodes, and reducing it extends yeast lifespan, though whether this occurs in mammals is unknown. We show that cryptic transcription is elevated in aged mammalian stem cells, including murine hematopoietic stem cells (mHSCs) and neural stem cells (NSCs) and human mesenchymal stem cells (hMSCs). Precise mapping allowed quantification of age-associated cryptic transcription in hMSCs aged . Regions with significant age-associated cryptic transcription have a unique chromatin signature: decreased H3K36me3 and increased H3K4me1, H3K4me3, and H3K27ac with age. Genomic regions undergoing such changes resemble known promoter sequences and are bound by TBP even in young cells. Hence, the more permissive chromatin state at intragenic cryptic promoters likely underlies increased cryptic transcription in aged mammalian stem cells.

摘要

抑制性染色质状态的特征是组蛋白 H3 上的赖氨酸 36 三甲基化（H3K36me3）和 DNA 甲基化，可抑制胚胎干细胞中的隐匿转录。在酵母和线虫中，随着年龄的增长，隐匿转录会增加，而降低隐匿转录会延长酵母的寿命，但这种情况是否发生在哺乳动物中尚不清楚。我们发现，衰老的哺乳动物干细胞中，包括鼠造血干细胞（mHSCs）和神经干细胞（NSCs）以及人骨髓间充质干细胞（hMSCs），隐匿转录水平升高。精确的图谱绘制允许定量分析 hMSCs 衰老过程中与年龄相关的隐匿转录。与年龄相关的隐匿转录显著增加的区域具有独特的染色质特征：随着年龄的增长，H3K36me3 减少，H3K4me1、H3K4me3 和 H3K27ac 增加。随着年龄的增长而发生这种变化的基因组区域类似于已知的启动子序列，即使在年轻细胞中，也由 TBP 结合。因此，在衰老的哺乳动物干细胞中，基因内隐匿启动子处更为宽松的染色质状态可能是隐匿转录增加的基础。

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