Cryptic transcription, the initiation of transcription from non-promoter regions within a gene body, is a type of transcriptional dysregulation that occurs throughout eukaryotes. In mammals, cryptic transcription is normally repressed at the level of chromatin, and this process is increased upon perturbation of complexes that increase intragenic histone H3 lysine 4 methylation or decrease intragenic H3 lysine 36 methylation, DNA methylation, or nucleosome occupancy. Significantly, similar changes to chromatin structure occur during aging, and, indeed, recent work indicates that cryptic transcription is elevated during aging in mammalian stem cells. Although increased cryptic transcription is known to promote aging in yeast, whether elevated cryptic transcription also contributes to mammalian aging is unclear. There is ample evidence that perturbations known to increase cryptic transcription are deleterious in embryonic and adult stem cells, and in some cases phenocopy certain aging phenotypes. Furthermore, an increase in cryptic transcription requires or impedes pathways that are known to have reduced function during aging, potentially exacerbating other aging phenotypes. Thus, we propose that increased cryptic transcription contributes to mammalian stem cell aging.

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染色质松动和转录失调：哺乳动物衰老过程中隐秘转录的视角

隐性转录，即从基因体内的非启动子区域开始转录，是一种在真核生物中发生的转录失调。在哺乳动物中，隐性转录通常在染色质水平受到抑制，并且在增加基因内组蛋白 H3 赖氨酸 4 甲基化或减少基因内 H3 赖氨酸 36 甲基化、DNA 甲基化或核小体占据的复合物的扰动下，这一过程会增加。值得注意的是，衰老过程中也会发生类似的染色质结构变化，事实上，最近的研究表明哺乳动物干细胞衰老过程中隐秘转录水平升高。尽管已知增加的隐性转录会促进酵母的衰老，但升高的隐性转录是否也有助于哺乳动物的衰老尚不清楚。有充分的证据表明，已知会增加隐秘转录的扰动对胚胎和成体干细胞有害，在某些情况下，表型复制某些衰老表型。此外，隐蔽转录的增加需要或阻碍已知在衰老过程中功能降低的途径，这可能会加剧其他衰老表型。因此，我们提出增加的隐秘转录有助于哺乳动物干细胞衰老。