Locus-specific induction of gene expression from heterochromatin loci during cellular senescence
Locus-specific induction of gene expression from heterochromatin loci during cellular senescence
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DOI：
10.1038/s43587-021-00147-y
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发表时间：
2022-01-01
期刊：
影响因子：
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通讯作者：
Narita, Masashi
中科院分区：
文献类型：
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作者：
Tomimatsu, Kosuke;Bihary, Dora;Narita, Masashi
衰老是一种命运决定的状态，伴随着异染色质的重组。虽然谱系适当的基因可以通过兼性异染色质暂时抑制，谱系不适当的基因的稳定沉默往往涉及组成型异染色质标记，组蛋白H3赖氨酸9三甲基化（H3 K9 me 3）。这些异染色质基因在衰老过程中的命运尚不清楚。在本研究中，我们发现，少数谱系不适当的基因，例如LCE 2皮肤基因，在成纤维细胞H3 K9 me 3区域衰老过程中被去抑制。DNA荧光原位杂交实验表明，这些基因位点，这是浓缩在增殖细胞的核周边，在衰老过程中被解压缩。基因座的分解不足以表达LCE 2，这需要p53和C/EBP β信号传导。NLRP 3主要在巨噬细胞中从开放拓扑相关结构域（open topologically associated domain，ERK）表达，由于含有NLRP 3的富含H3 K9 me 3的ERK的局部破坏，NLRP 3在衰老成纤维细胞中也被去抑制。突出了衰老细胞中来自“允许”H3 K9 me 3区域的基因诱导的功能相关性。表观遗传标记H3 K9 me 3与谱系不适当基因的沉默相关。在这里，作者表明，一些谱系不适当的基因在衰老细胞中通过H3 K9 me 3异染色质区域的物理解压缩而被去抑制。
Senescence is a fate-determined state, accompanied by reorganization of heterochromatin. Although lineage-appropriate genes can be temporarily repressed through facultative heterochromatin, stable silencing of lineage-inappropriate genes often involves the constitutive heterochromatic mark, histone H3 lysine 9 trimethylation (H3K9me3). The fate of these heterochromatic genes during senescence is unclear. In the present study, we show that a small number of lineage-inappropriate genes, exemplified by the LCE2 skin genes, are derepressed during senescence from H3K9me3 regions in fibroblasts. DNA FISH experiments reveal that these gene loci, which are condensed at the nuclear periphery in proliferative cells, are decompacted during senescence. Decompaction of the locus is not sufficient for LCE2 expression, which requires p53 and C/EBP beta signaling. NLRP3, which is predominantly expressed in macrophages from an open topologically associated domain (TAD), is also derepressed in senescent fibroblasts due to the local disruption of the H3K9me3-rich TAD that contains it. NLRP3 has been implicated in the amplification of inflammatory cytokine signaling in senescence and aging, highlighting the functional relevance of gene induction from 'permissive' H3K9me3 regions in senescent cells.The epigenetic mark H3K9me3 is associated with silencing of lineage-inappropriate genes. Here the authors show that some lineage-inappropriate genes are derepressed in senescent cells through physical decompaction of H3K9me3-heterochromatic regions.