Enhancer decommissioning imposes an epigenetic barrier to sensory hair cell regeneration.
Enhancer decommissioning imposes an epigenetic barrier to sensory hair cell regeneration.
复制标题
增强子退役对感觉毛细胞再生施加了表观遗传障碍。
DOI：
10.1016/j.devcel.2021.07.003
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发表时间：
2021-09-13
影响因子：
11.8
通讯作者：
Segil N
中科院分区：
文献类型：
--
作者：
Tao L;Yu HV;Llamas J;Trecek T;Wang X;Stojanova Z;Groves AK;Segil N
成年哺乳动物的组织，如心脏、脑、视网膜和内耳的感觉结构不能有效地再生，尽管在胚胎期和围产期存在潜在的再生能力。我们探讨了这种潜在的再生潜力在小鼠内耳和成熟过程中的快速损失的表观遗传基础。在围产期支持细胞中，其命运由Notch介导的侧抑制维持，毛细胞增强子网络在表观遗传上是启动的（H3K4me1），但沉默（活性H3K27去乙酰化和三甲基化）。在可塑性的围产期期间阻断Notch信号传导可快速消除表观遗传沉默，并允许支持细胞转分化为毛细胞。重要的是，H3K4me1启动的毛细胞增强子在支持细胞中被删除，在出生后的第一周，与转分化潜力的损失相一致。我们假设耳蜗成熟过程中增强子的退出导致成熟Corti器毛细胞再生失败。哺乳动物无法再生耳蜗感觉毛细胞，而其他脊椎动物则保留了强大的内耳再生能力。我们表明，围产期成熟期间支持细胞中毛细胞特异性增强子的表观遗传退役（H3 K4 me1的去除）导致哺乳动物内耳再生能力的丧失。
Adult mammalian tissues such as heart, brain, retina, and the sensory structures of the inner ear do not effectively regenerate, although a latent capacity for regeneration exists at embryonic and perinatal times. We explored the epigenetic basis for this latent regenerative potential in the mouse inner ear and its rapid loss during maturation. In perinatal supporting cells, whose fate is maintained by Notch-mediated lateral inhibition, the hair cell enhancer network is epigenetically primed (H3K4me1) but silenced (active H3K27 de-acetylation and trimethylation). Blocking Notch signaling during the perinatal period of plasticity rapidly eliminates epigenetic silencing and allows supporting cells to transdifferentiate into hair cells. Importantly, H3K4me1 priming of the hair cell enhancers in supporting cells is removed during the first post-natal week, coinciding with the loss of transdifferentiation potential. We hypothesize that enhancer decommissioning during cochlear maturation contributes to the failure of hair cell regeneration in the mature organ of Corti. Mammals are unable to regenerate cochlear sensory hair cells, while other vertebrates preserve robust inner ear regenerative capacity. We show that epigenetic decommissioning of hair-cell-specific enhancers (removal of H3K4me1) in supporting cells during perinatal maturation contributes to loss of regenerative capacity in the mammalian inner ear.
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影响因子：
56.9
作者：
Bermingham, NA;Hassan, BA;Zoghbi, HY
通讯作者：
Zoghbi, HY
影响因子：
56.9
作者：
CORWIN, JT;COTANCHE, DA
通讯作者：
COTANCHE, DA
影响因子：
64.8
作者：
Boyer, LA;Plath, K;Jaenisch, R
通讯作者：
Jaenisch, R
影响因子：
64.5
作者：
Bernstein, BE;Mikkelsen, TS;Lander, ES
通讯作者：
Lander, ES
DOI：
10.1073/pnas.97.22.11692
发表时间：
2000-10-24
影响因子：
11.1
作者：
Eddison, M;Le Roux, I;Lewis, J
通讯作者：
Lewis, J