Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Curr Biol. 2010 Mar 9;20(5):397-406. doi: 10.1016/j.cub.2010.01.017. Epub 2010 Feb 25.
Maintenance of differentiation programs requires stability, when appropriate, of transcriptional states. However, the extent to which inheritance of active transcriptional states occurs from mother to daughter cells has not been directly addressed in unperturbed cell populations.
By live imaging of single-gene transcriptional events in individual cells, we have directly recorded the potential for mitotic inheritance of transcriptional states down cell lineages. Our data showed strong similarity in frequency of transcriptional firing between mother and daughter cells. This memory persisted for complete cell cycles. Both transcriptional pulse length and pulsing rate contributed to overall inheritance, and memory was determined by lineage, not cell environment. Analysis of transcription in chromatin mutants demonstrated that the histone H3K4 methylase Set1 and Ash2, a component of the methylase complex, are required for memory. The effects of Set1 methylation may be mediated directly by chromatin, because loss of memory also occurred when endogenous H3K4 was replaced by alanine. Although methylated H3K4 is usually associated with active transcriptional units, the modification was not required for gene activity but stabilized transcriptional frequency between generations.
Our data indicate that methylated H3K4 can act as a chromatin mark reflecting the original meaning of "epigenetic."
分化程序的维持要求转录状态在适当的时候保持稳定。然而，在未受干扰的细胞群体中，母细胞到子细胞的活跃转录状态是否能够遗传尚未得到直接证实。
通过对单个细胞中单基因转录事件的实时成像，我们直接记录了转录状态在细胞谱系中经历有丝分裂遗传的潜力。我们的数据显示，母细胞和子细胞之间的转录激活频率具有很强的相似性。这种记忆可以持续整个细胞周期。转录脉冲长度和脉冲频率都有助于整体遗传，并且记忆是由谱系决定的，而不是由细胞环境决定的。对染色质突变体中转录的分析表明，组蛋白 H3K4 甲基转移酶 Set1 和 Ash2（甲基转移酶复合物的一个组成部分）对于记忆是必需的。Set1 甲基化的影响可能是通过染色质直接介导的，因为当内源性 H3K4 被丙氨酸取代时，记忆也会丢失。虽然甲基化的 H3K4 通常与活跃的转录单位相关联，但这种修饰并不是基因活性所必需的，而是在代际之间稳定了转录频率。
我们的数据表明，甲基化的 H3K4 可以作为一种染色质标记，反映“表观遗传”的原始含义。
