A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse
A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse
复制标题
DOI：
10.1101/gad.476008
复制
发表时间：
2008-08-01
影响因子：
10.5
通讯作者：
Jenuwein, Thomas
中科院分区：
文献类型：
--
作者：
Schotta, Gunnar;Sengupta, Roopsha;Jenuwein, Thomas
H4 K20甲基化是一种广泛的染色质修饰，与多种表观遗传功能有关。几种酶靶向H4 K20甲基化，这与控制不同生物输出的不同单、二和三甲基化状态一致。为了分析H4 K20甲基化状态的作用，我们在小鼠中产生了两个Suv 4 - 20 h组蛋白甲基转移酶（HMTase）基因的条件无效等位基因。Suv 4 - 20 h-双无效（dn）小鼠是围产期致死的，并且已经丧失了几乎所有的H4 K20 me 3和H4 K20 me 2状态。全基因组向H4 K20 me 1状态的转变导致对损伤性应激的敏感性增加，因为Suv 4 - 20 h-dn染色质对DNA双链断裂（DSB）修复的效率较低，并且易于发生染色体畸变。值得注意的是，Suv 4 - 20 h-dn B细胞在免疫球蛋白类别转换重组中有缺陷，并且Suv 4 - 20 h-dn缺陷损害淋巴样祖细胞的干细胞库。因此，转化为H4 K20 me 1状态导致受损的染色质，其不足以保护基因组完整性并在小鼠中处理DNA重排分化程序。
H4K20 methylation is a broad chromatin modification that has been linked with diverse epigenetic functions. Several enzymes target H4K20 methylation, consistent with distinct mono-, di-, and trimethylation states controlling different biological outputs. To analyze the roles of H4K20 methylation states, we generated conditional null alleles for the two Suv4-20h histone methyltransferase (HMTase) genes in the mouse. Suv4-20h-double-null (dn) mice are perinatally lethal and have lost nearly all H4K20me3 and H4K20me2 states. The genome-wide transition to an H4K20me1 state results in increased sensitivity to damaging stress, since Suv4-20h-dn chromatin is less efficient for DNA double-strand break (DSB) repair and prone to chromosomal aberrations. Notably, Suv4-20h-dn B cells are defective in immunoglobulin class-switch recombination, and Suv4-20h-dn deficiency impairs the stem cell pool of lymphoid progenitors. Thus, conversion to an H4K20me1 state results in compromised chromatin that is insufficient to protect genome integrity and to process a DNA-rearranging differentiation program in the mouse.