National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, 430070, China.
Institute of Plant Science Paris-Saclay (IPS2), CNRS, INRAE, University Paris-Saclay, 91405, Orsay, France.
Genome Biol. 2023 Aug 30;24(1):198. doi: 10.1186/s13059-023-03042-4.
The Fe (II)- and α-ketoglutarate-dependent AlkB family dioxygenases are implicated in nucleotide demethylation. AlkB homolog1 (ALKBH1) is shown to demethylate DNA adenine methylation (6mA) preferentially from single-stranded or unpaired DNA, while its demethylase activity and function in the chromatin context are unclear.
Here, we find that loss-of-function of the rice ALKBH1 gene leads to increased 6mA in the R-loop regions of the genome but has a limited effect on the overall 6mA level. However, in the context of mixed tissues, rather than on individual loci, the ALKBH1 mutation or overexpression mainly affects the expression of genes with a specific combination of chromatin modifications in the body region marked with H3K4me3 and H3K27me3 but depleted of DNA CG methylation. In the similar context of mixed tissues, further analysis reveals that the ALKBH1 protein preferentially binds to genes marked by the chromatin signature and has a function to maintain a high H3K4me3/H3K27me3 ratio by impairing the binding of Polycomb repressive complex 2 (PRC2) to the targets, which is required for both the basal and stress-induced expression of the genes.
Our findings unravel a function of ALKBH1 to control the balance between the antagonistic histone methylations for gene activity and provide insight into the regulatory mechanism of PRC2-mediated H3K27me3 deposition within the gene body region.
Fe（II）和α-酮戊二酸依赖的 AlkB 家族双加氧酶参与核苷酸去甲基化。 AlkB 同源物 1（ALKBH1）被证明优先从单链或未配对的 DNA 中去甲基化 DNA 腺嘌呤甲基化（6mA），但其在染色质背景下的去甲基酶活性和功能尚不清楚。
在这里，我们发现水稻 ALKBH1 基因的功能丧失会导致基因组 R 环区域的 6mA 增加，但对整体 6mA 水平的影响有限。然而，在混合组织的背景下，而不是在单个基因座上，ALKBH1 突变或过表达主要影响具有特定染色质修饰组合的基因的表达，这些基因在具有 H3K4me3 和 H3K27me3 标记的身体区域，且缺乏 DNA CG 甲基化。在类似的混合组织背景下，进一步的分析表明，ALKBH1 蛋白优先结合具有染色质特征标记的基因，并通过干扰多梳抑制复合物 2（PRC2）与靶标的结合来维持高 H3K4me3/H3K27me3 比值，这对于基因的基础表达和应激诱导表达都是必需的。
我们的研究结果揭示了 ALKBH1 控制基因活性拮抗组蛋白甲基化之间平衡的功能，并为 PRC2 介导的 H3K27me3 在基因体区域沉积的调控机制提供了新的见解。
