Human SETMAR is a DNA sequence-specific histone-methylase with a broad effect on the transcriptome

Transposons impart dynamism to the genomes they inhabit and their movements frequently rewire the control of nearby genes. Occasionally, their proteins are domesticated when they evolve a new function. SETMAR is a protein methylase with a sequence-specific DNA binding domain. It began to evolve about 50 million years ago when an Hsmar1 transposon integrated downstream of a SET-domain methylase gene. Here we show that the DNA-binding domain of the transposase targets the enzyme to transposon-end remnants and that this is capable of regulating gene expression, dependent on the methylase activity. When SETMAR was modestly overexpressed in human cells, almost 1500 genes changed expression by more than 2-fold (65% up- and 35% down-regulated). These genes were enriched for the KEGG Pathways in Cancer and include several transcription factors important for development and differentiation. Expression of a similar level of a methylase-deficient SETMAR changed the expression of many fewer genes, 77% of which were down-regulated with no significant enrichment of KEGG Pathways. Our data is consistent with a model in which SETMAR is part of an anthropoid primate-specific regulatory network centered on the subset of genes containing a transposon end. Examination of the effect of SETMAR or SETMAR N210A expression on U2OS transcriptome and ChIP-exo of Flag-SETMAR in U2OS cells.

转座子（transposon）可赋予其所整合的基因组以动态可塑性，其转座活动常能重塑邻近基因的调控网络。偶尔，转座子编码的蛋白会在演化获得新功能后被宿主驯化。SETMAR是一类带有序列特异性DNA结合结构域的蛋白甲基化酶，其演化起源可追溯至约5000万年前，彼时一条Hsmar1转座子整合至SET结构域甲基化酶基因的下游区域。本研究结果显示，转座酶的DNA结合结构域可将该酶靶向至转座子末端残迹区域，且该靶向过程依赖甲基化酶活性以调控基因表达。在人类细胞中轻度过表达SETMAR时，近1500个基因的表达量发生了2倍以上的变化（其中65%为表达上调，35%为表达下调），这些差异表达基因显著富集于癌症相关KEGG通路，且包含多个对发育与分化至关重要的转录因子。当以相近水平表达甲基化酶活性缺失的SETMAR突变体时，差异表达基因的数量大幅减少，其中77%为表达下调，且未富集到任何显著的KEGG通路。本研究数据支持如下模型：SETMAR是类人猿特异性调控网络的组成部分，该网络以携带转座子末端序列的基因子集为核心调控靶点。本研究还检测了SETMAR或SETMAR N210A在U2OS细胞中的表达对该细胞转录组的影响，并针对U2OS细胞中Flag标记的SETMAR开展了染色质免疫沉淀-外切酶测序（ChIP-exo）分析。