H4K16ac activates the transcription of transposable elements and contributes to their cis-regulatory function
H4K16ac activates the transcription of transposable elements and contributes to their cis-regulatory function
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H4K16ac 激活转座元件的转录并有助于其顺式调节功能
DOI：
10.1101/2022.04.29.488986
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Pal D
中科院分区：
文献类型：
--
作者：
Pal D
哺乳动物基因组中含有丰富的转座元件(TES)及其残基，许多表观遗传抑制机制被用来抑制TES转录。然而，TES在早期发育、神经元谱系和癌症中上调，尽管影响TES转录的表观遗传因素尚未完全阐明。在这里，我们证明了男性特异性致死(MSL)复合体介导组蛋白H4赖氨酸16乙酰化(H4K16ac)在人胚胎干细胞(HESCs)和癌细胞中富含TES。这进而激活全长长分散核元件(LINE1S，L1S)和内源性逆转录病毒(ERV)长末端重复序列(LTRS)的转录。此外，我们发现H4K16ac标记的L1和LTR亚家族显示出增强子样的功能，并在基因组位置上富含与活性增强子相关的染色质特征。重要的是，这样的区域通常位于拓扑相关结构域的边界，并与基因环路。基于CRISPR的L1s的表观遗传扰动和遗传缺失揭示了H4K16ac标记的L1s和Ltrs调控基因inci的表达。总体而言，富含H4K16ac的TES通过在TES保持活跃的染色质景观来促进特定基因组位置的整合调控格局。
Mammalian genomes harbor abundant transposable elements (TEs) and their remnants, with numerous epigenetic repression mechanisms enacted to silence TE transcription. However, TEs are upregulated during early development, neuronal lineage, and cancers, although the epigenetic factors contributing to the transcription of TEs have yet to be fully elucidated. Here, we demonstrate that the male-specific lethal (MSL)-complex-mediated histone H4 acetylation at lysine 16 (H4K16ac) is enriched at TEs in human embryonic stem cells (hESCs) and cancer cells. This in turn activates transcription of subsets of full-length long interspersed nuclear elements (LINE1s, L1s) and endogenous retrovirus (ERV) long terminal repeats (LTRs). Furthermore, we show that the H4K16ac-marked L1 and LTR subfamilies display enhancer-like functions and are enriched in genomic locations with chromatin features associated with active enhancers. Importantly, such regions often reside at boundaries of topologically associated domains and loop with genes. CRISPR-based epigenetic perturbation and genetic deletion of L1s reveal that H4K16ac-marked L1s and LTRs regulate the expression of genes incis. Overall, TEs enriched with H4K16ac contribute to thecis-regulatory landscape at specific genomic locations by maintaining an active chromatin landscape at TEs.
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