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H4K16ac 激活转座元件的转录，并有助于它们的顺式调控功能。

H4K16ac activates the transcription of transposable elements and contributes to their cis-regulatory function.

机构信息

Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK.

Bhabha Atomic Research Centre, Mumbai, India.

出版信息

Nat Struct Mol Biol. 2023 Jul;30(7):935-947. doi: 10.1038/s41594-023-01016-5. Epub 2023 Jun 12.

DOI:10.1038/s41594-023-01016-5
PMID:37308596
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10352135/
Abstract

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 in cis. Overall, TEs enriched with H4K16ac contribute to the cis-regulatory landscape at specific genomic locations by maintaining an active chromatin landscape at TEs.

摘要

哺乳动物基因组中含有丰富的转座元件 (TEs) 及其残余物，有许多表观遗传抑制机制来沉默 TE 的转录。然而，TEs 在早期发育、神经元谱系和癌症中被上调，尽管促进 TE 转录的表观遗传因素尚未完全阐明。在这里，我们证明了雄性特异性致死 (MSL) 复合物介导的组蛋白 H4 在赖氨酸 16 处的乙酰化 (H4K16ac) 在人类胚胎干细胞 (hESC) 和癌细胞中的 TE 上富集。这反过来又激活了全长长散布核元件 (LINE1s、L1s) 和内源性逆转录病毒 (ERV) 长末端重复序列 (LTR) 的子集的转录。此外，我们表明，H4K16ac 标记的 L1 和 LTR 亚家族具有增强子样功能，并在与活性增强子相关的染色质特征的基因组位置富集。重要的是，这些区域通常位于拓扑关联域的边界处，并与基因环。基于 CRISPR 的表观遗传扰动和 L1 的遗传缺失表明，H4K16ac 标记的 L1 和 LTR 调节顺式基因的表达。总的来说，富含 H4K16ac 的 TEs 通过在 TE 上维持活跃的染色质景观，有助于特定基因组位置的顺式调控景观。

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