德国马克斯·普朗克免疫生物学和表观遗传学研究所Asifa Akhtar及其团队的最新研究表明雄性特异性致死（MSL）2介导的RNA成核诱导了X染色体的选择性区室化。这一研究成果在线发表在2020年11月18日出版的《自然》杂志上。

研究人员发现MSL2的低重复C末端结构域（CTD）负责招募MSL2到对roX非编码RNA敏感的X染色体上。roX非编码RNA和MSL2 CTD形成稳定的结合状态，在果蝇和哺乳动物细胞中的功能分析表明，它们的相互作用对于体内剂量补偿至关重要。用果蝇MSL2的CTD代替哺乳动物的MSL2 CTD，并在顺式中表达roX，足以使哺乳动物细胞中的异位剂量补偿成核。因此，roX–MSL2CTD的缩合性质是果蝇X染色体特异性区室化的主要决定因素。

据悉，将X染色体限制在一个区域内以进行剂量补偿是阐明如何使用亚核区室化调节兆碱基规模转录的范例。在果蝇中，X染色体转录出两个性别特异的非编码RNA（roX1和roX2）。它们与MSL复合物结合，后者催化组蛋白H4 16位赖氨酸的乙酰化，从而导致雄性X连锁基因表达量增加了约两倍。当前模型表明，X-常染色体特异性是通过MSL2亚基识别顺式调控DNA高亲和力位点（HAS）来实现的。但是，在常染色体上也发现了HAS位点，表明其他因素参与了稳定MSL复合体与X染色体的结合。

附：英文原文

Title: RNA nucleation by MSL2 induces selective X chromosome compartmentalization

Author: Claudia Isabelle Keller Valsecchi, M. Felicia Basilicata, Plamen Georgiev, Aline Gaub, Janine Seyfferth, Tanvi Kulkarni, Amol Panhale, Giuseppe Semplicio, Vinitha Manjunath, Herbert Holz, Pouria Dasmeh, Asifa Akhtar

Issue&Volume: 2020-11-18

Abstract: Confinement of the X chromosome to a territory for dosage compensation is a prime example of how subnuclear compartmentalization is used to regulate transcription at the megabase scale. In Drosophila melanogaster, two sex-specific non-coding RNAs (roX1 and roX2) are transcribed from the X chromosome. They associate with the male-specific lethal (MSL) complex1, which acetylates histone H4 lysine 16 and thereby induces an approximately twofold increase in expression of male X-linked genes2,3. Current models suggest that X-over-autosome specificity is achieved by the recognition of cis-regulatory DNA high-affinity sites (HAS) by the MSL2 subunit4,5. However, HAS motifs are also found on autosomes, indicating that additional factors must stabilize the association of the MSL complex with the X chromosome. Here we show that the low-complexity C-terminal domain (CTD) of MSL2 renders its recruitment to the X chromosome sensitive to roX non-coding RNAs. roX non-coding RNAs and the MSL2 CTD form a stably condensed state, and functional analyses in Drosophila and mammalian cells show that their interactions are crucial for dosage compensation in vivo. Replacing the CTD of mammalian MSL2 with that from Drosophila and expressing roX in cis is sufficient to nucleate ectopic dosage compensation in mammalian cells. Thus, the condensing nature of roX–MSL2CTD is the primary determinant for specific compartmentalization of the X chromosome in Drosophila. Dosage compensation in Drosophila involves nucleation of the dosage compensation complex at the X chromosome by MSL2 and the non-coding RNA roX.

DOI: 10.1038/s41586-020-2935-z

Source: https://www.nature.com/articles/s41586-020-2935-z