RNA nucleation by MSL2 induces selective X chromosome compartmentalization

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 and Asifa Akhtar ()
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Claudia Isabelle Keller Valsecchi: Max Planck Institute of Immunobiology and Epigenetics
M. Felicia Basilicata: Max Planck Institute of Immunobiology and Epigenetics
Plamen Georgiev: Max Planck Institute of Immunobiology and Epigenetics
Aline Gaub: Max Planck Institute of Immunobiology and Epigenetics
Janine Seyfferth: Max Planck Institute of Immunobiology and Epigenetics
Tanvi Kulkarni: Max Planck Institute of Immunobiology and Epigenetics
Amol Panhale: Max Planck Institute of Immunobiology and Epigenetics
Giuseppe Semplicio: Max Planck Institute of Immunobiology and Epigenetics
Vinitha Manjunath: Max Planck Institute of Immunobiology and Epigenetics
Herbert Holz: Max Planck Institute of Immunobiology and Epigenetics
Pouria Dasmeh: University of Zurich
Asifa Akhtar: Max Planck Institute of Immunobiology and Epigenetics

Nature, 2021, vol. 589, issue 7840, 137-142

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-020-2935-z

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