MLL4-associated condensates counterbalance Polycomb-mediated nuclear mechanical stress in Kabuki syndrome.

Abstract

The genetic elements required to tune gene expression are partitioned in active and repressive nuclear condensates. Chromatin compartments include transcriptional clusters whose dynamic establishment and functioning depend on multivalent interactions occurring among transcription factors, cofactors and basal transcriptional machinery. However, how chromatin players contribute to the assembly of transcriptional condensates is poorly understood. By interrogating the effect of KMT2D (also known as MLL4) haploinsufficiency in Kabuki syndrome, we found that mixed lineage leukemia 4 (MLL4) contributes to the assembly of transcriptional condensates through liquid-liquid phase separation. MLL4 loss of function impaired Polycomb-dependent chromatin compartmentalization, altering the nuclear architecture. By releasing the nuclear mechanical stress through inhibition of the mechanosensor ATR, we re-established the mechanosignaling of mesenchymal stem cells and their commitment towards chondrocytes both in vitro and in vivo. This study supports the notion that, in Kabuki syndrome, the haploinsufficiency of MLL4 causes an altered functional partitioning of chromatin, which determines the architecture and mechanical properties of the nucleus.

• Authors: Alessandra Fasciani, Sarah D'Annunzio, Vittoria Poli, Luca Fagnocchi, Sven Beyes, Daniela Michelatti, Francesco Corazza, Laura Antonelli, Francesco Gregoretti, Gennaro Oliva, Romina Belli, Daniele Peroni, Enrico Domenici, Samuel Zambrano, Daniela Intartaglia, Carmine Settembre, Ivan Conte, Claudia Testi, Panagiotis Vergyris, Giancarlo Ruocco, Alessio Zippo
• Journal: Nature genetics (Nat Genet) Vol. 52 Issue 12 Pg. 1397-1411 (12 2020) ISSN: 1546-1718 [Electronic] United States
• PMID: 33169020 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chromatin
• Polycomb-Group Proteins
• Histone-Lysine N-Methyltransferase
• MLL4 protein, human

Topics

• 3T3 Cells
• Abnormalities, Multiple (genetics)
• Animals
• Cell Line
• Cell Lineage (genetics)
• Cell Nucleus (physiology)
• Chondrocytes (cytology)
• Chondrogenesis (genetics)
• Chromatin (metabolism)
• Face (abnormalities)
• Gene Expression Regulation (genetics)
• HEK293 Cells
• Haploinsufficiency (genetics)
• Hematologic Diseases (genetics)
• Histone-Lysine N-Methyltransferase (genetics)
• Humans
• Mechanotransduction, Cellular (physiology)
• Mesenchymal Stem Cells (cytology)
• Mice
• Osteocytes (cytology)
• Osteogenesis (genetics)
• Polycomb-Group Proteins (genetics)
• Stress, Mechanical
• Vestibular Diseases (genetics)