CARM1 and Paraspeckles Regulate Pre-implantation Mouse Embryo Development

• Published in: Cell Vol. 175; no. 7; pp. 1902 - 1916.e13
• Main Authors: Hupalowska, Anna, Jedrusik, Agnieszka, Zhu, Meng, Bedford, Mark T., Glover, David M., Zernicka-Goetz, Magdalena
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.12.2018; Cell Press
• Subjects: Animals; Blastocyst - cytology; Blastocyst - metabolism; CARM1; Cell Cycle Checkpoints; Cell Differentiation; cell fate; Cell Lineage; development; embryo; Embryonic Development; heterogeneity; Mice; nuclear bodies; Nuclear Matrix-Associated Proteins - genetics; Nuclear Matrix-Associated Proteins - metabolism; p54/nrb; paraspeckles; phase-separation; pre-implantation; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; p54/nrb; nuclear bodies; development; pre-implantation; CARM1; cell fate; paraspeckles; embryo; phase-separation; heterogeneity
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.11.027

Nuclear architecture has never been carefully examined during early mammalian development at the stages leading to establishment of the embryonic and extra-embryonic lineages. Heterogeneous activity of the methyltransferase CARM1 during these stages results in differential methylation of histone H3R26 to modulate establishment of these two lineages. Here we show that CARM1 accumulates in nuclear granules at the 2- to 4-cell stage transition in the mouse embryo, with the majority corresponding to paraspeckles. The paraspeckle component Neat1 and its partner p54nrb are required for CARM1’s association with paraspeckles and for H3R26 methylation. Conversely, CARM1 also influences paraspeckle organization. Depletion of Neat1 or p54nrb results in arrest at the 16- to 32-cell stage, with elevated expression of transcription factor Cdx2, promoting differentiation into the extra-embryonic lineage. This developmental arrest occurs at an earlier stage than following CARM1 depletion, indicating that paraspeckles act upstream of CARM1 but also have additional earlier roles in fate choice. [Display omitted] •CARM1 accumulates in paraspeckles in the 2- to 4-cell stage mouse embryo•Paraspeckles correlate with heterogeneity of H3R26 methylation•Neat1 and p54nrb are required for CARM1’s association with paraspeckles•Depletion of Neat1 or p54nrb elevates differentiation marker Cdx2 The association of the methyltransferase CARM1 with paraspeckles in 2- to 4-cell stage mouse embryos impacts proper lineage allocation and pre-implantation development.