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MOF-associated complexes ensure stem cell identity and Xist repression
Tomasz Chelmicki1, Friederike Dündar2, Matthew James Turley1
1Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
Abstract:
Histone acetyl transferases (HATs) play distinct roles in many cellular processes and are frequently misregulated in cancers. Here, we study the regulatory potential of MYST1-(MOF)-containing MSL and NSL complexes in mouse embryonic stem cells (ESCs) and neuronal progenitors. We find that both complexes influence transcription by targeting promoters and TSS-distal enhancers. In contrast to flies, the MSL complex is not exclusively enriched on the X chromosome, yet it is crucial for mammalian X chromosome regulation as it specifically regulates Tsix, the major repressor of Xist lncRNA. MSL depletion leads to decreased Tsix expression, reduced REX1 recruitment, and consequently, enhanced accumulation of Xist and variable numbers of inactivated X chromosomes during early differentiation. The NSL complex provides additional, Tsix-independent repression of Xist by maintaining pluripotency. MSL and NSL complexes therefore act synergistically by using distinct pathways to ensure a fail-safe mechanism for the repression of X inactivation in ESCs.DOI: http://dx.doi.org/10.7554/eLife.02024.001.
Insights
Two histone acetyl transferase complexes, MSL and NSL, ensure proper X chromosome inactivation in mouse embryonic stem cells (ESCs). They synergistically regulate Xist lncRNA, preventing premature inactivation and maintaining pluripotency.
Area of Science:
- Epigenetics and Gene Regulation
- Developmental Biology
- Cancer Biology
Background:
- Histone acetyl transferases (HATs) are crucial for cellular processes and often dysregulated in cancer.
- MYST1-(MOF)-containing MSL and NSL complexes are key regulators of transcription.
- Understanding their roles in stem cells and neuronal progenitors is vital.
Purpose of the Study:
- To investigate the regulatory functions of MSL and NSL complexes in mouse embryonic stem cells (ESCs) and neuronal progenitors.
- To elucidate the mechanisms by which these complexes control X chromosome regulation and pluripotency.
- To determine the synergistic interplay between MSL and NSL complexes in repressing X inactivation.
Main Methods:
- Chromatin immunoprecipitation sequencing (ChIP-seq) to identify target genes.
- RNA sequencing (RNA-seq) to assess gene expression changes.
- Depletion studies using siRNA or shRNA to analyze the effects of MSL and NSL complex loss.
Main Results:
- Both MSL and NSL complexes target promoters and enhancers, influencing transcription.
- MSL complex is essential for mammalian X chromosome regulation by specifically targeting Tsix, a repressor of Xist lncRNA.
- MSL depletion causes increased Xist accumulation and variable X inactivation, while NSL complex provides Tsix-independent repression of Xist, maintaining pluripotency.
Conclusions:
- MSL and NSL complexes act synergistically to ensure robust repression of X inactivation in ESCs.
- Distinct pathways involving Tsix regulation (MSL) and pluripotency maintenance (NSL) contribute to a fail-safe mechanism.
- These findings highlight the critical role of these HAT complexes in early mammalian development and X chromosome dosage compensation.