Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming

Area of Science:

• Epigenetics
• Stem Cell Biology
• Molecular Biology

Background:

• Embryonic stem cells (ESCs) maintain self-renewal and pluripotency via regulatory pathways.
• Somatic cell reprogramming reactivates pluripotent transcriptional networks.
• The role of epigenetic regulators in somatic cell reprogramming remains unclear.

Purpose of the Study:

• To identify early epigenetic regulators essential for somatic cell reprogramming.
• To elucidate the mechanisms by which epigenetic factors influence pluripotency acquisition.

Main Methods:

• Functional RNA interference (RNAi) screen to identify key regulators.
• Analysis of protein-protein interactions between epigenetic modifiers and transcription factors.
• Assessment of alternative splicing events during reprogramming.

Main Results:

• Components of the SAGA histone acetyltransferase complex, specifically Gcn5, were identified as critical for reprogramming initiation.
• Gcn5 was found to associate strongly with Myc in mouse pluripotent stem cells.
• A positive feed-forward loop between Gcn5 and Myc was observed, activating alternative splicing networks and promoting early pluripotency-associated splicing.

Conclusions:

• The SAGA complex, particularly Gcn5, plays a crucial role in the initiation of somatic cell reprogramming.
• A novel Myc-SAGA pathway is essential for driving alternative splicing networks during reprogramming.
• This pathway facilitates the rapid acquisition of pluripotency-associated splicing events, advancing our understanding of cell fate transitions.