Antisense transcription can induce expression memory via stable promoter repression.

Area of Science:

• Molecular Biology
• Genomics
• Systems Biology

Background:

• Cellular memory of signals is crucial for fate acquisition and adaptation.
• Gene expression memory can arise from mutual repression, forming a toggle switch.
• Antisense loci, where convergent genes repress each other in cis, are implicated in this memory, but conditions for its generation are unclear.

Purpose of the Study:

• To understand the conditions required for generating gene expression memory via antisense transcription.
• To develop a quantitative framework for antisense-mediated cis-memory.

Main Methods:

• Mathematical modeling
• Genomics
• Synthetic biology approach
• Genome-wide analysis of nascent transcription
• Construction of synthetic antisense loci in mouse embryonic stem cells (mESCs)

Main Results:

• Simulations predict stable memory emergence when antisense genes transcribe via convergent promoters and induce repressive chromatin.
• Genome-wide analysis confirms antisense-mediated promoter repression, showing mutually exclusive expression in overlapping gene pairs.
• Synthetic antisense loci in mESCs demonstrate that antisense transcription induces stable repression, a prerequisite for memory.
• Repression stability increases during mESC differentiation, indicating cell type-specific epigenetic memory.

Conclusions:

• A quantitative framework predicts antisense-mediated cis-memory under physiological conditions.
• Antisense transcription can encode stable gene expression states through the interplay of molecular processes.
• Stem cells adjust memory capacity during differentiation, potentially clarifying stemness maintenance mechanisms.