A predictable conserved DNA base composition signature defines human core DNA replication origins

Area of Science:

• Molecular Biology
• Genomics
• Cell Biology

Background:

• DNA replication initiates from specific genomic sites known as replication origins.
• The DNA sequences dictating replication origin selection in multicellular organisms (metazoa) are not well understood.

Purpose of the Study:

• To investigate the nature and genomic distribution of DNA replication origins across various human cell types.
• To identify conserved DNA sequence features associated with replication origin activity.
• To explore how cellular processes like differentiation and immortalization affect replication origin usage.

Main Methods:

• Analysis of pluripotent, primary, differentiating, and immortalized human cells.
• Detection of DNA sequence signatures associated with replication origins.
• Development and application of computational algorithms for origin prediction based on sequence patterns.

Main Results:

• A class of 'core origins' is shared across different cell types, accounting for approximately 80% of replication initiation events.
• A conserved G-rich DNA sequence signature is associated with most core origins in human and mouse genomes.
• Core origins can be computationally predicted from DNA sequence patterns, independent of consensus motifs, and are influenced by transcription.
• Cellular immortalization, unlike normal differentiation, alters replication origin firing patterns, increasing stochastic initiation from heterochromatin.

Conclusions:

• Replication origins are not entirely stochastic but are selected from a defined set of genomic regions, primarily 'core origins'.
• Conserved G-rich DNA sequences play a significant role in specifying core replication origins.
• Cellular state, particularly immortalization, impacts the regulation and genomic distribution of DNA replication origins.