A link between genome and epigenome for regulation of replication timing

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06129
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43050:Genome biology-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: SHARIF Jafar 国立研究開発法人理化学研究所, 生命医科学研究センター, 専任研究員 (00577968)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: Replication timing / SINE / H2Bub / CTCF

Outline of Final Research Achievements

The vertebrate genome is organized into transcriptionally active euchromatin and incative heterochromatin. During the S-phase, euchromatin replicates early and heterochromatin replicates late, and this phenomenon is known as replication timing. In this project, I sought to identify the genetic and epigenetic features that regulate replication timing. I found that SINE (short interspersed nuclear elements) retrotransposons that are enriched in euchromatin, play a role to regulate early replication timing. Mechanistically, SINEs promote the deposition of histone H2B monoubiquitination (H2Bub), a transcription-coupled epigenetic mark, in euchromatin. Furthermore, SINEs mediate a crosstalk between H2Bub and the chromatin insulator protein CTCF, and this crosstalk plays a role for regulation of early replication timing. Taken together, my research reveals a previously unknown mechanism mediated by SINEs and H2Bub for regulation of replication timing.

Free Research Field

Epigenetics

Academic Significance and Societal Importance of the Research Achievements

Replication timing defects have been linked with increased DNA damage, chromosomal translocations, and inappropriate cellular differentiation. By understanding the molecular mechanisms that regulate replication timing, it might be possible to therapeutically address the above cellular defects.