Stochastic asynchronous replication timing (AS-RT) is a phenomenon in which the time of replication of each allele is different, and the identity of the early allele varies between cells. By taking advantage of stable clonal pre-B cell populations derived from C57BL6/Castaneous mice, we have mapped the genome-wide AS-RT loci, independently of genetic differences. These regions are characterized by differential chromatin accessibility, mono-allelic expression and include new gene families involved in specifying cell identity. By combining population level mapping with single cell FISH, our data reveal the existence of a novel regulatory program that coordinates a fixed relationship between AS-RT regions on any given chromosome, with some loci set to replicate in a parallel and others set in the anti-parallel orientation. Our results show that AS-RT is a highly regulated epigenetic mark established during early embryogenesis that may be used for facilitating the programming of mono-allelic choice throughout development.
Bibliographical noteFunding Information:
We thank the members of the Core Research Facility in the Hebrew University School of Medicine; Dr. Dan Lehmann and Dr. Eleonora Medvedev for assistance with the FACS analysis; Dr. Idit Shiff, Dr. Abed Nasereddin and Ms. Alexia Azoulay for generating genomic data. This work was supported by research grants from the Israel Academy of Sciences (grant # 734/13 and #1228/18 to Y.B., grant #282/16 to H.C., grant # 184/16 to I.S.), ISF-NSFC (grant #2013/14 to Y.B., grant #2555/16 to I.S.), the Israel Cancer Research Foundation (I.S. and grant # 211410 to Y.B., grant #210910 to H.C.,), The Binational Science Foundation (grant # 2100289 to Y.B.), the Emanuel Rubin Chair in Medical Sciences (Y.B.), the Israel Center of Excellence Program (grant #1796/12 to Y.B.), the German Israeli Foundation (grant # 1424 to Y.B.), Rosetrees Foundation (H.C.).
© 2021, The Author(s).