Equalizing epigenetically imprinted centromeres in early mammalian embryos

Manske, G.; Jorgensen, K.; Ma, B.; Aboelenain, M.; Tower, C.; Chakraborty, S.; Ranjan, R.; Das, A.; Lampson, M. A.; Black, B. E.; Schindler, K.; Chen, X.; Hammoud, S. S.

doi:10.1101/2022.10.27.514094

bioRxiv · 10.1101/2022.10.27.514094

Equalizing epigenetically imprinted centromeres in early mammalian embryos

Manske, G.·Jorgensen, K.·Ma, B.·Aboelenain, M.·Tower, C.·Chakraborty, S.·Ranjan, R.·Das, A.·Lampson, M. A.·Black, B. E.·Schindler, K.·Chen, X.·Hammoud, S. S.

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Abstract

The CENP-A histone variant epigenetically defines centromeres, where its levels and locations are precisely maintained through mitotic cell divisions. However, differences in centromere CENP-A propagation in soma versus female/male germline remains poorly understood. Here, we generated CenpamScarlet mice and followed CENP-A dynamics in gametes, zygotes, and embryos. We found that, unlike somatic cells, progenitor female and male germ cells carry high centromeric CENP-A levels that decrease upon terminal differentiation. The reduction in CENP-A is differentially regulated between sexes, resulting in a ten-fold higher level in oocytes compared to sperm. In the zygote, the parent-of-origin CENP-A asymmetry is equalized prior to initial S-phase by redistribution of nuclear CENP-A from maternal to paternal chromosomes. Redistribution of CENP-A requires both CDK1/2 and PLK1 centromeric machinery. These experiments provide direct evidence for resetting of epigenetically imprinted centromeres in early pronuclear stage embryos and imply a mechanism to sense the non-equivalency of parental chromosomes. HighlightsO_LIIncreased CENP-A density at centromeres is a conserved property of germline stem cells while CENP-A reduction is coincident with germ cell differentiation C_LIO_LIPaternal and maternal CENP-A containing nucleosomes are intergenerationally inherited C_LIO_LICENP-A density at centromeres differs between male and female mature gametes C_LIO_LIUpon fertilization, maternal nuclear CENP-A is redistributed to equalize with parental CENP-A C_LIO_LICENP-C and MIS18BP1 are asymmetrically enriched in the parental pronuclei in accordance with CENP-A asymmetry. C_LIO_LILicensing for centromere equalization begins before zygotic DNA replication C_LI

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Manske, G., Jorgensen, K., Ma, B., Aboelenain, M., Tower, C., Chakraborty, S., Ranjan, R., Das, A., Lampson, M. A., Black, B. E., Schindler, K., Chen, X., Hammoud, S. S.. 2022-10-28. Equalizing epigenetically imprinted centromeres in early mammalian embryos. https://doi.org/10.1101/2022.10.27.514094

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