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Epigenetic, genetic and maternal effects enable stable centromere inheritance

Abstract

Centromeres are defined epigenetically by the histone H3 variant CENP-A. The propagation cycle by which pre-existing CENP-A nucleosomes serve as templates for nascent assembly predicts the epigenetic memory of weakened centromeres. Using a mouse model with reduced levels of CENP-A nucleosomes, we find that an embryonic plastic phase precedes epigenetic memory through development. During this phase, nascent CENP-A nucleosome assembly depends on the maternal Cenpa genotype rather than the pre-existing template. Weakened centromeres are thus limited to a single generation, and parental epigenetic differences are eliminated by equal assembly on maternal and paternal centromeres. These differences persist, however, when the underlying DNA of parental centromeres differs in repeat abundance, as assembly during the plastic phase also depends on sufficient repetitive centromere DNA. With contributions of centromere DNA and the Cenpa maternal effect, we propose that centromere inheritance naturally minimizes fitness costs associated with weakened centromeres or epigenetic differences between parents.

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Fig. 1: Evidence for epigenetic centromere memory through mouse reproduction.
Fig. 2: Male and female soma show reduced CENP-A compared to oocytes.
Fig. 3: Epigenetic differences between parental centromeres are not maintained.
Fig. 4: Centromere strength depends on maternally inherited CENP-A.
Fig. 5: CENP-A chromatin recovers in adult male F2 progeny from Cenpa+/+ WT F1 parents.
Fig. 6: Genetic contributions to centromere equalization in early embryogenesis.

Data availability

Previously published microarray data for long poly-(A) tailed Cenpa mRNA in pre-implantation development is available freely on the NCBI Gene Expression Omnibus (GEO) database (accession no. GDS813 from reference series GSE1749). The 12 mouse genomes used for Cenpa 3′ UTR analysis are available from the NCBI BioProject database (https://www.ncbi.nlm.nih.gov/bioproject) under accession no. PRJNA669840. Data supporting the findings of this study are available from the corresponding author on reasonable request. Source data are provided with this paper.

Code availability

All codes used for statistical and distribution analysis are freely available as part of the R package ‘multimode’, described in ref. 58.

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Acknowledgements

We thank D. P. Dudka, V. Fu and M. Barmada for assistance with genotyping, G. Logsdon for cloning a protein expression vector, M. Gerace for antigen preparation, D. P. Dudka for help with multiple sequence alignments and R. M. Schultz, M. S. Bartolomei and M. T. Levine for comments and discussion. This work was supported by the NIH (HD058730 to B.E.B. and M.A.L).

Author information

Authors and Affiliations

Authors

Contributions

A. Das contributed to experiments, quantifications, data analysis and statistical analysis, animal husbandry and genotyping. A.I.-O. carried out experiments and quantification for some of Fig. 3g. J.D.-M. prepared and characterized new reagents and assisted with statistical analysis. A. Destouni performed the initial experimentation in zygotes and early embryos. K.G.B. carried out animal husbandry and genotyping. A. Das, B.E.B. and M.A.L. contributed to experimental design, data interpretation and writing. B.E.B. and M.A.L. provided supervision and sourced funding.

Corresponding authors

Correspondence to Ben E. Black or Michael A. Lampson.

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Nature Cell Biology thanks Hiroshi Kimura and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 CENP-A chromatin is reduced in the soma of Cenpa+/− heterozygous animals in the P0 generation.

a, Bone marrow metaphase spreads: each pair of CENP-A foci represents sister centromeres in mitosis. Scale bars: 5 μm (main panel), 1μm (inset). b, Quantification of CENP-A foci intensities in control (grey) and P0 (yellow) generation in soma. N = 166, 170 centromeres (top to bottom). ** P < 0.0001, Mann–Whitney U test (two-tailed). Error bars: median ± 95% CI. Source numerical data are available in source data.

Source data

Extended Data Fig. 2 Weakened centromeres in the male germline are independent of meiotic stage.

. Because oocytes were analysed at metaphase I and spermatocytes at prophase I (Fig. 1), we confirmed that F1 spermatocytes also show weakened centromeres at metaphase I. Images (a) and quantification (b) of F1 spermatocytes show CENP-A reduced to a similar level at metaphase I (70.54 ± 7.1% of control) as prophase I. Each of the CENP-A foci represents four centromeres (a pair of homologous chromosomes, each with two sisters). N = 330 (control), 284 (F1 progeny). Scale bars: 5 μm (main panel), 1μm (inset). Quantification of SYCP3 foci from the same cells (c) shows no decrease (114.90 ± 5.6% of control). N = 235 (control), 259 (F1 progeny). ** P < 0.001, Mann–Whitney U Test (two-tailed). Error bars: median ± 95% CI. Source numerical data are available in source data.

Source data

Extended Data Fig. 3 Littermate analysis showing that weakened centromeres persist in the male but not female germline.

a, Data from Fig. 1c replotted as CENP-A levels per animal, averaged over all centromeres in each animal and normalized to controls (dashed line). N = 10,10,10, 9, 7 animals. The F1 male but not the female germline and the male and female soma are significantly lower than the controls **P < 0.001, *P < 0.05 n.s.: P > 0.05, Wilcoxon signed sum rank test (two-tailed). b, CENP-A quantifications in spermatocytes and oocytes from littermates from one set of parents. N = 121, 431, 60, 259, 246, 105 centromeres (top to bottom). Female germline levels are significantly elevated compared to littermate male germline levels. **P < 0.0001, Mann–Whitney U Test (two-tailed). Error bars: median ± 95% CI. Source numerical data are available in source data.

Source data

Extended Data Fig. 4 CENP-A nucleosomes are retained through the replacement of canonical nucleosomes with protamines during spermiogenesis.

a, Quantification and b, images showing CENP-A levels are reduced to 42.7 ± 1.5% in spermatids from Cenpa+/− males compared to WT males, similar to the reduction measured in prophase spermatocytes (Fig. 1c). N = 20 (control), 32 (Cenpa+/−) spermatids. Error bars: median ± 95% CI. Scale bars: 5 μm (main panel), 1 μm (inset). Source numerical data are available in source data.

Source data

Extended Data Fig. 5 Model to explain equalization of epigenetic differences and subsequent memory.

a, Assumptions used for the modelling. b, Epigenetic inheritance of CENP-A as determined in cycling somatic cells in culture by replication coupled dilution and G1 reloading. c, Example calculation and graph for CENP-A assembly in the first two embryonic cell cycles for progeny of a WT x WT cross. For simplicity, initial CENP-A levels are set to 100 and 50 on the maternal and paternal centromeres, respectively, based on our measurements in zygotes (Fig. 3c). At each S-phase, CENP-A levels are diluted by half on each centromere, and we assume equal assembly on maternal and paternal centromeres in the following G1. Assembly in the first cell cycle depends on the maternal pool, set to 100 for a zygote from a WT female, giving an increase of 50 on both maternal and paternal centromeres. Assembly in the second cell cycle depends on the zygotic pool, which is set to 100 for a WT zygotic genotype. d, Graphs from similar calculations as b, for the designated crosses. Initial CENP-A levels are set to 50 for maternal centromeres from Cenpa+/− mothers and 40 for paternal centromeres from Cenpa+/− fathers, based on our measurements (Fig. 1c and Fig. 3c). Arrows indicate equal assembly on maternal and paternal centromeres. In the first cell cycle, assembly is from a maternal pool of 100 (black arrows) or 50 (yellow arrows) for WT or Cenpa+/− mothers, respectively. In the second cell cycle, assembly is from a zygotic pool of 100 (purple arrows), reflecting a WT zygotic genotype. Calculations show equalization by the four-cell stage in all crosses. Furthermore, crosses with reduced maternal contribution (H♀) equalize to a lower level, which is then remembered through development. Source numerical data are available in source data.

Source data

Extended Data Fig. 6 3’ UTR of Cenpa message has hallmarks of dormant maternal mRNA.

a, Polyadenylation (addition of a poly (A) tail) of mRNA is a mechanism to control gene expression. Nuclear polyadenylation is an essential part of post-transcriptional processing of most mRNAs, dictated by the ubiquitous cis-element 3’ UTR hexameric motif AATAAA (nuclear polyadenylation element, NPE). Dormant maternal mRNAs are deposited in the oocyte with short poly(A) tails and are translationally inactive. After fertilization, these maternal mRNAs undergo translation by elongation of the poly(A) tail, controlled by a cytoplasmic polyadenylation element (CPE) usually present within 100 nt upstream of the NPE28. We find conserved CPEs in the mouse, human and frog Cenpa 3’ UTRs (CPE I = TTTTAT or CPE II = TTTTAA) upstream of the NPE as expected for dormant maternal mRNAs. b, Analysis of 12 sequenced rodent species38 reveals that CPEs (CPE I in bold boxes and CPE II in dashed boxes) are present upstream of the NPE in every species as expected for a maternal effect gene.

Extended Data Fig. 7 Symmetric distribution of H3K9me3 at the four-cell stage.

Representative cell from four-cell embryos for each of the two denoted crosses with H3K9me3 (red), CENP-A (green) and DNA (blue). H3K9me3 is present on both maternal and paternal chromatin at this stage, in contrast to zygotes (Fig. 3b and Fig. 6b–e). Scale bars: 5 μm.

Extended Data Fig. 8 CENP-A intensity distribution changes from bimodal to unimodal in early embryogenesis.

Graphs show locations of the modes in each distribution from Fig. 6a. a, The WT x WT and WT♀ x H♂ zygote distributions contain two modes (dashed lines) on either side of a central antimode (dip, pointed lines) characteristic of bimodal distributions52. The separation between the two modes is greater in the WT♀ x H♂ cross as expected. In addition, the ratios of the values of the two modes (x-axis) denoted under each cross agree well with the ratios of paternal to maternal centromere intensities calculated in Figs. 3c and 6f. b,c, Similar plots of four-cell embryos (b) from the same crosses show a single central mode characteristic of a unimodal population, like the F1 adult spermatocytes (c), which represents a uniform centromere population. The ratio of the modes in bimodal or the value of the mode in unimodal distribution is indicated below the graphs. Source numerical data are available in source data.

Source data

Extended Data Fig. 9 Genetic pathway for centromere equalization.

a, Quantifications of maternal (pink) and paternal (blue) CENP-A and CENP-C intensities in zygotes from a WT x WT control for the Cenpb−/− strain38, with average paternal/maternal CENP-A or CENP-C ratios above; N = 46, 42, 237, 231 centromeres (left to right). Error bars: median ± 95% CI. Although these animals are in a CF-1/C57BL/6J/DBA/2J background, CENP-A and CENP-C ratios in WT zygotes using mothers from this background are consistent with those of C57BL/6J alone (Fig. 6b,f). Source numerical data are available in source data.

Source data

Supplementary information

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Das, A., Iwata-Otsubo, A., Destouni, A. et al. Epigenetic, genetic and maternal effects enable stable centromere inheritance. Nat Cell Biol 24, 748–756 (2022). https://doi.org/10.1038/s41556-022-00897-w

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