Abstract
Centromeres are epigenetically determined nuclear domains strictly required for chromosome segregation and genome stability. However, the mechanisms regulating centromere and kinetochore chromatin modifications are not known. Here, we demonstrate that LSH is enriched at meiotic kinetochores and its targeted deletion induces centromere instability and abnormal chromosome segregation. Superresolution chromatin analysis resolves LSH at the inner centromere and kinetochores during oocyte meiosis. LSH knockout pachytene oocytes exhibit reduced HDAC2 and DNMT-1. Notably, mutant oocytes show a striking increase in histone H3 phosphorylation at threonine 3 (H3T3ph) and accumulation of major satellite transcripts in both prophase-I and metaphase-I chromosomes. Moreover, knockout oocytes exhibit centromere fusions, ectopic kinetochore formation and abnormal exchange of chromatin fibers between paired bivalents and asynapsed chromosomes. Our results indicate that loss of LSH affects the levels and chromosomal localization of H3T3ph and provide evidence that, by maintaining transcriptionally repressive heterochromatin, LSH may be essential to prevent deleterious meiotic recombination events at repetitive centromeric sequences.
Highlights
Centromeres are epigenetically determined nuclear domains strictly required for chromosome segregation and genome stability
Our results indicate that LSH exhibits a previously unrecognized localization to the meiotic kinetochore and inner centromere and its targeted deletion affects the levels and chromosomal localization of H3T3ph, centromere transcription as well as abnormal chromosome segregation during oocyte meiosis
LSH is an abundant nuclear protein that becomes enriched at the inner centromere where it is partially co-localized with the CREST signals detected at sister kinetochores (Fig. 1a)
Summary
Centromeres are epigenetically determined nuclear domains strictly required for chromosome segregation and genome stability. Our results indicate that loss of LSH affects the levels and chromosomal localization of H3T3ph and provide evidence that, by maintaining transcriptionally repressive heterochromatin, LSH may be essential to prevent deleterious meiotic recombination events at repetitive centromeric sequences. Germ cell-specific mechanisms of heterochromatin formation are, critical to fulfill the segregation requirements of meiotic chromosomes[3,4]. Little is known about the molecular mechanisms regulating histone modifications required for meiotic centromere function. We define the function of LSH during mouse prophase-I and M-I, two key stages of oocyte meiosis essential to regulate accurate chromosome segregation. Our results indicate that LSH exhibits a previously unrecognized localization to the meiotic kinetochore and inner centromere and its targeted deletion affects the levels and chromosomal localization of H3T3ph, centromere transcription as well as abnormal chromosome segregation during oocyte meiosis. Our results have important implications to understand the long-sought mechanisms involved in the centromere effect during meiosis as well as the mechanisms of formation of human trisomies
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