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  • While histone modifications can alter inter nucleosomal inte

    2022-06-22

    While histone modifications can alter inter-nucleosomal interactions that govern the compaction state of a chromatin fiber (Francis et al., 2004, Kalashnikova et al., 2013, Lu et al., 2008), the potential impact of histone modifications on higher-order chromosome organization beyond chromatin-fiber compaction is not well understood. Only recently has super-resolution imaging shown that chromatin domains enriched in H3K27me3 and polycomb proteins adopt unique folded states (Boettiger et al., 2016). Once the polycomb repressive complex 1 is recruited to H3K27me3-enriched chromatin, it generates chromatin domains 20–140 kb in size that are distinct from previously defined TADs (Kundu et al., 2017). Our results show that H4K20me1 controls chromosome structure over a larger length scale. H4K20me1 modulates the formation of TADs (≥1 Mb) by enhancing long-range DNA interactions across X. Our combined data support a two-tier model for the DCC-dependent remodeling of X chromosome topology. In the first stage, the condensin DCC initiates TAD boundary formation via a demethylase-independent mechanism that promotes long-range interactions between the highest affinity DCC binding sites (rex sites) prior to DPY-21’s assembly onto X. In the second stage, DPY-21 demethylase catalyzes enrichment of H4K20me1 on X, thereby enhancing long-range DNA interactions across X. X chromosome compaction is generally increased, and TAD boundaries are strengthened by the elevation of long-range rex interactions critical for TAD formation. Unexpectedly, higher-order chromosome structure is also regulated in germ cells by DPY-21. In meiotic nuclei of both sexes, DPY-21 is localized to Dipraglurant via a DCC-independent mechanism. The targeted H4K20me1 enrichment then condenses the lengths of autosomal axes, providing broad evidence for H4K20me1’s regulation of higher-order chromosome structure. Axis expansion can alter crossover frequency and distribution (Mets and Meyer, 2009), raising the possibility that autosomal H4K20me1 might have consequences for crossover recombination as well as gene expression. DPY-21’s DCC-independent activity is relevant for recent findings that DPY-21 modulates nematode growth and metabolism through the TORC2 pathway (Webster et al., 2013) and entry into the quiescent dauer state through the insulin-signaling pathway (Delaney et al., 2017, Dumas et al., 2013). Evidence in both cases suggests at least partial DCC-independence for DPY-21’s functions. Determining the effect of JmjC-specific mutations on both pathways will be key for distinguishing the contribution of demethylase activity from general DCC functions. Moreover, because metabolism is altered in both biological contexts and α-KG is a necessary DPY-21 co-factor and a product of the Krebs cycle, the worm’s metabolic state, rather than the DCC, could influence DPY-21’s functions (Chin et al., 2014). Relevance of our studies for mammalian development is underscored by the enrichment of H4K20me1 on the inactive female X chromosome (Kohlmaier et al., 2004). Mechanisms underlying the H4K20me1 enrichment and its role in chromosome silencing are not known. The long non-coding RNA XIST, the trigger of mammalian X inactivation, induces accumulation of H4K20me1 on X, but X inactivation per se is not required for H4K20me1 deposition, suggesting that H4K20me1 might contribute to establishing inactivation. Consistent with this idea, knockout of the H4K20me1 methyltransferase causes decondensation of X (Oda et al., 2009). Our discoveries offer new directions for unraveling the regulation and function of H4K20me1 in X chromosome inactivation and other long-range mechanisms of gene control.
    STAR★Methods
    Author Contributions
    Acknowledgments We thank D. Fujimori, D. Minor, T. Cline, E. Ralston, and M. Marletta for general discussions; J. Dekker for Hi-C discussions; D. Stalford for figures; T. Cline, J. Berger, B. Farboud, and N. Fuda for manuscript comments; and J. Doudna for sharing equipment and expertise. We used the Vincent J. Coates Genomics Sequencing Laboratory at UC Berkeley, supported by an NIH Instrumentation Grant (S10 OD018174). X-ray data were collected at the Lawrence Berkeley National Laboratory Advanced Light Source (Beamline 8.3.1). Huygens software was licensed to the CNR Biological Imaging Facility at UC Berkeley. Research was supported, in part, by Miller Institute funds and NIGMS grants (R01 GM030702 to B.J.M.; F32 GM100647 to B.S.W.). B.J.M. is an investigator of the Howard Hughes Medical Institute.