Abstract
Organization of the genome into euchromatin and heterochromatin appears to be evolutionarily conserved and relatively stable during lineage differentiation. In an effort to unravel the basic principle underlying genome folding, here we focus on the genome itself and report a fundamental role for L1 (LINE1 or LINE-1) and B1/Alu retrotransposons, the most abundant subclasses of repetitive sequences, in chromatin compartmentalization. We find that homotypic clustering of L1 and B1/Alu demarcates the genome into grossly exclusive domains, and characterizes and predicts Hi-C compartments. Spatial segregation of L1-rich sequences in the nuclear and nucleolar peripheries and B1/Alu-rich sequences in the nuclear interior is conserved in mouse and human cells and occurs dynamically during the cell cycle. In addition, de novo establishment of L1 and B1 nuclear segregation is coincident with the formation of higher-order chromatin structures during early embryogenesis and appears to be critically regulated by L1 and B1 transcripts. Importantly, depletion of L1 transcripts in embryonic stem cells drastically weakens homotypic repeat contacts and compartmental strength, and disrupts the nuclear segregation of L1- or B1-rich chromosomal sequences at genome-wide and individual sites. Mechanistically, nuclear co-localization and liquid droplet formation of L1 repeat DNA and RNA with heterochromatin protein HP1α suggest a phase-separation mechanism by which L1 promotes heterochromatin compartmentalization. Taken together, we propose a genetically encoded model in which L1 and B1/Alu repeats blueprint chromatin macrostructure. Our model explains the robustness of genome folding into a common conserved core, on which dynamic gene regulation is overlaid across cells.
Highlights
The mammalian genomic DNA that is roughly 2 meters long in a cell is folded extensively in order to fit the size of the nucleus with a diameter of ~5–10 μm.[1]
The compartments marked by B1 repeats show enrichment of active histone marks (H3K4me[3], H3K9ac, H3K27ac, H3K36me3), strong binding of RNA polymerase II (Pol II), and high levels of chromatin accessibility and transcription activity
The compartments marked by L1 repeats show signatures of heterochromatin, including enrichment of the repressive H3K9me[2] and H3K9me[3] marks, and strong binding of heterochromatin proteins such as HP1α and the nuclear corepressor KRAB-associated protein-1 (KAP1 or TRIM28) (Fig. 1a and Supplementary information, Fig. S1b)
Summary
The mammalian genomic DNA that is roughly 2 meters long in a cell is folded extensively in order to fit the size of the nucleus with a diameter of ~5–10 μm.[1] Microscopic and 3C-based approaches reveal a hierarchical organization of the genome.[2,3,4,5] At the megabase scale, chromatin is subdivided into two spatially segregated compartments, arbitrarily labeled as A and B, with distinct transcriptional activity and histone modification as well as other features such as CpG frequency and DNA replication timing.[6,7,8,9,10] The euchromatic A compartment adopts a central position, whereas the heterochromatic B compartment moves towards the nuclear periphery and nucleolar regions.[11] This nuclear organization appears to be conserved from ciliates to humans and has been maintained in eukaryotes over 500 million years of evolution.[12] Within compartments at the kilobase-tomegabase scale, chromatin is organized in topologically associated domains (TADs), which serve as functional platforms for physical interactions between co-regulated genes and regulatory elements.[13] At a finer scale, TADs are divided into smaller loop domains, in which distal regulatory elements such as enhancers come into direct contact with their target genes via chromatin loops.[14] Intriguingly, most A/B compartments and TADs are relatively stable in different mouse and human cell types (Supplementary information, Text S1), whereas sub-TAD loops and a small fraction of lineage-specific regions with less pronounced compartment associations tend to be more variable for differential gene expression during cell-fate transition.[13,15,16,17,18,19]
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