Abstract
Membraneless pericentromeric heterochromatin (PCH) domains play vital roles in chromosome dynamics and genome stability. However, our current understanding of 3D genome organization does not include PCH domains because of technical challenges associated with repetitive sequences enriched in PCH genomic regions. We investigated the 3D architecture of Drosophila melanogaster PCH domains and their spatial associations with the euchromatic genome by developing a novel analysis method that incorporates genome-wide Hi-C reads originating from PCH DNA. Combined with cytogenetic analysis, we reveal a hierarchical organization of the PCH domains into distinct "territories." Strikingly, H3K9me2-enriched regions embedded in the euchromatic genome show prevalent 3D interactions with the PCH domain. These spatial contacts require H3K9me2 enrichment, are likely mediated by liquid-liquid phase separation, and may influence organismal fitness. Our findings have important implications for how PCH architecture influences the function and evolution of both repetitive heterochromatin and the gene-rich euchromatin.
Highlights
Nuclear architecture and dynamics regulate many important genome functions
We reveal a hierarchical organization of the Peri-Centromeric Heterochromatin (PCH) domains into distinct “territories.” Strikingly, H3K9me2-enriched regions embedded in the euchromatic genome show prevalent 3D interactions with the PCH domain
Most of our understanding of this critical architecture has been limited to the gene-rich euchromatin, and largely ignores the gene-poor and repeat-rich pericentromeric heterochromatin, or PCH
Summary
Nuclear architecture and dynamics regulate many important genome functions (reviewed in [1,2,3,4]). The development of Hi-C, which combines chromosome conformation capture (3C) [5] with genome-wide sequencing [6], has led to major breakthroughs in our understanding of global nuclear architecture (reviewed in [7]). Recent studies have shown that specific biophysical properties of HP1a and liquid-liquid phase separation (LLPS) may mediate the formation of PCH domains [22,23]. This widely observed spatial organization of PCH domains could significantly influence transcription and other genome functions [24], such as silencing of euchromatic genes transposed near or in PCH genomic regions [25,26,27]. PCH-PCH interactions have recently been proposed to drive global genome architecture [28]
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