Heterochromatin, typically marked by histone H3 trimethylation at lysine 9 (H3K9me3) or lysine 27 (H3K27me3), represses different protein-coding genes in different cells, as well as repetitive elements. The basis for locus specificity is unclear. Previously, we identified 172 proteins that are embedded in sonication-resistant heterochromatin (srHC) harbouring H3K9me3. Here, we investigate in humans how 97 of the H3K9me3-srHC proteins repress heterochromatic genes. We reveal four groups of srHC proteins that each repress many common genes and repeat elements. Two groups repress H3K9me3-embedded genes with different extents of flanking srHC, one group is specific for srHC genes with H3K9me3 and H3K27me3, and one group is specific for genes with srHC as the primary feature. We find that the enhancer of rudimentary homologue (ERH) is conserved from Schizosaccharomyces pombe in repressing meiotic genes and, in humans, now represses other lineage-specific genes and repeat elements. The study greatly expands our understanding of H3K9me3-based gene repression in vertebrates.

异染色质通常以赖氨酸 9 (H3K9me3) 或赖氨酸 27 (H3K27me3) 处的组蛋白 H3 三甲基化为标志，抑制不同细胞中的不同蛋白质编码基因以及重复元件。位点特异性的基础尚不清楚。此前，我们鉴定了 172 种蛋白质，它们嵌入含有 H3K9me3 的耐超声处理异染色质 (srHC) 中。在这里，我们在人类中研究了 97 种 H3K9me3-srHC 蛋白如何抑制异染色质基因。我们揭示了四组 srHC 蛋白，每组都抑制许多常见基因和重复元件。两组以不同程度的侧翼 srHC 抑制 H3K9me3 嵌入基因，一组特异于具有 H3K9me3 和 H3K27me3 的 srHC 基因，一组特异于以 srHC 作为主要特征的基因。我们发现，在粟酒裂殖酵母中，基本同源物（ERH）的增强子在抑制减数分裂基因方面是保守的，并且在人类中，现在也抑制其他谱系特异性基因和重复元件。这项研究极大地扩展了我们对脊椎动物中基于 H3K9me3 的基因抑制的理解。