LAUSR

DNA sequence and inherited gene silencing Cell fate decisions require a gene's transcriptional status, whether on or off, to be stably and heritably maintained over multiple cell generations. For silenced genes, heterochromatin domains are associated with specific histone posttranslational modifications, and these histone marks are maintained during DNA replication and chromosome duplication (see the Perspective by De and Kassis). Laprell et al. show that parental methylated histone H3 lysine 27 (H3K27) nucleosomes in Drosophila are inherited in daughter cells after replication and can repress transcription, but that they are not sufficient to propagate the mark. Trimethylation of newly incorporated nucleosomes requires recruitment of the methyltransferase Polycomb repressive complex 2 (PRC2) to neighboring cis-regulatory DNA elements. Coleman and Struhl demonstrate that H3K27 trimethylated nucleosomes play a causal role in transmitting epigenetic memory at a Drosophila HOX gene through anchoring of PRC2 at the Polycomb response element binding site. Wang and Moazed examine fission yeast and show that both sequence-dependent and chromodomain sequence-independent mechanisms are required for stable epigenetic inheritance of histone modifications and the epigenetic maintenance of silencing. These studies highlight the crucial role of DNA binding for heritable gene silencing during growth and development. Science, this issue p. 85, p. eaai8236, p. 88; see also p. 28 Specific DNA sequences work together with histone methyl marks to maintain epigenetic states of gene expression. Epigenetic inheritance mechanisms play fundamental roles in maintaining cellular memory of gene expression states. In fission yeast, histone H3 lysine 9 (H3K9) is methylated (H3K9me) at heterochromatic domains. These domains can be epigenetically inherited when epe1+, encoding an enzyme that promotes H3K9 demethylation, is deleted. How native epigenetic states are stably maintained in epe1+ cells remains unknown. Here, we developed a system to examine the role of DNA sequence and genomic context in propagation of a cis-heritable H3K9me-dependent silenced state. We show that in epe1+ cells, in addition to sequence-independent mechanisms that propagate H3K9me, epigenetic inheritance of silencing requires binding sites for sequence-dependent activating transcription factor (ATF)–adenosine 3′,5′-monophosphate (cAMP) response element–binding protein (CREB) family transcription factors within their native chromosomal context. Thus, specific DNA sequences contribute to cis inheritance of H3K9me and silent epigenetic states.