DNA sequence-dependent epigenetic inheritance of gene silencing and histone H3K9 methylation

Abstract

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.

A non-enzymatic function associated with a putative histone demethylase licenses epigenetic inheritance

“…Tethering Clr3 at an ectopic site renders heterochromatin refractory to the anti-silencing effects of Epe1. Our observations are in part, similar to previous findings relating to the fission yeast mating type locus where DNA binding proteins, Atf1 and Pcr1 recruit Clr3 to maintain epigenetic silencing following an RNAi dependent initiation mechanism (Wang and Moazed, 2017;Yamada et al, 2005). We also recapitulate a unique requirement for the sequence dependent recruitment of HDAC proteins in cis in order to facilitate the inheritance of silent epigenetic states despite the presence of anti-silencing factors such as Epe1.…”

Emerging roles of the histone chaperone CAF-1 in cellular plasticity

“…Recent evidence suggests that maintenance of gene silencing at heterochromatin loci and Polycomb targets is maintained through self-propagation of the respective histone marks or sequence-specific recruitment of silencing factors to replicated chromatin [56–59]. Considering the dual effect of CAF-1 in nucleosome assembly and heterochromatin maintenance, it is tempting to speculate that the complex contributes to this process by propagating silenced gene expression patterns through cell division and thus perpetuating an epigenetic memory.…”

RNA-mediated regulation of heterochromatin

“…Finally, these mechanisms are less susceptible to DNA mutations than a mechanism in which heterochromatin factors simply recognize a DNA sequence; which is especially advantageous for regions with high mutation rates, such as centromeres. Consistent with this idea, a heterochromatin region in fission yeast with a lower mutation rate than centromeres — the mating-type locus — relies on specific transcription factor binding DNA sequences for both establishment and maintenance of heterochromatin [40], and only requires RNAi for establishment [41]. In contrast, pericentric heterochromatin requires RNAi for both establishment and maintenance, with no known specific DNA binding factors.…”