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. 2020 Sep 18;48(18):10199–10210. doi: 10.1093/nar/gkaa724

Figure 5.

Figure 5.

HCHC catalytic activity and DNA methylation become necessary for heterochromatin formation with increasingly GC-rich DNA. (A) Metaplot displaying the averaged profile of H3K9me3 enrichment in WT and Δhda-1 strains as determined by ChIP-seq and averaged %GC-content over all constitutive heterochromatin domains in wild type. (B) Model showing interactions between factors involved in establishing heterochromatin with decreasing DNA AT-content. (Left) In the absence of HCHC catalytic activity, the significant AT-richness of the interior of heterochromatin domains is sufficient to recruit the histone lysine methyltransferase complex, DCDC, to establish H3K9me3 and subsequent methylation of underlying DNA. However, the abruptly decreasing AT content at heterochromatin borders is insufficient for DCDC-induced heterochromatin, and without HCHC, heterochromatin is unable to properly spread over the canonical domain. (Middle) In a wild-type scenario, HCHC is able to localize to heterochromatin boundaries through binding of H3K9me3 catalyzed by DCDC, as well as through AT-hook domains in the CHAP subunit. Histone deacetylation activity by HCHC is able to recruit DCDC to further mark H3K9me3 on neighboring chromatin and establish a propagating feedback loop capable of spreading heterochromatin across the entirety of the canonical domain. Here, factors such as LSD1 that limit heterochromatin spreading act to keep the expansion in check within proper limits of what should be heterochromatin. (Right) In the absence of such limiting factors where heterochromatin spreads over its boundary into euchromatin, or in DLDM where convergent transcription induces H3K9me3 and DNA methylation, heterochromatin is established over DNA with AT-content well below the level for RIP-induced DNA methylation. Typically, DNA methylation is dependent on the H3K9me3 mark and loss of DNA methylation has no impact on H3K9me3 (21,37,38). In instances of heterochromatin over low (∼50%) AT-richness, DNA methylation now becomes essential for H3K9me3 and further spreading.