Mendelian disorders of the epigenetic machinery: postnatal malleability and therapeutic prospects

Abstract

The epigenetic machinery in conjunction with the transcriptional machinery is responsible for maintaining genome-wide chromatin states and dynamically regulating gene expression. Mendelian disorders of the epigenetic machinery (MDEMs) are genetic disorders resulting from mutations in components of the epigenetic apparatus. Though individually rare, MDEMs have emerged as a collectively common etiology for intellectual disability (ID) and growth disruption. Studies in model organisms and humans have demonstrated dosage sensitivity of this gene group with haploinsufficiency as a predominant disease mechanism. The epigenetic machinery consists of three enzymatic components (writers, erasers and chromatin remodelers) as well as one non-enzymatic group (readers). A tally of the entire census of such factors revealed that although multiple enzymatic activities never coexist within a single component, individual enzymatic activities often coexist with a reader domain. This group of disorders disrupts both the chromatin and transcription states of target genes downstream of the given component but also DNA methylation on a global scale. Elucidation of these global epigenetic changes may inform our understanding of disease pathogenesis and have diagnostic utility. Moreover, many therapies targeting epigenetic marks already exist, and some have proven successful in treating cancer. This, along with the recent observation that neurological dysfunction in these disorders may in fact be treatable in postnatal life, suggests that the scientific community should prioritize this group as a potentially treatable cause of ID. Here we summarize the recent expansion and major characteristics of MDEMs, as well as the unique therapeutic prospects for this group of disorders.

Figure 1

The MDEMs. Seventy genes with defined epigenetic domains (reader, writer, eraser, remodeler, middle icons) have been linked to Mendelian phenotypes. The majority of genes cause disease in the heterozygous state (filled circle). Enzyme domains (writer, eraser, remodeler) are mutually exclusive in any given factor but many coexist with a reader domain (gray shading). ID is seen in the vast majority (blue), as are growth abnormalities (orange). A indicates genes on autosomes; X indicates genes on the X chromosome.

Figure 2

Molecular pathogenesis, malleability and therapeutic considerations for the MDEMs. (Top panel) Epigenetic machinery maintains open (Gene 1; green triangles, acetylation; green hexagons, H3K4me3) and closed (Gene 2; red hexagons, H3K9me3 or H3K27me3; red lollipops, DNA methylation) chromatin states, which influence transcriptional programs in cells. Specifically, an expressed target of the writer (Gene 1) has associated writers of activating marks (green highlighters; HAT; HMT), erasers of silencing marks (erasers; KDMs, lysine demethylases), dual-function chromatin remodelers (bull dozer) and other readers (green glasses; bromodomain and chromodomain proteins). A silenced non-target of the writer (Gene 2) has associated writers of silencing marks (red highlighters; HMT; DNMT, DNA methyltransferases), erasers of activating marks (erasers; KDM, lysine demethylases; HDAC) and readers (red glasses; chromodomain proteins and methyl-CpG binding proteins). (Bottom panel) Upon loss of a writer of an open chromatin modification (broken highlighter) due to an MDEM, direct target genes may lose the relevant activating marks and transition to an abnormally closed chromatin state with associated DNA hypermethylation and aberrant gene silencing (Gene 1). Non-targets (Gene 2) may adopt an abnormal open chromatin state and become aberrantly expressed. Multiple potential therapeutic strategies exist to revert the abnormal chromatin and transcription states back to normal and are described in the text (arrow, inset box).