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Review
. 2014:15:269-93.
doi: 10.1146/annurev-genom-090613-094245.

Mendelian disorders of the epigenetic machinery: tipping the balance of chromatin states

Jill A Fahrner  1 , Hans T Bjornsson
Affiliations
Review

Mendelian disorders of the epigenetic machinery: tipping the balance of chromatin states

Jill A Fahrner et al. Annu Rev Genomics Hum Genet. 2014.

Abstract

Mendelian disorders of the epigenetic machinery are a newly delineated group of multiple congenital anomaly and intellectual disability syndromes resulting from mutations in genes encoding components of the epigenetic machinery. The gene products affected in these inherited conditions act in trans and are expected to have widespread epigenetic consequences. Many of these syndromes demonstrate phenotypic overlap with classical imprinting disorders and with one another. The various writer and eraser systems involve opposing players, which we propose must maintain a balance between open and closed chromatin states in any given cell. An imbalance might lead to disrupted expression of disease-relevant target genes. We suggest that classifying disorders based on predicted effects on this balance would be informative regarding pathogenesis. Furthermore, strategies targeted at restoring this balance might offer novel therapeutic avenues, taking advantage of available agents such as histone deacetylase inhibitors and histone acetylation antagonists.

Keywords: DNA methylation; chromatin; epigenetics; epigenomics; histone tail modifications; therapeutic development.

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Figures

Figure 1
Figure 1
Components of the epigenetic machinery. This machinery consists of writers (highlighters) and erasers of marks [for example, trimethylation of lysine 4 on histone H3 (H3K4me3)] as well as readers of those marks. A net balance between systems that remove and add a particular mark must be achieved. In many ways, the interacting epigenetic systems have certain distinct aspects that make them powerful final integrators of cellular signals (59). For instance, many of the marks placed/removed by writers/erasers can directly affect gene expression, either in a permissive (H3K4me3, shown) or nonpermissive (H3K9me3, not shown) manner. This change in expression, presumably of multiple genes, has the potential to form feedback loops by affecting the amount and availability of the modification in question. Various internal metabolites can directly affect the prevalence of marks. For instance, S-adenosyl-methionine (SAM) is a donor for methylation reactions, including both DNA and histone methylation. Use of critical metabolic intermediates like SAM as donors for histone tail modifications or for DNA methylation allows environmental influences to impact and be integrated into the system and to potentially affect gene expression directly (76).
Figure 2
Figure 2
Selected Mendelian disorders of the histone machinery caused by alterations of writers (highlighters) and erasers. Acetylation is a binary mark (present or not), and histone lysine methylation is a quaternary mark (mono-, di-, tri-, or unmethylated). The diagram illustrates these two types of modifications (see key) on two of the N-terminal histone tails, histone H3 and histone H4. The writers (highlighters) and erasers place and remove the modifications, respectively; some of these are associated with open, permissive chromatin (green), and others are associated with closed, repressive chromatin (red). Based on the enzymatic component of the epigenetic machinery involved and the predicted consequence of the reported mutations for each disorder, the diagram shows conditions that would be expected to shift the balance toward closed chromatin states at target loci (top) and those that would be expected to shift the balance toward open chromatin states at target loci (bottom). The former category includes Rubinstein–Taybi syndrome (RTS) (93, 101), Kabuki syndrome (KS) (71, 86), Wiedemann–Steiner syndrome (WSS) (61), and possibly Weaver syndrome (WS) and Sotos syndrome (SS) (41, 69, 116); the latter category includes brachydactyly–mental retardation (BDMR) syndrome (128), Kleefstra syndrome (KLFS) (66), Claes–Jensen syndrome (CJS) (60), and possibly Sotos syndrome (SS) (69). For EZH2 in WS and NSD1 in SS (marked with asterisks), the epigenetic consequences are currently unclear.
Figure 3
Figure 3
Therapeutic approaches based on understanding and restoring the balance of chromatin states. Our balance hypothesis offers a starting point for proof-of-principle studies for individual Mendelian disorders of the epigenetic machinery, which are potentially treatable causes of intellectual disability. If abnormalities of the expression of target genes are the culprit, then these disorders would be prime candidates for therapeutic development because the target genes would be expected to be fully functional, albeit improperly expressed, in patients with these disorders. For instance, Kabuki syndrome (KS) is related to a deficiency of trimethylation of lysine 4 on histone H3 (H3K4me3) or an inability to remove H3K27me3, marks that are predominantly seen in open and repressive chromatin, respectively. If the pathophysiology of KS is related to an imbalance between open and closed chromatin states (top left), with an inability to use critical gene transcripts, then this balance could be restored by inhibiting the transition to closed chromatin with a histone deacetylase (HDAC) inhibitor (bottom left). In contrast, brachydactyly–mental retardation (BDMR) syndrome would be expected to lead to an overrepresentation of open chromatin states (top right), with excessive transcription of disease-relevant target genes. Therefore, a histone acetyltransferase (HAT) inhibitor could be a useful therapeutic strategy (bottom right).
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