Impaired Regulation of Histone Methylation and Acetylation Underlies Specific Neurodevelopmental Disorders

Abstract

Epigenetic processes are critical for governing the complex spatiotemporal patterns of gene expression in neurodevelopment. One such mechanism is the dynamic network of post-translational histone modifications that facilitate recruitment of transcription factors or even directly alter chromatin structure to modulate gene expression. This is a tightly regulated system, and mutations affecting the function of a single histone-modifying enzyme can shift the normal epigenetic balance and cause detrimental developmental consequences. In this review, we will examine select neurodevelopmental conditions that arise from mutations in genes encoding enzymes that regulate histone methylation and acetylation. The methylation-related conditions discussed include Wiedemann-Steiner, Kabuki, and Sotos syndromes, and the acetylation-related conditions include Rubinstein-Taybi, KAT6A, genitopatellar/Say-Barber-Biesecker-Young-Simpson, and brachydactyly mental retardation syndromes. In particular, we will discuss the clinical/phenotypic and genetic basis of these conditions and the model systems that have been developed to better elucidate cellular and systemic pathological mechanisms.

Keywords: acetylation; epigenetics; histone; methylation; neurodevelopment.

Figure 1

Histone methylation regulates gene expression through recruitment of different transcription factors rather than by directly altering chromatin structure. (A) When histone methyltransferases (HMT) methylate lysine or arginine residues on H3 and H4 associated with active chromatin (yellow hexagons), transcriptional activators (TA) can be recruited to those sites to promote gene expression. (B) However, when HMTs target different residues on H3 and H4 that are associated with chromatin repression, these methylated regions (red hexagons) can recruit transcriptional repressors to silence the gene. The transcriptional effects of histone methylation can be reversed by histone demethylases (HDM). Proper gene expression is dependent on the homeostasis of HMT and HDM enzyme activity. (C) Lysine methylation occurs primarily on H3 and H4. Each KMT/KDM will only target select residues, and the enzymes discussed have high specificity for these targets. Mutations that impair the function of these enzymes would be expected to affect the methylation status of these residues. Each enzyme and their lysine methylation sites are color coded. Other lysine methylation sites not specifically targeted by these enzymes are indicated in gray. Arginine methylation sites are not indicated in this figure.

Figure 2

(A) Histone acetyltransferases (HAT) will acetylate histone lysine residues using acetyl CoA cofactor (blue circles). This weakens the electrostatic interactions between positively-charged histones and negatively-charged DNA to loosen chromatin structure. This results in DNA exposure, allowing for the recruitment of transcriptional activators (TA). (B) Conversely, transcriptional repressor (TR) complexes can interact with histone deacetylases (HDAC) to remove these modifications. This strengthens the electrostatic interactions between the DNA and the histones, resulting in compact chromatin, inhibiting transcription. The homeostasis between histone acetylation and deacetylation is critical for proper gene expression. (C) Lysine acetylation can occur on all four histone subunits. Each HAT/HDAC has preferred target sites. While KAT6A and KAT6B acetylate residues with high specificity, CBP and HDAC4/HDAC3 complexes have a broader range of targets. The lysine residues targeted by each enzyme are color coded. There is some target redundancy between HAT/HDACs, and other histone (de)acetylating enzymes can also target common sites (not indicated on figure). Additional lysine acetylation sites not specifically targeted by these enzymes are indicated in gray.

Figure 3

Neurological and peripheral symptoms common to different epigenetic-linked developmental conditions.