Recent genome-sequencing studies in human neurodevelopmental and psychiatric disorders have revealed mutations in chromatin-modifying enzymes, such as chromatin remodellers and histone-modifying enzymes. Such studies are improving our understanding of the roles of these modifiers in human neurodevelopment, and this article discusses the emerging roles for several of these enzymes in development and disease.

/pdf/from-neural-development-to-cognition-unexpected-roles-for-1pjdtzvuuv.pdf

From neural development to cognition: unexpected roles for chromatin

The orchestrated organization of epigenetic factors that control chromatin dynamism, including DNA methylation, histone marks, non-coding RNAs (ncRNAs) and chromatin-remodeling proteins, is essential for the proper function of tissue homeostasis, cell identity and development. Indeed, deregulation of epigenetic profiles has been described in several human pathologies, including complex diseases (such as cancer, cardiovascular and neurological diseases), metabolic pathologies (type 2 diabetes and obesity) and imprinting disorders. Over the last decade it has become increasingly clear that mutations of genes involved in epigenetic mechanism, such as DNA methyltransferases, methyl-binding domain proteins, histone deacetylases, histone methylases and members of the SWI/SNF family of chromatin remodelers are linked to human disorders, including Immunodeficiency Centromeric instability Facial syndrome 1, Rett syndrome, Rubinstein–Taybi syndrome, Sotos syndrome or alpha-thalassemia/mental retardation X-linked syndrome, among others. As new members of the epigenetic machinery are described, the number of human syndromes associated with epigenetic alterations increases. As recent examples, mutations of histone demethylases and members of the non-coding RNA machinery have recently been associated with Kabuki syndrome, Claes-Jensen X-linked mental retardation syndrome and Goiter syndrome. In this review, we describe the variety of germline mutations of epigenetic modifiers that are known to be associated with human disorders, and discuss the therapeutic potential of epigenetic drugs as palliative care strategies in the treatment of such disorders.

https://static.springer.com/sgw/documents/1390418/application/pdf/HG1.pdf

Genetic syndromes caused by mutations in epigenetic genes

HDAC4, 5, 7 and 9 constitute the class IIa histone deacetylases (HDACs) within the large family of protein deacetylases. Class IIa HDACs have unique features that distinguish them from other HDACs. They contain an N-terminal domain that is required for their interaction with tissue-specific transcription factors and recruitment to their target genes. The N-terminal domain on class IIa HDACs also bears conserved serine residues that undergo signal-dependent phosphorylation, which brings about nuclear export of the enzymes and de-repression of their targets. One of the most important aspects of class IIa HDACs is their expression in specific tissues and organs within the organism, where they have crucial roles in development and differentiation processes. This review brings up to date our knowledge of the physiological and pathological functions of class IIa HDACs, focusing in particular on the most recent discoveries from in vivo studies of mouse model systems.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/febs.13061

Class IIa HDACs - new insights into their functions in physiology and pathology.

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.

/pdf/mendelian-disorders-of-the-epigenetic-machinery-tipping-the-2f5wmfue7u.pdf

Mendelian Disorders of the Epigenetic Machinery: Tipping the Balance of Chromatin States

Deletions of the chromosomal region 2q37 cause brachydactyly-mental retardation syndrome (BDMR), also known as Albright hereditary osteodystrophy-like syndrome. Recently, histone deacetylase 4 (HDAC4) haploinsufficiency has been postulated to be the critical genetic mechanism responsible for the main clinical characteristics of the BDMR syndrome like developmental delay and behavioural abnormalities in combination with brachydactyly type E (BDE). We report here on the first three generation familial case of BDMR syndrome with inheritance of an interstitial microdeletion of chromosome 2q37.3. The deletion was detected by array comparative genomic hybridization and comprises the HDAC4 gene and two other genes. The patients of this pedigree show a variable severity of psychomotor and behavioural abnormalities in combination with a specific facial dysmorphism but without BDE. Given that only about half of the patients with 2q37 deletions have BDE; we compared our patients with other patients carrying 2q37.3 deletions or HDAC4 mutations known from the literature to discuss the diagnostic relevance of the facial dysmorphism pattern in 2q37.3 deletion cases involving the HDAC4 gene. We conclude that HDAC4 haploinsufficiency is responsible for psychomotor and behavioural abnormalities in combination with the BDMR syndrome-specific facial dysmorphism pattern and that these clinical features have a central diagnostic relevance.

/pdf/phenotypic-variant-of-brachydactyly-mental-retardation-32vvb00hcu.pdf

Phenotypic variant of Brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4

Histone deacetylase 4 (HDAC4) serves important roles in multiple human systems, including neurological, cardiac, and skeletal functions. Mutation or deletion of HDAC4 causes brachydactyly mental retardation syndrome (BDMR), a disorder that includes intellectual disability, behavioral abnormalities, autism spectrum disorder, and craniofacial and skeletal anomalies, including brachydactyly type E. We present a case of familial BDMR, including a parent with mild symptoms of the disorder and a child exhibiting a more severe phenotype. Cytogenetic testing showed a cryptic balanced translocation in the mother that resulted in a 2q37.1 monosomy and a 10q26.1 trisomy in the son. Gene expression analyses demonstrated 67% HDAC4 expression in the mother and 23% HDAC4 expression in the son relative to normal controls, lending evidence to the hypothesis that HDAC4 modulates severity of this disorder in a dosage-dependent manner.

Sandrine Reynaud-Perrine

Papers

Dose dependent expression of HDAC4 causes variable expressivity in a novel inherited case of brachydactyly mental retardation syndrome.