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Molecular and Cellular Basis of Chromatinopathies

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Special Issue Editor

Special Issue Information

Dear Colleagues,

The regulation of the chromatin state by epigenetic mechanisms plays a central role in gene expression, cell function, and the maintenance of cell identity. Chromatinopathies are a large group of Mendelian disorders caused by genetic alterations of the various components of the epigenetic machinery. Although most chromatinopathies are characterized by intellectual and neurological dysfunctions and a constellation of ancillary findings and/or facial dysmorphic features, the clinical and molecular overlap among them is being increasingly described as an expected result of convergent pathogenesis.

Studies of model organisms and patients’ cells have demonstrated dosage sensitivity of the causing genes with haploinsufficiency as the predominant disease mechanism. Experimental evidence has shown that chromatinopathies’ genes disrupt both the chromatin and transcription states of target genes downstream and also modify the DNA methylation on a global scale.

Finally, many therapies targeting epigenetic marks already exist. Therefore, along with the observation that neurological dysfunction in these disorders may be treatable in postnatal life, it can be suggested that chromatinopathies are potentially curable.

This Special Issue on chromatinoapthies aims to highlight the current knowledge on relevant pathogenetic mechanisms of chromatinopathies as well as therapeutic prospects for this very particular and well-defined group of disorders. Reviews and original research articles are welcome in this regard.

Dr. Giuseppe Merla
Guest Editor

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Published Papers (1 paper)

Research

19 pages, 3863 KiB

Open AccessArticle

Loss of Function of the Gene Encoding the Histone Methyltransferase KMT2D Leads to Deregulation of Mitochondrial Respiration

by Consiglia Pacelli, Iolanda Adipietro, Natascia Malerba, Gabriella Maria Squeo, Claudia Piccoli, Angela Amoresano, Gabriella Pinto, Pietro Pucci, Ji-Eun Lee, Kai Ge, Nazzareno Capitanio and Giuseppe Merla

Cells 2020, 9(7), 1685; https://doi.org/10.3390/cells9071685 - 13 Jul 2020

Cited by 9 | Viewed by 5609

Abstract

KMT2D encodes a methyltransferase responsible for histone 3 lysine 4 (H3K4) mono-/di-methylation, an epigenetic mark correlated with active transcription. Here, we tested the hypothesis that KMT2D pathogenic loss-of-function variants, which causes the Kabuki syndrome type 1, could affect the mitochondrial metabolic profile. By using Seahorse technology, we showed a significant reduction of the mitochondrial oxygen consumption rate as well as a reduction of the glycolytic flux in both Kmt2d knockout MEFs and skin fibroblasts of Kabuki patients harboring heterozygous KMT2D pathogenic variants. Mass-spectrometry analysis of intermediate metabolites confirmed alterations in the glycolytic and TCA cycle pathways. The observed metabolic phenotype was accompanied by a significant increase in the production of reactive oxygen species. Measurements of the specific activities of the mitochondrial respiratory chain complexes revealed significant inhibition of CI (NADH dehydrogenase) and CIV (cytochrome c oxidase); this result was further supported by a decrease in the protein content of both complexes. Finally, we unveiled an impaired oxidation of glucose and larger reliance on long-chain fatty acids oxidation. Altogether, our findings clearly indicate a rewiring of the mitochondrial metabolic phenotype in the KMT2D-null or loss-of-function context that might contribute to the development of Kabuki disease, and represents metabolic reprogramming as a potential new therapeutic approach. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis of Chromatinopathies)

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