Chromatin Alterations in Neurological Disorders and Strategies of (Epi)Genome Rescue

Abstract

Neurological disorders (NDs) comprise a heterogeneous group of conditions that affect the function of the nervous system. Often incurable, NDs have profound and detrimental consequences on the affected individuals’ lives. NDs have complex etiologies but commonly feature altered gene expression and dysfunctions of the essential chromatin-modifying factors. Hence, compounds that target DNA and histone modification pathways, the so-called epidrugs, constitute promising tools to treat NDs. Yet, targeting the entire epigenome might reveal insufficient to modify a chosen gene expression or even unnecessary and detrimental to the patients’ health. New technologies hold a promise to expand the clinical toolkit in the fight against NDs. (Epi)genome engineering using designer nucleases, including CRISPR-Cas9 and TALENs, can potentially help restore the correct gene expression patterns by targeting a defined gene or pathway, both genetically and epigenetically, with minimal off-target activity. Here, we review the implication of epigenetic machinery in NDs. We outline syndromes caused by mutations in chromatin-modifying enzymes and discuss the functional consequences of mutations in regulatory DNA in NDs. We review the approaches that allow modifying the (epi)genome, including tools based on TALENs and CRISPR-Cas9 technologies, and we highlight how these new strategies could potentially change clinical practices in the treatment of NDs.

Intellectual disability: A potentially treatable condition

“…HDAC inhibitors are best known as a novel category of anti-cancer drugs, but they have also been used in several clinical trials in patients with adult-onset neurodegeneration, providing lessons that may be applicable in children with MDCMs. 36 A potential limitation of HDAC inhibitors is that because they are non-targeted, they may have undesirable off target effects. 37 MPSII -Limitations of Enzyme Therapies, Transplantation and Gene Therapy MPSII (Hunter syndrome) is an X-linked disorder caused by pathogenic variants in the gene IDS, which encodes the enzyme iduronate 2-sulfatase.…”

“…Another potential treatment mechanism for Arboleda‐Tham syndrome and other disorders with impaired histone acetylation is to reduce the removal of acetyl groups from histones, using a class of drugs called as histone deacetylase (HDAC) inhibitors. HDAC inhibitors are best known as a novel category of anti‐cancer drugs, but they have also been used in several clinical trials in patients with adult‐onset neurodegeneration, providing lessons that may be applicable in children with MDCMs 36 . A potential limitation of HDAC inhibitors is that because they are non‐targeted, they may have undesirable off target effects 37 …”

CTCF shapes chromatin structure and gene expression in health and disease

“…In humans, mutations in chromatin‐related factors often manifest themselves with neurological syndromes including intellectual impediments (Janowski et al , 2021). Patients with a heterozygous, four base pair deletion in the 5' end of the coding sequence of CTCF display developmental delay, intellectual disability and microcephaly (MIM#615502).…”

Introduction

“…Research on epidrugs for other conditions is also prolific. Recent projects have aimed at targeting conditions such as COVID-19 (Zannella et al, 2021), hypercholesterolaemia (Paez et al, 2020), neurodegenerative diseases (Janowski et al, 2021), autoimmune diseases such as chronic kidney disease (Tejedor-Santamaria et al, 2022), and depression (Tsankova et al, 2007).…”