The Therapeutic Potential of Epigenome-Modifying Drugs in Cardiometabolic Disease

Berjawi, Marwa; Bell, Christopher G.

doi:10.1007/s40142-021-00198-y

Cited by 1 publication

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“…The epigenome consists of histone modifications as well as DNA modifications. Epigenomic readers, writers and erasers are required to precisely co-ordinate the epigenomic machinery (Figure from Berjawi & Bell [ 55 ]) …”

Section: The Epigenome Is a Co-ordinated Multi-layered Apparatusmentioning

confidence: 99%

“…This applicability of these epigenomic modifiers was made clear through the large-scale cancer sequencing projects that identified that mutations in the epigenomic machinery were frequent, as with developmental orders, with ~ 50% of human cancers possessing mutations in chromatin organisation enzymes [ 303 ]. However, modulation of the epigenome has considerable potential for non-malignant diseases as well, with potential for BETi and HDACi in vascular inflammation and atherosclerosis, respectively [ 55 ]. The wide-ranging therapeutic possibilities of H3K27 demethylase inhibitors involve KDM6A/B inhibition as an anti-inflammatory mechanism for autoimmune and inflammatory disorders, as well as an immunopathological suppressant for infectious pathogens [ 304 ].…”

Section: Therapeutic Modulation Of the Epigenome Through Epidrugsmentioning

confidence: 99%

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Epigenomic insights into common human disease pathology

Bell

2024

Cell. Mol. Life Sci.

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The epigenome—the chemical modifications and chromatin-related packaging of the genome—enables the same genetic template to be activated or repressed in different cellular settings. This multi-layered mechanism facilitates cell-type specific function by setting the local sequence and 3D interactive activity level. Gene transcription is further modulated through the interplay with transcription factors and co-regulators. The human body requires this epigenomic apparatus to be precisely installed throughout development and then adequately maintained during the lifespan. The causal role of the epigenome in human pathology, beyond imprinting disorders and specific tumour suppressor genes, was further brought into the spotlight by large-scale sequencing projects identifying that mutations in epigenomic machinery genes could be critical drivers in both cancer and developmental disorders. Abrogation of this cellular mechanism is providing new molecular insights into pathogenesis. However, deciphering the full breadth and implications of these epigenomic changes remains challenging. Knowledge is accruing regarding disease mechanisms and clinical biomarkers, through pathogenically relevant and surrogate tissue analyses, respectively. Advances include consortia generated cell-type specific reference epigenomes, high-throughput DNA methylome association studies, as well as insights into ageing-related diseases from biological ‘clocks’ constructed by machine learning algorithms. Also, 3rd-generation sequencing is beginning to disentangle the complexity of genetic and DNA modification haplotypes. Cell-free DNA methylation as a cancer biomarker has clear clinical utility and further potential to assess organ damage across many disorders. Finally, molecular understanding of disease aetiology brings with it the opportunity for exact therapeutic alteration of the epigenome through CRISPR-activation or inhibition.

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Section: The Epigenome Is a Co-ordinated Multi-layered Apparatusmentioning

confidence: 99%