Domain architecture and protein–protein interactions regulate KDM5A recruitment to the chromatin

Abstract

Tri-methylation of Histone 3 lysine 4 (H3K4) is an important epigenetic modification whose deposition and removal can affect the chromatin at structural and functional levels. KDM5A is one of the four known H3K4-specific demethylases. It is a part of the KDM5 family, which is characterized by a catalytic Jumonji domain capable of removing H3K4 di- and tri-methylation marks. KDM5A has been found to be involved in multiple cellular processes such as differentiation, metabolism, cell cycle, and transcription. Its link to various diseases, including cancer, makes KDM5A an important target for drug development. However, despite several studies outlining its significance in various pathways, our lack of understanding of its recruitment and function at the target sites on the chromatin presents a challenge in creating effective and targeted treatments. Therefore, it is essential to understand the recruitment mechanism of KDM5A to chromatin, and its activity therein, to comprehend how various roles of KDM5A are regulated. In this review, we discuss how KDM5A functions in a context-dependent manner on the chromatin, either directly through its structural domain, or through various interacting partners, to bring about a diverse range of functions.

Mechanism of KDM5A‐mediated H3K4me3 modification in the osteogenic differentiation of mesenchymal stem cells in steroid‐induced osteonecrosis of the femoral head

“…10 As a demethylase targeting H3K4me3 trimethylation, KDM5A plays a pivotal role in modulating chromatin structure and function. 10,11 Recent investigations have implicated KDM5A dysregulation in osteoporosis, with its overexpression linked to detrimental effects on bone health. Conversely, inhibition of KDM5A has been associated with enhanced differentiation and maturation abilities of BMSCs, potentially through epigenetic upregulation of key osteogenic regulators such as runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and osteopontin (OPN).…”

“…Lysine‐specific demethylase 5A (KDM5A) serves as a crucial epigenetic regulator influencing diverse cellular processes, including cell differentiation, metabolism, and transcription 10 . As a demethylase targeting H3K4me3 trimethylation, KDM5A plays a pivotal role in modulating chromatin structure and function 10,11 . Recent investigations have implicated KDM5A dysregulation in osteoporosis, with its overexpression linked to detrimental effects on bone health.…”