Abstract
The importance of chromatin regulation to human disease is highlighted by the growing number of mutations identified in genes encoding chromatin remodeling proteins. While such mutations were first identified in severe developmental disorders, or in specific cancers, several genes have been implicated in both, including the plant homeodomain finger protein 6 (PHF6) gene. Indeed, germline mutations in PHF6 are the cause of the Börjeson–Forssman–Lehmann X-linked intellectual disability syndrome (BFLS), while somatic PHF6 mutations have been identified in T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Studies from different groups over the last few years have made a significant impact towards a functional understanding of PHF6 protein function. In this review, we summarize the current knowledge of PHF6 with particular emphasis on how it interfaces with a distinct set of interacting partners and its functional roles in the nucleoplasm and nucleolus. Overall, PHF6 is emerging as a key chromatin adaptor protein critical to the regulation of neurogenesis and hematopoiesis.
Highlights
Mutations in proteins that chemically modify chromatin, or possess reader domains to bind these modifications are documented in a growing number of developmental diseases [1]
PZP motifs consist of a PHD domain, followed by a zinc knuckle, followed by an atypical PHD domain, each zinc finger domain of PHF6 is a degenerate version of this structure as they consist only of the zinc knuckle and the atypical PHD (ZaP) [14]
The role of PHF6 was categorized based on its homology with chromatin remodelling proteins, several recent studies have shed an early light upon how its molecular responsibilities may contribute to the developmental processes of neurogenesis and hematopoiesis; activities that become compromised during development and/or in cancer
Summary
Mutations in proteins that chemically modify chromatin, or possess reader domains to bind these modifications are documented in a growing number of developmental diseases [1]. The high-throughput screening of various cancer genomes using next-generation screening technologies (e.g., Roche/454, Illumina/Solexa) has yielded mutations in many of these same epigenetic regulators [2,3,4] These mutations target genes encoding proteins that are responsible for ATP-dependent nucleosome reorganization (e.g., ATRX), histone tail modifiers (e.g., JARID1C), histone variants (e.g., histone H3.3), DNA methyltransferases (e.g., DNMT3A/B), and proteins that interface with chromatin (e.g., MECP2) [4,5,6,7,8]. We review recent advances in a gene that encodes another such protein, plant homeodomain finger protein 6 (PHF6), which possesses two chromatin-binding zinc finger domains and has been implicated in the Börjeson–Forssman–Lehmann X-linked intellectual disability syndrome (BFLS), T-cell acute lymphoblastic leukemia (T-ALL), and acute myeloid leukemia (AML) [9,10,11]
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