Epigenetic Regulation and Neurodevelopmental Disorders: From MeCP2 to the TCF20/PHF14 Complex

Abstract

Background: Neurodevelopmental disorders (NDDs) affect approximately 15% of children and adolescents worldwide. This group of disorders is often polygenic with varying risk factors, with many associated genes converging on shared molecular pathways, including chromatin regulation and transcriptional control. Understanding how NDD-associated chromatin regulators and protein complexes orchestrate these regulatory pathways is crucial for elucidating NDD pathogenesis and developing targeted therapeutic strategies. Recently, the TCF20/PHF14 chromatin complex was identified in the mammalian brain, expanding the list of chromatin regulatory remodelers implicated in NDDs. This complex-which includes MeCP2, RAI1, TCF20, PHF14, and HMG20A-plays a vital role in epigenetic and transcriptional regulation.

Methods: We review and summarize current research and clinical reports pertaining to the different components of the MeCP2-interacting TCF20/PHF14 complex. We examine the NDDs associated with the TCF20/PHF14 complex, explore the molecular and neuronal functions of its components, and discuss emerging therapeutic strategies targeting this complex to mitigate symptoms, with broader applicability to other NDDs.

Results: Mutations in the genes encoding the components of the MeCP2-interacting TCF20/PHF14 complex have been linked to various NDDs, underscoring its critical contribution to brain development and NDD pathogenesis.

Conclusions: The MeCP2-interacting TCF20/PHF14 complex and its associated NDDs could serve as a model system to provide insight into the interplay between epigenetic regulation and NDD pathogenesis.

Keywords: HMG20A; MeCP2; PHF14; RAI1; Rett syndrome; TCF20; chromatin regulators; neurodevelopmental disorders; neuronal activity; transcription.

Figure 1

Structural features of the MeCP2-interacting TCF20/PHF14 protein complex, its components, and the known interactions between them. The MeCP2-interacting TCF20/PHF14 protein complex (A) and their known interaction (B). This figure illustrates the interactions between the components of TCF20/PHF14 protein complex based on biochemical data. The complex is hypothesized to modulate shared downstream targets as depicted in (A). Blue arrows denote interactions where the domains between proteins have been mapped. Orange arrows pointing from protein domains to a protein name indicate that the interaction between the protein domains has not been fully established. N’: N-protein terminus; C’: C-protein terminus; IDR: intrinsically disordered domain; HMG: high-mobility group; CC: coiled-coil domain; MBD: methyl-CpG-binding domain; ID: intervening domain; TRD: transcriptional repression domain; PHD: plant homeodomain; TAD: transactivation domain; P1: PEST1 domain; DBD: DNA-binding domain; NBD: nucleosome-binding domain.