PHF6 Degrees of Separation: The Multifaceted Roles of a Chromatin Adaptor Protein

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.

Keywords: AML; BFLS; NuRD; PAF1; PHF6; T-ALL; XLID; hematopoiesis; neurogenesis; nucleolus.

Figure 1

PHF6 gene and protein domain structures. (A) The PHF6 gene contains 11 exons and is located on the X chromosome. Source: UCSC Genome Browser [21]. (B) The gene encodes a protein of 365 amino acids with two ZaP (zinc knuckle, atypical PHD) domains and localization signals for the nucleus (_*) and nucleolus (••).

Figure 2

PHF6 interacting proteins. PHF6 associates with (A) the NuRD complex via a direct interaction between amino acid residues 162–170 with the β propeller surface of RBBP4; (B) the PAF1 complex; and (C) UBF, via its ZaP1 domain.

Figure 3

Model for the putative CDK2- and PLK1-dependent phosphorylation of PHF6. Large-scale proteomic studies identified PHF6 Ser-145, -154, and -155 as phosphorylated residues. The phosphorylation of these sites during mitosis or in response to T-cell receptor signalling likely occurs through a mechanism whereby (A) CDK2 phosphorylates Ser-155, allowing recognition by the Polo-binding domain (PBD) of PLK1 (B), which subsequently phosphorylates Ser-145, which is situated in a PLK1 consensus sequence (143-EESFNE-148), resulting in PHF6 becoming dually phosphorylated at these two sites (C).

Figure 4

Model for PHF6-dependent transcriptional regulation at developmental or rDNA gene targets. (A) At developmental genes, PHF6 recruits NuRD to promoters to either activate or repress transcription. Similarly, PHF6 can regulate transcriptional elongation at developmental genes through its interaction with the PAF1 complex. (B) Another possible mechanism is that PHF6 interactions with NuRD and PAF1 occur at the same gene whereby PHF6 promotes the formation of a NuRD-PAF1 supercomplex to allow for productive elongation. The existence of a PHF6-mediated supercomplex would be analogous to an IKAROS-driven complex previously described [119]. (C) At rRNA genes, PHF6 interacts with UBF to mediate the initiation of rRNA transcription (left). Promoter regulation may also involve NuRD, although this remains to be shown. Similarly, PHF6-PAF1 may mediate rRNA transcriptional elongation, although experimental validation is still required.