Handpicking epigenetic marks with PHD fingers

Abstract

Plant homeodomain (PHD) fingers have emerged as one of the largest families of epigenetic effectors capable of recognizing or 'reading' post-translational histone modifications and unmodified histone tails. These interactions are highly specific and can be modulated by the neighboring epigenetic marks and adjacent effectors. A few PHD fingers have recently been found to also associate with non-histone proteins. In this review, we detail the molecular mechanisms and biological outcomes of the histone and non-histone targeting by PHD fingers. We discuss the significance of crosstalk between the histone modifications and consequences of combinatorial readout for selective recruitment of the PHD finger-containing components of chromatin remodeling and transcriptional complexes.

Figure 1.

PHD fingers as epigenetic effectors. (a) Histone-recognizing PHD fingers are commonly found in enzymes (left) and proteins that stabilize enzymatic complexes at chromatin (right) to further modify DNA and histones. (b–d) The specificity of a PHD finger can be increased by (b) sensitivity to multiple PTMs, (c) combinatorial readout by multiple effectors in the same protein and (d) combinatorial action of multiple effectors in different subunits of a complex. The effectors could recognize PTMs on a single histone tail (cis mechanism) or different histone tails (trans mechanism).

Figure 2.

The molecular mechanism of histone recognition by the PHD fingers. PHD fingers are specific for (a) H3K4me3 or (b) unmodified H3K4. The histone-binding sites of the BPTF (2F6J), ING2 (2G6Q), BHC80 (2PUY) and AIRE (2KE1) PHD fingers are shown. The binding pockets for Ala1, Arg2, Lys4me3 (or Lys4) and Lys9 of the H3K4me3 and H3K4 peptides are colored light blue, orange, pink and light green, respectively. The bound peptides are shown as a ribbon diagram and colored green. (c) Binding of the PHD fingers to H3K4me3 and H3K4 is modulated by additional PTMs. The structures of the PHD fingers of RAG2 (2V87), TAF3 (2K17), CHD4 (2L75) and DPF3 (2KWJ) are colored as in (a and b). PTMs that enhance or inhibit recognition of the primary PTM are listed and colored red and blue, respectively. An aspartate residue in the aromatic cage of TAF3 and the Lys14ac-binding pocket of DPF3 are colored wheat and yellow, respectively.

Figure 3.

The structural basis of non-histone recognition by PHD fingers. (a) The ternary complex of the PHD finger of PYGO1 (2VPG). (b) The PHD finger of MLL1 binds to H3K4me3 (3LQJ) and the RRM domain of Cyp33 (2KU7).

Figure 4.

The biological outcome of the recognition of histone or non-histone proteins by a PHD finger depends on the function of the complex in which the PHD finger resides and the local regulatory environment.