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The Prdm family: expanding roles in stem cells and development.
Members of the Prdm family are characterized by an N-terminal PR domain that is related to the SET methyltransferase domain, and multiple zinc fingers that mediate sequence-specific DNA binding and protein-protein interactions. Prdm factors either act as direct histone methyltransferases or recruit a suite of histone-modifying enzymes to target promoters. In this way, they function in many developmental contexts to drive and maintain cell state transitions and to modify the activity of developmental signalling pathways. Here, we provide an overview of the structure and function of Prdm family members and discuss the roles played by these proteins in stem cells and throughout development.
Prdm family domain structure and relationships. (A) The domain structure for each human Prdm family member is illustrated, along with the relationships between their positive regulatory (PR) domains. Only the longest reported isoform is shown. Orange lines highlight the Prdms conserved in C. elegans and Drosophila; a putative Prdm9 without zinc fingers has been reported in C. elegans. Prdm11 alone does not contain zinc fingers; instead, it has a smaller protein-protein interaction motif known as a zinc knuckle that is also present in several other family members (Briknarova et al., 2008). Protein features marked with asterisks are derived from UniProt. (B) An example of cross-species conservation of Prdm structure. The orthologues of mouse Prdm3, Drosophila Hamlet and C. elegans EGL-43, are shown. Zinc fingers with high sequence similarity between the homologues are shown in the same colour, and the positions and sequences of shared CtBP-binding sites are also shown. AWS, associated with SET domain; CtBP, C-terminal binding protein; KRAB, Krüppel-associated box; Rb, retinoblastoma; SSX, synovial sarcoma X. (C) Sequence alignment of the SET domains of Drosophila Suppressor of variegation 3-9, Enhancer of zeste and Trithorax factors with the PR domains of the murine Prdm family founding factors Prdm1 and Prdm2, and with Prdm3 and its Drosophila and C. elegans homologues Hamlet and EGL-43 (made using JalView and ClustalW2 default parameters) (Waterhouse et al., 2009). Red boxes indicate motifs present in most PR domains but absent in most SET domains that can be used for discrimination. Blocks a to c indicate regions containing highly conserved amino acid sequences (Huang, 2002). The orange box denotes the H/RxxNHxC motif that is exclusive to SET domains and has been associated with intrinsic enzyme activity (Rea et al., 2000). Crucial cysteine residues within this motif are indicated with purple boxes. Dashed red boxes indicate conserved residues between the vertebrate Prdm factors and the Prdm3 homologues Drosophila Hamlet and C. elegans EGL-43.
Prdm1 regulates photoreceptor development. Chx10-positive progenitors give rise to both photoreceptors and bipolar cells. Daughters that maintain Chx10 become bipolar cells, whereas those that downregulate Chx10 become photoreceptors. In nascent photoreceptors, a pulse of Prdm1 expression keeps Chx10 repressed. Loss of Prdm1 leads to re-expression of Chx10 in the nascent photoreceptors and they re-specify as Chx10-positive bipolar- or progenitor-like cells. Subsequently, many of these cells undergo apoptosis.
Prdm16 promotes brown fat and represses white fat cell fate. (A) Myf5-positive precursors give rise to both skeletal muscle (myocytes) and brown adipose tissue (BAT). Prdm16 induces the formation of brown preadipocytes, and continued Prdm16 expression drives BAT differentiation. Loss of Prdm16 from the preadipocytes causes loss of BAT gene expression with accompanying induction of myocyte gene expression and morphological differentiation. (B) Prdm16 (blue) associates with C/EBPβ (CCAAT/enhancer-binding protein β; green) to promote the formation of a brown preadipocyte. Among the genes induced by Prdm16 are Pparg (peroxisome-proliferator-activated receptor γ; yellow) and Ppargc1a (PPARγ co-activator 1α; grey). These factors then associate with Prdm16 and other factors to promote full BAT maturation. Simultaneously, Prdm16 recruits CtBP (C-terminal-binding protein; pink) and acts as a repressor at a number of WAT (white adipose tissue) gene loci. Rxr, retinoid X receptor; Tf, additional unidentified transcription factors that may be involved in Prdm1b targeting.
Hamlet controls mechanosensory cell differentiation. The four cells of the Drosophila external sensory organ derive from a single precursor. The external cells – the hair and socket cells – are determined by a binary Notch (N) signalling event. The internal cells – the external sensory (ES) neuron and glial cells – are similarly determined. Hamlet expression initiates in the IIIB cell (orange), which is the precursor of ES neurons and glia. Its expression continues during IIIB division and is then downregulated in nascent internal cells. Loss of hamlet (red arrows) does not prevent initial expression of neural and glial cell markers. However, during differentiation, the cells lose these markers and re-specify as hair and socket cells. Remarkably, during these transformations, the internal cells re-specify to the opposite identity of that normally specified by N in the external cells.
Prdm interactions with signalling pathways. (A) Hamlet (Ham; light blue) modulates the Notch response at the Enhancer of split m3 [E(Spl)m3] promoter. In Ham-positive cells, a Ham/CtBP (C-terminal-binding protein; pink) complex suppresses H3K4 and enhances H3K27 trimethylation at E(Spl)m3. This correlates with an increased histone density at the Suppressor of Hairless (SuH)-binding site and reduced accessibility of the transcription activator complex to the promoter, thus preventing E(Spl)m3 induction. NICD, Notch intracellular domain (green); Mam, mastermind [NICD/Su(H)/Mam activator complex in green and orange]. (B) A Prdm2/p300 (Prdm2 in light blue; p300 in grey) complex modulates oestrogen receptor (ER; dark blue) signalling at the pS2 promoter. In the absence of oestrogen, the pS2 promoter is silenced by the endogenous H3K9 methyltransefase activity of Prdm2. Upon ER activation and translocation to the nucleus, the Prdm2/p300 complex associates with the ER, leading to a change whereby the histone acetylation activity of p300 now promotes transcriptional activation.