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PRDF1 and RIZ1 homology domain containing (PRDMs) are a subfamily of Krüppel-like zinc finger proteins controlling key processes in metazoan development and in cancer. PRDMs exhibit unique dualities: (a) PR domain/ZNF arrays—their structure combines a SET-like domain known as a PR domain, typically found in methyltransferases, with a variable array of C2H2 zinc fingers (ZNF) characteristic of DNA-binding transcription factors; (b) transcriptional activators/repressors—their physiological function is context- and cell-dependent; mechanistically, some PRDMs have a PKMT activity and directly catalyze histone lysine methylation, while others are rather pseudomethyltransferases and act by recruiting transcriptional cofactors; (c) oncogenes/tumor suppressors—their pathological function depends on the specific PRDM isoform expressed during tumorigenesis. This duality is well known as the ‘Yin and Yang’ of PRDMs and involves a complex regulation of alternative splicing or alternative promoter usage, to generate full-length or PR-deficient isoforms with opposing functions in cancer. In conclusion, once their dualities are fully appreciated, PRDMs represent a promising class of targets in oncology by virtue of their widespread upregulation across multiple tumor types and their somatic dispensability, conferring a broad therapeutic window and limited toxic side effects. The recent discovery of a first-in-class compound able to inhibit PRDM9 activity has paved the way for the identification of further small molecular inhibitors able to counteract PRDM oncogenic activity.

Background Galloway-Mowat syndrome (GAMOS) is characterized by neurodevelopmental defects and a progressive nephropathy, which typically manifests as steroid-resistant nephrotic syndrome. The prognosis of GAMOS is poor, and the majority of children progress to renal failure. The discovery of monogenic causes of GAMOS has uncovered molecular pathways involved in the pathogenesis of disease. Methods Homozygosity mapping, whole-exome sequencing, and linkage analysis were used to identify mutations in four families with a GAMOS-like phenotype, and high-throughput PCR technology was applied to 91 individuals with GAMOS and 816 individuals with isolated nephrotic syndrome. In vitro and in vivo studies determined the functional significance of the mutations identified. Results Three biallelic variants of the transcriptional regulator PRDM15 were detected in six families with proteinuric kidney disease. Four families with a variant in the protein's zinc-finger (ZNF) domain have additional GAMOS-like features, including brain anomalies, cardiac defects, and skeletal defects. All variants destabilize the PRDM15 protein, and the ZNF variant additionally interferes with transcriptional activation. Morpholino oligonucleotide-mediated knockdown of Prdm15 in Xenopus embryos disrupted pronephric development. Human wild-type PRDM15 RNA rescued the disruption, but the three PRDM15 variants did not. Finally, CRISPR-mediated knockout of PRDM15 in human podocytes led to dysregulation of several renal developmental genes. Conclusions Variants in PRDM15 can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis. PRDM15 regulates multiple developmental kidney genes, and is likely to play an essential role in renal development in humans.

PRDM (PRDI-BF1 and RIZ homology domain containing) family members are sequence-specific transcriptional regulators involved in cell identity and fate determination, often dysregulated in cancer. The PRDM15 gene is of particular interest, given its low expression in adult tissues and its overexpression in B-cell lymphomas. Despite its well characterized role in stem cell biology and during early development, the role of PRDM15 in cancer remains obscure. Herein, we demonstrate that while PRDM15 is largely dispensable for mouse adult somatic cell homeostasis in vivo, it plays a critical role in B-cell lymphomagenesis. Mechanistically, PRDM15 regulates a transcriptional program that sustains the activity of the PI3K/AKT/mTOR pathway and glycolysis in B-cell lymphomas. Abrogation of PRDM15 induces a metabolic crisis and selective death of lymphoma cells. Collectively, our data demonstrate that PRDM15 fuels the metabolic requirement of B-cell lymphomas and validate it as an attractive and previously unrecognized target in oncology., The transcriptional regulator PRDM15 is expressed at low levels in normal tissues but overexpressed in B-cell lymphomas. Here, the authors show that PRDM15 depletion does not affect adult somatic cell homeostasis but leads to a metabolic crisis which impairs B-cell lymphomagenesis.

Protein arginine methylation is an abundant post-translational modification involved in the modulation of essential cellular processes ranging from transcription, post-transcriptional RNA metabolism, and propagation of signaling cascades to the regulation of the DNA damage response. Excitingly for the field, in the past few years there have been remarkable advances in the development of molecular tools and clinical compounds able to selectively and potently inhibit protein arginine methyltransferase (PRMT) functions. In this review, we first discuss how the somatic mutations that confer advantages to cancer cells are often associated with vulnerabilities that can be exploited by PRMTs' inhibition. In a second part, we discuss strategies to uncover synthetic lethal combinations between existing therapies and PRMT inhibitors.

Triple-negative (TN) breast cancer are characterized by lack of estrogen receptor (OR) and progesterone receptor (PR) expression, and the absence of overexpression of human epidermal growth factor receptor 2 (HER2). It is a heterogeneous group of tumors with a more pejorative prognosis than other subtypes of breast cancer. Androgen receptors (AR) are nuclear receptors whose expression varies from 80 to 85% of primary breast cancers and 60 to 75% of metastatic cancers. Among the TN breast cancers, the luminal androgen receptor (LAR) subtype expresses AR more frequently, up to 53% of the cases. AR are associated with lower tumor size, histological grade, Ki67, and lymph node involvement. The results of recent clinical trials evaluating anti-androgen therapies in locally advanced or metastatic TN breast cancer are promising. Many new therapies are tested, including enzalutamide or abiraterone acetate, and numerous therapeutic combinations including PI3K/AKT/mTOR inhibitors or CDK inhibitors. These therapies would allow an alternative treatment of patients with TN breast cancer for which there is often a therapeutic impasse.

Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer.

Global epigenetic reprogramming is vital to purge germ cell-specific epigenetic features to establish the totipotent state of the embryo. This process transpires to be carefully regulated and is not an undirected, radical erasure of parental epigenomes. The TRIM28 complex has been shown to be crucial in embryonic epigenetic reprogramming by regionally opposing DNA demethylation to preserve vital parental information to be inherited from germline to soma. Yet the DNA-binding factors guiding this complex to specific targets are largely unknown. Here, we uncover and characterize a novel, maternally expressed, TRIM28-interacting KRAB zinc-finger protein: ZFP708. It recruits the repressive TRIM28 complex to RMER19B retrotransposons to evoke regional heterochromatin formation. ZFP708 binding to these hitherto unknown TRIM28 targets is DNA methylation and H3K9me3 independent. ZFP708 mutant mice are viable and fertile, yet embryos fail to inherit and maintain DNA methylation at ZFP708 target sites. This can result in activation of RMER19B-adjacent genes, while ectopic expression of ZFP708 results in transcriptional repression. Finally, we describe the evolutionary conservation of ZFP708 in mice and rats, which is linked to the conserved presence of the targeted RMER19B retrotransposons in these species., Summary: Analysis of the function and targets of a maternal KRAB-zinc-finger protein, ZFP708, found to specifically mediate maintenance of DNA methylation at a subset of LTR retrotransposons during embryonic epigenetic reprogramming.