The recent discovery of H3K27me3 demethylases suggests that H3K27me3 may dynamically regulate gene expression, but this potential role in mammalian tissue homeostasis remains uncharacterized. In the epidermis, a tissue that balances stem cell self-renewal with differentiation, H3K27me3, occupies the promoters of many differentiation genes. During calcium-induced differentiation, H3K27me3 was erased at these promoters in concert with loss of PcG protein occupancy and increased binding by the H3K27me3 demethylase, JMJD3. Within epidermal tissue, JMJD3 depletion blocked differentiation, while active JMJD3 dominantly induced it. These results indicate that epigenetic derepression by JMJD3 controls mammalian epidermal differentiation.Supplemental material is available at http://www.genesdev.org.Received March 12, 2008; revised version accepted May 22, 2008. Post-translational modifications of core histone octamer proteins, in the form of phosphorylation, acetylation, ubiquitination, and methylation, have been increasingly appreciated as powerful regulators of gene expression. In Drosophila and mammals, the histone 3 Lys 27 trimethylation mark (H3K27me3) is associated with repression of gene transcription (Lund and van Lohuizen 2004;Barski et al. 2007). Polycomb group proteins (PcG) and their antagonists, the histone demethylases, are epigenetic regulators that control gene expression by modifying the methylation status of H3K27 (Grimaud et al. 2006;Swigut and Wysocka 2007). The PcG protein, Enhancer of Zest Homolog 2 (EZH2), is a histone methyltransferase that can trimethylate H3K27. Two other PcG proteins, Embryonic Ectoderm Development (EED) and Suppressor of Zeste 12 homolog (SUZ12), are necessary for EZH2 to function properly (Pasini et al. 2004). Genome-wide mapping of H3K27me3 marks and PcG target sites in embryonic stem cells has recently suggested a major role for PcG proteins in maintaining H3K27me3 to allow for repression of the differentiated state and promotion of embryonic stem cell self-renewal, with significant enrichment of these proteins on genes encoding homeodomain proteins and other putative differentiation factors Lee et al. 2006). The mechanism reversing such potential repressive influences on differentiation gene expression by H3K27me3 and other histone modifications in somatic tissue is not fully characterized.Among potential mediators of differentiation gene derepression are newly characterized Jumanji C (JmjC) domain-containing proteins, UTX and JMJD3, which are enzymes capable of demethylating promoters marked by H3K27me3. Recently, the H3K27 demethylase activity of UTX and JMJD3 has been shown to act at HOX gene promoters to derepress HOX gene transcription (Agger et al. 2007;Lan et al. 2007;Lee et al. 2007). These histone demethylases were demonstrated in mammalian cells and in live zebrafish to antagonize PcG gene silencing by modifying chromatin to permit gene transcription. During inflammation, bacterial products and cytokines induce JMJD3, which then removes H3K27me3 marks to dere...

A B S T R A C T PurposeTo determine the prevalence and type of BRCA1 and BRCA2 (BRCA) mutations among Hispanics in the Southwestern United States and their potential impact on genetic cancer risk assessment (GCRA). Patients and MethodsHispanics (n ϭ 746) with a personal or family history of breast and/or ovarian cancer were enrolled in an institutional review board-approved registry and received GCRA and BRCA testing within a consortium of 14 clinics. Population-based Hispanic breast cancer cases (n ϭ 492) enrolled in the Northern California Breast Cancer Family Registry, negative by sequencing for BRCA mutations, were analyzed for the presence of the BRCA1 ex9-12del large rearrangement. ResultsDeleterious BRCA mutations were detected in 189 (25%) of 746 familial clinic patients (124 BRCA1, 65 BRCA2); 21 (11%) of 189 were large rearrangement mutations, of which 62% (13 of 21) were BRCA1 ex9-12del. Nine recurrent mutations accounted for 53% of the total. Among these, BRCA1 ex9-12del seems to be a Mexican founder mutation and represents 10% to 12% of all BRCA1 mutations in clinic-and population-based cohorts in the United States. ConclusionBRCA mutations were prevalent in the largest study of Hispanic breast and/or ovarian cancer families in the United States to date, and a significant proportion were large rearrangement mutations. The high frequency of large rearrangement mutations warrants screening in every case. We document the first Mexican founder mutation (BRCA1 ex9-12del), which, along with other recurrent mutations, suggests the potential for a cost-effective panel approach to ancestry-informed GCRA.