TY  - JOUR
AB  - Background Pharmacologic inhibition of bromodomain and extra-terminal (BET) proteins is currently being explored as a new therapeutic approach in cancer. Some studies have also implicated BET proteins as regulators of cell identity and differentiation through their interactions with lineage-specific factors. However, the role of BET proteins has not yet been investigated in melanocyte differentiation. Melanocyte inducing transcription factor (MITF) is the master regulator of melanocyte differentiation, essential for pigmentation and melanocyte survival. In this study, we tested the hypothesis that BET proteins regulate melanocyte differentiation through interactions with MITF. Results Here we show that chemical inhibition of BET proteins prevents differentiation of unpigmented melanoblasts into pigmented melanocytes and results in de-pigmentation of differentiated melanocytes. BET inhibition also slowed cell growth, without causing cell death, increasing the number of cells in G1. Transcriptional profiling revealed that BET inhibition resulted in decreased expression of pigment-specific genes, including many MITF targets. The expression of pigment-specific genes was also down-regulated in melanoma cells, but to a lesser extent. We found that RNAi depletion of the BET family members, bromodomain-containing protein 4 (BRD4) and bromodomain-containing protein 2 (BRD2) inhibited expression of two melanin synthesis enzymes, TYR and TYRP1. Both BRD4 and BRD2 were detected on melanocyte promoters surrounding MITF-binding sites, were associated with open chromatin structure, and promoted MITF binding to these sites. Furthermore, BRD4 and BRD2 physically interacted with MITF. Conclusion These findings indicate a requirement for BET proteins in the regulation of pigmentation and melanocyte differentiation. We identified changes in pigmentation specific gene expression that occur upon BET inhibition in melanoblasts, melanocytes, and melanoma cells.
AU  - Trivedi, A.*
AU  - Mehrotra, A.*
AU  - Baum, C.E.*
AU  - Lewis, B.*
AU  - Basuroy, T.*
AU  - Blomquist, T.*
AU  - Trumbly, R.*
AU  - Filipp, F.V.
AU  - Setaluri, V.*
AU  - de la Serna, I.L.*
C1  - 58550
C2  - 48215
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Bromodomain and extra-terminal domain (BET) proteins regulate melanocyte differentiation.
JO  - Epigenetics Chromatin
VL  - 13
IS  - 1
PB  - Bmc
PY  - 2020
ER  - 

TY  - JOUR
AB  - Background: Genetic data are known to harbor information about human demographics, and genotyping data are commonly used for capturing ancestry information by leveraging genome-wide differences between populations. In contrast, it is not clear to what extent population structure is captured by whole-genome DNA methylation data. Results: We demonstrate, using three large-cohort 450K methylation array data sets, that ancestry information signal is mirrored in genome-wide DNA methylation data and that it can be further isolated more effectively by leveraging the correlation structure of CpGs with cis-located SNPs. Based on these insights, we propose a method, EPISTRUCTURE, for the inference of ancestry from methylation data, without the need for genotype data. Conclusions: EPISTRUCTURE can be used to infer ancestry information of individuals based on their methylation data in the absence of corresponding genetic data. Although genetic data are often collected in epigenetic studies of large cohorts, these are typically not made publicly available, making the application of EPISTRUCTURE especially useful for anyone working on public data. Implementation of EPISTRUCTURE is available in GLINT, our recently released toolset for DNA methylation analysis at: http://glint-epigenetics.readthedocs.io.
AU  - Rahmani, E.*
AU  - Shenhav, L.*
AU  - Schweiger, R.*
AU  - Yousefi, P.*
AU  - Huen, K.*
AU  - Eskenazi, B.*
AU  - Eng, C.*
AU  - Huntsman, S.*
AU  - Hu, D.*
AU  - Galanter, J.*
AU  - Oh, S.S.*
AU  - Waldenberger, M.
AU  - Strauch, K.
AU  - Grallert, H.
AU  - Meitinger, T.
AU  - Gieger, C.
AU  - Holland, N.*
AU  - Burchard, E.G.*
AU  - Zaitlen, N.*
AU  - Halperin, E.*
C1  - 50453
C2  - 42272
CY  - London
TI  - Genome-wide methylation data mirror ancestry information.
JO  - Epigenetics Chromatin
VL  - 10
PB  - Biomed Central Ltd
PY  - 2017
ER  - 

TY  - JOUR
AB  - Background: Disease risk and incidence between males and females reveal differences, and sex is an important component of any investigation of the determinants of phenotypes or disease etiology. Further striking differences between men and women are known, for instance, at the metabolic level. The extent to which men and women vary at the level of the epigenome, however, is not well documented. DNA methylation is the best known epigenetic mechanism to date. Results: In order to shed light on epigenetic differences, we compared autosomal DNA methylation levels between men and women in blood in a large prospective European cohort of 1799 subjects, and replicated our findings in three independent European cohorts. We identified and validated 1184 CpG sites to be differentially methylated between men and women and observed that these CpG sites were distributed across all autosomes. We showed that some of the differentially methylated loci also exhibit differential gene expression between men and women. Finally, we found that the differentially methylated loci are enriched among imprinted genes, and that their genomic location in the genome is concentrated in CpG island shores. Conclusion: Our epigenome-wide association study indicates that differences between men and women are so substantial that they should be considered in design and analyses of future studies.
AU  - Singmann, P.
AU  - Shem-Tov, D.*
AU  - Wahl, S.
AU  - Grallert, H.
AU  - Fiorito, G.*
AU  - Shin, S.Y.*
AU  - Schramm, K.
AU  - Wolf, P.
AU  - Kunze, S.
AU  - Baran, Y.*
AU  - Guarrera, S.*
AU  - Vineis, P.*
AU  - Krogh, V.*
AU  - Panico, S.*
AU  - Tumino, R.*
AU  - Kretschmer, A.
AU  - Gieger, C.
AU  - Peters, A.
AU  - Prokisch, H.
AU  - Relton, C.L.*
AU  - Matullo, G.*
AU  - Illig, T.
AU  - Waldenberger, M.
AU  - Halperin, E.*
C1  - 47130
C2  - 39144
TI  - Characterization of whole-genome autosomal differences of DNA methylation between men and women.
JO  - Epigenetics Chromatin
VL  - 8
IS  - 1
PY  - 2015
ER  -