1. LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation.

    Neuron 86(3):696 (2015) PMID 25892301 PMCID PMC4486257

    One of the exceptional properties of the brain is its ability to acquire new knowledge through learning and to store that information through memory. The epigenetic mechanisms linking changes in neuronal transcriptional programs to behavioral plasticity remain largely unknown. Here, we identify ...
  2. Enhancer-bound LDB1 regulates a corticotrope promoter-pausing repression program.

    PNAS 112(5):1380 (2015) PMID 25605944 PMCID PMC4321301

    Substantial evidence supports the hypothesis that enhancers are critical regulators of cell-type determination, orchestrating both positive and negative transcriptional programs; however, the basic mechanisms by which enhancers orchestrate interactions with cognate promoters during activation an...
  3. Ligand-dependent enhancer activation regulated by topoisomerase-I activity.

    Cell 160(3):367 (2015) PMID 25619691 PMCID PMC4422651

    The discovery that enhancers are regulated transcription units, encoding eRNAs, has raised new questions about the mechanisms of their activation. Here, we report an unexpected molecular mechanism that underlies ligand-dependent enhancer activation, based on DNA nicking to relieve torsional stre...
  4. Tyrosine phosphorylation of histone H2A by CK2 regulates transcriptional elongation.

    Nature 516(7530):267 (2014) PMID 25252977 PMCID PMC4461219

    Post-translational histone modifications have a critical role in regulating transcription, the cell cycle, DNA replication and DNA damage repair. The identification of new histone modifications critical for transcriptional regulation at initiation, elongation or termination is of particular inte...
  5. Enhancer activation requires trans-recruitment of a mega transcription factor complex.

    Cell 159(2):358 (2014) PMID 25303530 PMCID PMC4465761

    Enhancers provide critical information directing cell-type-specific transcriptional programs, regulated by binding of signal-dependent transcription factors and their associated cofactors. Here, we report that the most strongly activated estrogen (E2)-responsive enhancers are characterized by tr...
  6. Required enhancer-matrin-3 network interactions for a homeodomain transcription program.

    Nature 514(7521):257 (2014) PMID 25119036 PMCID PMC4358797

    Homeodomain proteins, described 30 years ago, exert essential roles in development as regulators of target gene expression; however, the molecular mechanisms underlying transcriptional activity of homeodomain factors remain poorly understood. Here investigation of a developmentally required POU-...
  7. Chem-seq permits identification of genomic targets of drugs against androgen receptor regulation selected by functional phenotypic screens.

    PNAS 111(25):9235 (2014) PMID 24928520 PMCID PMC4078819

    Understanding the mechanisms by which compounds discovered using cell-based phenotypic screening strategies might exert their effects would be highly augmented by new approaches exploring their potential interactions with the genome. For example, altered androgen receptor (AR) transcriptional pr...
  8. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs.

    Nature 500(7464):598 (2013) PMID 23945587 PMCID PMC4034386

    Although recent studies have indicated roles of long non-coding RNAs (lncRNAs) in physiological aspects of cell-type determination and tissue homeostasis, their potential involvement in regulated gene transcription programs remains rather poorly understood. The androgen receptor regulates a larg...
  9. DICER- and AGO3-dependent generation of retinoic acid-induced DR2 Alu RNAs regulates human stem cell proliferation.

    Nature Structural & Molecular Biology 19(11):1168 (2012) PMID 23064648 PMCID PMC3743530

    Although liganded nuclear receptors have been established to regulate RNA polymerase II (Pol II)-dependent transcription units, their role in regulating Pol III-transcribed DNA repeats remains largely unknown. Here we report that ~2-3% of the ~100,000-200,000 total human DR2 Alu repeats located ...
  10. A protective strategy against hyperinflammatory responses requiring the nontranscriptional actions of GPS2.

    Molecular Cell 46(1):91 (2012) PMID 22424771 PMCID PMC3327812

    The association between hyperinflammatory states and numerous diseases is widely recognized, but our understanding of the molecular strategies that have evolved to prevent uncontrolled activation of inflammatory responses remains incomplete. Here, we report a critical, nontranscriptional role of...
  11. ncRNA- and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs.

    Cell 147(4):773 (2011) PMID 22078878 PMCID PMC3297197

    Although eukaryotic nuclei contain distinct architectural structures associated with noncoding RNAs (ncRNAs), their potential relationship to regulated transcriptional programs remains poorly understood. Here, we report that methylation/demethylation of Polycomb 2 protein (Pc2) controls relocati...
  12. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA.

    Nature 474(7351):390 (2011) PMID 21572438 PMCID PMC3117022

    Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell-type-specific gene expression programs, but how those enhancers are exploited to institute alternative, signal-dependent transcriptional responses remains poorly understood. Here we present evidence...
  13. PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression.

    Nature 466(7305):508 (2010) PMID 20622854 PMCID PMC3059551

    While reversible histone modifications are linked to an ever-expanding range of biological functions, the demethylases for histone H4 lysine 20 and their potential regulatory roles remain unknown. Here we report that the PHD and Jumonji C (JmjC) domain-containing protein, PHF8, while using multi...
  14. Enhancing nuclear receptor-induced transcription requires nuclear motor and LSD1-dependent gene networking in interchromatin granules.

    PNAS 105(49):19199 (2008) PMID 19052240

    Although the role of liganded nuclear receptors in mediating coactivator/corepressor exchange is well-established, little is known about the potential regulation of chromosomal organization in the 3-dimensional space of the nucleus in achieving integrated transcriptional responses to diverse sig...
  15. Nuclear receptor-enhanced transcription requires motor- and LSD1-dependent gene networking in interchromatin granules.

    Cell 134(1):189 (2008) PMID 18630350

  16. TBL1 and TBLR1 phosphorylation on regulated gene promoters overcomes dual CtBP and NCoR/SMRT transcriptional repression checkpoints.

    Molecular Cell 29(6):755 (2008) PMID 18374649 PMCID PMC2364611

    A key strategy to achieve regulated gene expression in higher eukaryotes is to prevent illegitimate signal-independent activation by imposing robust control on the dismissal of corepressors. Here, we report that many signaling pathways, including Notch, NF-kappaB, and nuclear receptor ligands, a...
  17. Nuclear receptor-enhanced transcription requires motor- and LSD1-dependent gene networking in interchromatin granules.

    Cell 132(6):996 (2008) PMID 18358812

    While the transcriptional machinery has been extensively dissected at the molecular level, little is known about regulation of chromosomal organization in the three-dimensional space of the nucleus to achieve integrated transcriptional responses to diverse signaling events. Here, we report that ...
  18. Histone H2A monoubiquitination represses transcription by inhibiting RNA polymerase II transcriptional elongation.

    Molecular Cell 29(1):69 (2008) PMID 18206970 PMCID PMC2327256

    Solving the biological roles of covalent histone modifications, including monoubiquitination of histone H2A, and the molecular mechanisms by which these modifications regulate specific transcriptional programs remains a central question for all eukaryotes. Here we report that the N-CoR/HDAC1/3 c...
  19. A histone H2A deubiquitinase complex coordinating histone acetylation and H1 dissociation in transcriptional regulation.

    Molecular Cell 27(4):609 (2007) PMID 17707232 PMCID PMC2709280

    Deciphering the epigenetic "code" remains a central issue in transcriptional regulation. Here, we report the identification of a JAMM/MPN(+) domain-containing histone H2A deubiquitinase (2A-DUB, or KIAA1915/MYSM1) specific for monoubiquitinated H2A (uH2A) that has permitted delineation of a stra...
  20. Developmentally regulated activation of a SINE B2 repeat as a domain boundary in organogenesis.

    Science 317(5835):248 (2007) PMID 17626886

    The temporal and spatial regulation of gene expression in mammalian development is linked to the establishment of functional chromatin domains. Here, we report that tissue-specific transcription of a retrotransposon repeat in the murine growth hormone locus is required for gene activation. This ...