Prostate Cancer Susceptibility in Men of African Ancestry at 8q24.
JNCI Journal of the National Cancer Institute 108(7) (2016)
The 8q24 region harbors multiple risk variants for distinct cancers, including >8 for prostate cancer. In this study, we conducted fine mapping of the 8q24 risk region (127.8-128.8Mb) in search of novel associations with common and rare variation in 4853 prostate cancer case patients and 4678 co...
Enhancers as non-coding RNA transcription units: recent insights and future perspectives.
Nature Reviews: Genetics 17(4):207 (2016)
Networks of regulatory enhancers dictate distinct cell identities and cellular responses to diverse signals by instructing precise spatiotemporal patterns of gene expression. However, 35 years after their discovery, enhancer functions and mechanisms remain incompletely understood. Intriguingly, ...
CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of Syntaxins.
eLife 5 (2016)
Axon injury triggers dramatic changes in gene expression. While transcriptional regulation of injury-induced gene expression is widely studied, less is known about the roles of RNA binding proteins (RBPs) in post-transcriptional regulation during axon regeneration. In C. elegans the CELF (CUGBP ...
Notch-Dependent Pituitary SOX2(+) Stem Cells Exhibit a Timed Functional Extinction in Regulation of the Postnatal Gland.
Stem cell reports 5(6):1196 (2015)
Although SOX2(+) stem cells are present in the postnatal pituitary gland, how they are regulated molecularly and whether they are required for pituitary functions remain unresolved questions. Using a conditional knockout animal model, here we demonstrate that ablation of the canonical Notch sign...
P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma.
Molecular Cell 59(6):931 (2015)
Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age, and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unkno...
LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control.
Nature Neuroscience 18(9):1256 (2015)
We found that a neuron-specific isoform of LSD1, LSD1n, which results from an alternative splicing event, acquires a new substrate specificity, targeting histone H4 Lys20 methylation, both in vitro and in vivo. Selective genetic ablation of LSD1n led to deficits in spatial learning and memory, r...
Condensin I and II Complexes License Full Estrogen Receptor α-Dependent Enhancer Activation.
Molecular Cell 59(2):188 (2015)
Enhancers instruct spatio-temporally specific gene expression in a manner tightly linked to higher-order chromatin architecture. Critical chromatin architectural regulators condensin I and condensin II play non-redundant roles controlling mitotic chromosomes. But the chromosomal locations of con...
Arginine methylation of HSP70 regulates retinoid acid-mediated RARβ2 gene activation.
PNAS 112(26):E3327 (2015)
Although "histone" methyltransferases and demethylases are well established to regulate transcriptional programs and to use nonhistone proteins as substrates, their possible roles in regulation of heat-shock proteins in the nucleus have not been investigated. Here, we report that a highly conser...
An epigenomic role of Fe65 in the cellular response to DNA damage.
Previous findings describe Fe65 as a key protein in the cellular response to genotoxic stress. However, the precise molecular mechanism by which Fe65 contributes to DNA damage signaling remains unclear. In this study, we hypothesized that the transcriptional activity of Fe65 may contribute to DN...
LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation.
Neuron 86(3):696 (2015)
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 ...
Enhancer-bound LDB1 regulates a corticotrope promoter-pausing repression program.
PNAS 112(5):1380 (2015)
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...
Ligand-dependent enhancer activation regulated by topoisomerase-I activity.
Cell 160(3):367 (2015)
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...
Nuclear matrix revisited?
Cell Cycle 14(10):1487 (2015)
Tyrosine phosphorylation of histone H2A by CK2 regulates transcriptional elongation.
Nature 516(7530):267 (2014)
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...
Enhancer activation requires trans-recruitment of a mega transcription factor complex.
Cell 159(2):358 (2014)
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...
Required enhancer-matrin-3 network interactions for a homeodomain transcription program.
Nature 514(7521):257 (2014)
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-...
Neural stem cell differentiation is dictated by distinct actions of nuclear receptor corepressors and histone deacetylases.
Stem cell reports 3(3):502 (2014)
Signaling factors including retinoic acid (RA) and thyroid hormone (T3) promote neuronal, oligodendrocyte, and astrocyte differentiation of cortical neural stem cells (NSCs). However, the functional specificity of transcriptional repressor checkpoints controlling these differentiation programs r...
CtBPs sense microenvironmental oxygen levels to regulate neural stem cell state.
Cell Reports 8(3):665 (2014)
Bone morphogenetic proteins (BMPs) secreted by the dorsal neural tube and overlying ectoderm are key signals for the specification of the roof plate and dorsal interneuron populations. However, the signals that confer nonneurogenic character to the roof plate region are largely unknown. We repor...
GPS2/KDM4A pioneering activity regulates promoter-specific recruitment of PPARγ.
Cell Reports 8(1):163 (2014)
Timely and selective recruitment of transcription factors to their appropriate DNA-binding sites represents a critical step in regulating gene activation; however, the regulatory strategies underlying each factor's effective recruitment to specific promoter and/or enhancer regions are not fully ...
Chem-seq permits identification of genomic targets of drugs against androgen receptor regulation selected by functional phenotypic screens.
PNAS 111(25):9235 (2014)
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...