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Publications


Image: Royalactin binding of mouse embryonic fibroblasts

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Publications


Image: Royalactin binding of mouse embryonic fibroblasts

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Morgan, Stefanie L, Mariano, Natasha C., Bermudez, Abel, Arruda, Nicole L., Wu, Fangting, Luo, Uynhai, Shankar, Gautam, Jia, Lin, Chen, Huiling, Hu, Ji-Fan, Hoffman, Andrew R., Huang, Chiao-Chain, Pitteri, Sharon J., & Wang, K.C.,  (2017). Manipulation of nuclear architecture through CRISPR-mediated chromosomal looping. Nature Communications; 8:15993. doi: 10.1038.

Chromatin looping is key to gene regulation, yet no broadly applicable methods to selectively modify chromatin loops have been described. We have engineered a method for chromatin loop reorganization using CRISPR-dCas9 (CLOuD9) to selectively and reversibly establish chromatin loops. We demonstrate the power of this technology to selectively modulate gene expression at targeted loci.


Wang, K. C., & Chang, H. Y. (2011). Molecular Mechanisms
of Long Noncoding RNAs.  Molecular Cell, 43(6),
904-914.

Long noncoding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. Here we discuss the emerging archetypes of molecular functions that lncRNAs execute—as signals, decoys, guides, and scaffolds.
For each archetype, examples from several disparate biological contexts illustrate the commonality of the molecular mechanisms,and these mechanistic views provide useful explanations and predictions of biological outcomes. These archetypes of lncRNA function may be a useful framework to consider how lncRNAs acquire properties as biological signal transducers and hint at their possible origins in evolution. As new lncRNAs are being discovered at a rapid pace, the molecular mechanisms of lncRNAs are likely to be enriched and diversified.


Chen, Y., Wan, B., Wang, K.C., Cao, F., Yang, Y., Protacio, A., Dou, Y., Chang, H.Y., Lei, M. (2011). Crystal structure of the N-terminal region of human Ash2L shows a winged-
helix motif involved in DNA binding.  EMBO reports, 12(8), 797-803.

Ash2L is a core component of the MLL family histone methyltransferases and has an important role in regulating the methylation of histone  H3 on lysine 4. Here, we report the crystal structure of the N-terminal domain of Ash2L and reveal a new function of Ash2L. The structure shows that Ash2L contains an atypical PHD finger that does not have histone tail-binding activity. Unexpectedly, the structure shows a previously unrecognized winged-helix motif that directly binds to DNA. The DNA-binding-deficient mutants of Ash2L reduced Ash2L localization to the HOX locus. Strikingly, a single mutation in Ash2LWH (K131A) breaks the chromatin domain boundary, suggesting that Ash2L also has a role in chromosome demarcation. Keywords: Ash2L; histone methyl- transferase; MLL; transcription; winged helix motif.


Wang, K.C., Yang, Y.W., Liu, B., Sanyal, A., Corces-Zimmerman, R., Chen, Y., ... Chang, H.H. (2011). A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature, 472 (7341), 120-126.

The genome is extensively transcribed into long intergenic noncoding RNAs (lincRNAs), many of which are implicated in gene silencing. Potential roles of lincRNAs in gene activation are much less understood. Development and homeostasis require coordinate regulation of neighbouring genes through a process termed locus control. Some locus control elements and enhancers transcribe lincRNAs, hinting at possible roles in long-range control. In vertebrates, 39 Hox genes, encoding homeodomain transcription factors critical for positional identity, are clustered in four chromosomal loci; the Hox genes are expressed in nested anterior-posterior and proximal-distal patterns colinear with their genomic position from 3' to 5'of the cluster. Here we identify HOTTIP, a lincRNA transcribed from the 5' tip of the HOXA locus that coordinates the activation of several 5' HOXA genes in vivo. Chromosomal looping brings HOTTIP into close proximity to its target genes. HOTTIP RNA binds the adaptor protein WDR5 directly and targets WDR5/MLL complexes across HOXA, driving histone H3 lysine 4 trimethylation and gene transcription. Induced proximity is necessary and sufficient for HOTTIP RNA activation of its target genes. Thus, by serving as key intermediates that transmit information from higher order chromosomal looping into chromatin modifications, lincRNAs may organize chromatin domains to coordinate long-range gene activation.


When you’re faced with the necessity to do something, that’s a stimulus to invention.
— Arnold O. Beckman
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Publications


Image: Early embryonic development of Gallus gallus domesticus

Publications


Image: Early embryonic development of Gallus gallus domesticus

Wang, K.C., Kim, J.A., Sivasankaran, R., Segal, R., He, Z. (2002). P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature, 420(6911), 74-8.

In inhibiting neurite outgrowth, several myelin components, including the extracellular domain of Nogo-A (Nogo-66), oligodendrocyte myelin glycoprotein (OMgp) and myelin-associated glycoprotein (MAG), exert their effects through the same Nogo receptor (NgR). The glycosyl phosphatidylinositol (GPI)-anchored nature of NgR indicates the requirement for additional transmembrane protein(s) to transduce the inhibitory signals into the interior of responding neurons. Here, we demonstrate that p75, a transmembrane protein known to be a receptor for the neurotrophin family of growth factors, specifically interacts with NgR. p75 is required for NgR-mediated signalling, as neurons from p75 knockout mice are no longer responsive to myelin and to each of the known NgR ligands. Blocking the p75-NgR interaction also reduces the activities of these inhibitors. Moreover, a truncated p75 protein lacking the intracellular domain, when overexpressed in primary neurons, attenuates the same set of inhibitory activities, suggesting that p75 is a signal transducer of the NgR-p75 receptor complex. Thus, interfering with p75 and its downstream signalling pathways may allow lesioned axons to overcome most of the inhibitory activities associated with central nervous system myelin.


Wang K.C., Koprivica V, Kim JA, Sivasankaran R, Guo Y, Neve RL, He Z. (2002).Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowthNature, 417(6892):941-4.

The inhibitory activity associated with myelin is a major obstacle for successful axon regeneration in the adult mammalian central nervous system (CNS). In addition to myelin-associated glycoprotein (MAG) and Nogo-A, available evidence suggests the existence of additional inhibitors in CNS myelin. We show here that a glycosylphosphatidylinositol (GPI)-anchored CNS myelin protein, oligodendrocyte-myelin glycoprotein (OMgp), is a potent inhibitor of neurite outgrowth in cultured neurons. Like Nogo-A, OMgp contributes significantly to the inhibitory activity associated with CNS myelin. To further elucidate the mechanisms that mediate this inhibitory activity of OMgp, we screened an expression library and identified the Nogo receptor (NgR) as a high-affinity OMgp-binding protein. Cleavage of NgR and other GPI-linked proteins from the cell surface renders axons of dorsal root ganglia insensitive to OMgp. Introduction of exogenous NgR confers OMgp responsiveness to otherwise insensitive neurons. Thus, OMgp is an important inhibitor of neurite outgrowth that acts through NgR and its associated receptor complex. Interfering with the OMgp/NgR pathway may allow lesioned axons to regenerate after injury in vivo.


Image: Mouse embryonic stems cells grown in the absence of leukemia inhibitory factor

Image: Mouse embryonic stems cells grown in the absence of leukemia inhibitory factor