Kevin C. Wang, M.D., Ph.D., is an Assistant Professor of Dermatology, former director of the inpatient dermatology consult service at Stanford, and Attending Physician at the Palo Alto VA. He is a Faculty Member in the Program in Epithelial Biology, Bio-X, and Cancer Biology Ph.D. Program, and his research focuses on epigenetic mechanisms of gene regulation in stem cells, development, and cancer. His clinical interests include complex adult medical dermatology, pruritus, neuropathic dermatoses, and inpatient dermatology.
- Pruritus (Itching)
- Complex Medical Dermatology
- Neuropathic/Neurogenic Dermatosis
- Inpatient Dermatology
Fellowship: Stanford University Hospital and Clinics - Dermatology Department (2010) CA
Board Certification: American Board of Dermatology, Dermatology (2009)
Residency: UCSF (2009) CA
Internship: Brigham and Women's Hospital Harvard Medical School (2006) MA
Medical Education: UCSF (2005) CA
Professional Education: Harvard Medical School (2003) MA
Current Research and Scholarly Interests
The Wang lab takes an interdisciplinary approach to studying fundamental mechanisms controlling gene expression in mammalian cells, and how epigenetic mechanisms such as DNA methylation, chromatin modifications, and RNA influence chromatin dynamics to affect gene regulation.
Independent Studies (9)
- Directed Reading in Cancer Biology
CBIO 299 (Win, Spr)
- Directed Reading in Dermatology
DERM 299 (Aut, Win, Spr)
- Early Clinical Experience in Dermatology
DERM 280 (Aut, Win, Spr, Sum)
- Graduate Research
CBIO 399 (Aut, Win, Spr, Sum)
- Graduate Research
DERM 399 (Win, Spr)
- Medical Scholars Research
DERM 370 (Aut, Win, Spr)
- Out-of-Department Undergraduate Research
BIO 199X (Spr)
- Teaching in Cancer Biology
CBIO 260 (Spr)
- Undergraduate Research
DERM 199 (Aut, Win, Spr, Sum)
- Directed Reading in Cancer Biology
Graduate and Fellowship Programs
Integrative single-cell analysis of cardiogenesis identifies developmental trajectories and non-coding mutations in congenital heart disease.
2022; 185 (26): 4937
To define the multi-cellular epigenomic and transcriptional landscape of cardiac cellular development, we generated single-cell chromatin accessibility maps of human fetal heart tissues. We identified eight major differentiation trajectories involving primary cardiac cell types, each associated with dynamic transcription factor (TF) activity signatures. We contrasted regulatory landscapes of iPSC-derived cardiac cell types and their invivo counterparts, which enabled optimization of invitro differentiation of epicardial cells. Further, we interpreted sequence based deep learning models of cell-type-resolved chromatin accessibility profiles to decipher underlying TF motif lexicons. De novo mutations predicted to affect chromatin accessibility in arterial endothelium were enriched in congenital heart disease (CHD) cases vs. controls. Invitro studies in iPSCs validated the functional impact of identified variation on the predicted developmental cell types. This work thus defines the cell-type-resolved cis-regulatory sequence determinants of heart development and identifies disruption of cell type-specific regulatory elements in CHD.
View details for DOI 10.1016/j.cell.2022.11.028
View details for PubMedID 36563664
The spectrum of oligogenic variants in the RAS pathway in a PHACE cohort
ELSEVIER SCIENCE INC. 2022: S81
View details for Web of Science ID 000829693001036
- Modeling Effects of Immunosuppressive Drugs on Human Hearts Using Induced Pluripotent Stem Cell-Derived Cardiac Organoids and Single-Cell RNA Sequencing. Circulation 2022; 145 (17): 1367-1369
CLOuD9: CRISPR-Cas9-Mediated Technique for Reversible Manipulation of Chromatin Architecture.
Methods in molecular biology (Clifton, N.J.)
2022; 2532: 293-309
The spatial organization of the genome plays a critical role in cell-specific biological functions such as gene expression. Existing genome-wide technologies reveal a dynamic interplay between chromatin looping and gene regulation, but the mechanisms by which regulatory interactions between genetic elements are established or maintained remain unclear. Here, we present CLOuD9, a CRISPR-based technology that can create de novo, pairwise chromatin interactions in cells. This technique for chromatin loop reorganization employs dCas9-targeting and ABI1-PYL heterodimerization. It is reversible, but can also establish epigenetic memory under certain conditions, which provides a way to dissect gene regulation mechanisms.
View details for DOI 10.1007/978-1-0716-2497-5_14
View details for PubMedID 35867255
Clinical trial in a dish using iPSCs shows lovastatin improves endothelial dysfunction and cellular cross-talk in LMNA cardiomyopathy.
Science translational medicine
2020; 12 (554)
Mutations in LMNA, the gene that encodes lamin A and C, causes LMNA-related dilated cardiomyopathy (DCM) or cardiolaminopathy. LMNA is expressed in endothelial cells (ECs); however, little is known about the EC-specific phenotype of LMNA-related DCM. Here, we studied a family affected by DCM due to a frameshift variant in LMNA Human induced pluripotent stem cell (iPSC)-derived ECs were generated from patients with LMNA-related DCM and phenotypically characterized. Patients with LMNA-related DCM exhibited clinical endothelial dysfunction, and their iPSC-ECs showed decreased functionality as seen by impaired angiogenesis and nitric oxide (NO) production. Moreover, genome-edited isogenic iPSC lines recapitulated the EC disease phenotype in which LMNA-corrected iPSC-ECs showed restoration of EC function. Simultaneous profiling of chromatin accessibility and gene expression dynamics by combining assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing (RNA-seq) as well as loss-of-function studies identified Kruppel-like factor 2 (KLF2) as a potential transcription factor responsible for the EC dysfunction. Gain-of-function studies showed that treatment of LMNA iPSC-ECs with KLF2 agonists, including lovastatin, rescued the EC dysfunction. Patients with LMNA-related DCM treated with lovastatin showed improvements in clinical endothelial dysfunction as indicated by increased reactive hyperemia index. Furthermore, iPSC-derived cardiomyocytes (iPSC-CMs) from patients exhibiting the DCM phenotype showed improvement in CM function when cocultured with iPSC-ECs and lovastatin. These results suggest that impaired cross-talk between ECs and CMs can contribute to the pathogenesis of LMNA-related DCM, and statin may be an effective therapy for vascular dysfunction in patients with cardiolaminopathy.
View details for DOI 10.1126/scitranslmed.aax9276
View details for PubMedID 32727917
The antifibrotic adipose-derived stromal cell: Grafted fat enriched with CD74+ adipose-derived stromal cells reduces chronic radiation-induced skin fibrosis.
Stem cells translational medicine
Fat grafting can reduce radiation-induced fibrosis. Improved outcomes are found when fat grafts are enriched with adipose-derived stromal cells (ASCs), implicating ASCs as key drivers of soft tissue regeneration. We have identified a subpopulation of ASCs positive for CD74 with enhanced antifibrotic effects. Compared to CD74- and unsorted (US) ASCs, CD74+ ASCs have increased expression of hepatocyte growth factor, fibroblast growth factor 2, and transforming growth factor β3 (TGF-β3) and decreased levels of TGF-β1. Dermal fibroblasts incubated with conditioned media from CD74+ ASCs produced less collagen upon stimulation, compared to fibroblasts incubated with media from CD74- or US ASCs. Upon transplantation, fat grafts enriched with CD74+ ASCs reduced the stiffness, dermal thickness, and collagen content of overlying skin, and decreased the relative proportions of more fibrotic dermal fibroblasts. Improvements in several extracellular matrix components were also appreciated on immunofluorescent staining. Together these findings indicate CD74+ ASCs have antifibrotic qualities and may play an important role in future strategies to address fibrotic remodeling following radiation-induced fibrosis.
View details for DOI 10.1002/sctm.19-0317
View details for PubMedID 32563212
Multivalent chromatin looping orchestrates cellular reprogramming for advanced gene therapy
ELSEVIER SCIENCE INC. 2019: S63
View details for Web of Science ID 000465561503082
Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments.
Accumulation of trimethylation of histone H3 at lysine 4 (H3K4me3) on immune-related gene promoters underlies robust transcription during trained immunity. However, the molecular basis for this remains unknown. Here we show three-dimensional chromatin topology enables immune genes to engage in chromosomal contacts with a subset of long noncoding RNAs (lncRNAs) we have defined as immune gene-priming lncRNAs (IPLs). We show that the prototypical IPL, UMLILO, acts in cis to direct the WD repeat-containing protein 5 (WDR5)-mixed lineage leukemia protein 1 (MLL1) complex across the chemokine promoters, facilitating their H3K4me3 epigenetic priming. This mechanism is shared amongst several trained immune genes. Training mediated by beta-glucan epigenetically reprograms immune genes by upregulating IPLs in manner dependent on nuclear factor of activated T cells. The murine chemokine topologically associating domain lacks an IPL, and the Cxcl genes are not trained. Strikingly, the insertion of UMLILO into the chemokine topologically associating domain in mouse macrophages resulted in training of Cxcl genes. This provides strong evidence that lncRNA-mediated regulation is central to the establishment of trained immunity.
View details for PubMedID 30531872
Honey bee Royalactin unlocks conserved pluripotency pathway in mammals.
2018; 9 (1): 5078
Royal jelly is the queen-maker for the honey bee Apis mellifera, and has cross-species effects on longevity, fertility, and regeneration in mammals. Despite this knowledge, how royal jelly or its components exert their myriad effects has remained poorly understood. Using mouse embryonic stem cells as a platform, here we report that through its major protein component Royalactin, royal jelly can maintain pluripotency by activating a ground-state pluripotency-like gene network. We further identify Regina, a mammalian structural analog of Royalactin that also induces a naive-like state in mouse embryonic stem cells. This reveals an important innate program for stem cell self-renewal with broad implications in understanding the molecular regulation of stem cell fate across species.
View details for PubMedID 30510260
CRISPR-Mediated Reorganization of Chromatin Loop Structure.
Journal of visualized experiments : JoVE
Recent studies have clearly shown that long-range, three-dimensional chromatin looping interactions play a significant role in the regulation of gene expression, but whether looping is responsible for or a result of alterations in gene expression is still unknown. Until recently, how chromatin looping affects the regulation of gene activity and cellular function has been relatively ambiguous, and limitations in existing methods to manipulate these structures prevented in-depth exploration of these interactions. To resolve this uncertainty, we engineered a method for selective and reversible chromatin loop re-organization using CRISPR-dCas9 (CLOuD9). The dynamism of the CLOuD9 system has been demonstrated by successful localization of CLOuD9 constructs to target genomic loci to modulate local chromatin conformation. Importantly, the ability to reverse the induced contact and restore the endogenous chromatin conformation has also been confirmed. Modulation of gene expression with this method establishes the capacity to regulate cellular gene expression and underscores the great potential for applications of this technology in creating stable de novo chromatin loops that markedly affect gene expression in the contexts of cancer and development.
View details for PubMedID 30272647
Epigenomics: Technologies and Applications.
2018; 122 (9): 1191–99
The advent of high-throughput epigenome mapping technologies has ushered in a new era of multiomics where powerful tools can now delineate and record different layers of genomic output. Integrating various components of the epigenome from these multiomics measurements allows the interrogation of cellular heterogeneity in addition to the discovery of molecular connectivity maps between the genome and its functional output. Mapping of chromatin accessibility dynamics and higher-order chromatin structure has enabled new levels of understanding of cell fate decisions, identity, and function in normal development, physiology, and disease. We provide a perspective on the progress of the epigenomics field and applications and anticipate an even greater revolution in our understanding of the human epigenome for years to come.
View details for PubMedID 29700067
Noncoding RNAs in Wound Healing: A New and Vast Frontier
ADVANCES IN WOUND CARE
2018; 7 (1): 19–27
Significance: Wound healing requires a highly orchestrated coordination of processes that are not yet fully understood. Therefore, available clinical therapies are thus far limited in their efficacy in preventing and treating both chronic wounds and scars. Current gene-based therapeutics is largely based on our understanding of the protein-coding genome and proteins involved in known wound healing pathways. Recent Advances: Noncoding RNAs such as microRNAs and long noncoding RNAs have recently been found to be significant modulators of gene expression in diverse cellular pathways. Research has now implicated noncoding RNAs in nearly every stage of the wound healing process, suggesting that they may serve as clinical therapeutic targets. Noncoding RNAs are critical regulators in processes such as angiogenesis and cutaneous cell migration and proliferation, including classically described biological pathways previously attributed to mostly protein constituents. Critical Issues: The complexity and diversity of the interactions of noncoding RNAs with their targets and other binding partners require thorough characterization and understanding of their functions before they may be altered to modulate human wound healing pathways. Future Directions: Research in the area of noncoding RNAs continues to rapidly expand our understanding of their potential roles in physiological and pathological wound healing. Coupled with improving technologies to enhance or suppress target noncoding RNA in vivo, these advances hold great promise in the development of new therapies for wound healing.
View details for PubMedID 29344431
View details for PubMedCentralID PMC5770091
- Long Noncoding RNA and Its Role in the Control of Gene Expression in the Skin EPIGENETIC REGULATION OF SKIN DEVELOPMENT AND REGENERATION 2018: 197–213
Transcription coactivator and lncRNA duet evoke Hox genes
2017; 13 (6): e1006797
View details for PubMedID 28662057
Manipulation of nuclear architecture through CRISPR-mediated chromosomal looping.
2017; 8: 15993
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.
View details for PubMedID 28703221
PICSAR: Long Noncoding RNA in Cutaneous Squamous Cell Carcinoma.
journal of investigative dermatology
2016; 136 (8): 1541-1542
It is increasingly evident that long noncoding RNAs may play the roles of both oncogenes and tumor suppressors during cancer development. A new study from Piipponen et al. provides evidence that a long noncoding RNA, PICSAR, promotes cutaneous squamous cell carcinoma development through activation of extracellular signal-regulated kinase signaling. Because specific inhibition of PICSAR suppresses tumor growth, this long noncoding RNA may serve as a useful diagnostic marker and therapeutic target for cutaneous squamous cell carcinoma.
View details for DOI 10.1016/j.jid.2016.04.013
View details for PubMedID 27450499
Factors That May Promote an Effective Local Research Environment
JOURNAL OF INVESTIGATIVE DERMATOLOGY
2016; 136 (8): 1529–31
View details for PubMedID 27450496
- Cutaneous Neonatal Lupus Arising in an Infant Conceived From an Oocyte Donation Pregnancy JAMA DERMATOLOGY 2016; 152 (7): 846-847
The Phenotypic Effects of Royal Jelly on Wild-Type D. melanogaster Are Strain-Specific.
2016; 11 (8)
The role for royal jelly (RJ) in promoting caste differentiation of honeybee larvae into queens rather than workers is well characterized. A recent study demonstrated that this poorly understood complex nutrition drives strikingly similar phenotypic effects in Drosophila melanogaster, such as increased body size and reduced developmental time, making possible the use of D. melanogaster as a model system for the genetic analysis of the cellular mechanisms underlying RJ and caste differentiation. We demonstrate here that RJ increases the body size of some wild-type strains of D. melanogaster but not others, and report significant delays in developmental time in all flies reared on RJ. These findings suggest that cryptic genetic variation may be a factor in the D. melanogaster response to RJ, and should be considered when attempting to elucidate response mechanisms to environmental changes in non-honeybee species.
View details for DOI 10.1371/journal.pone.0159456
View details for PubMedID 27486863
View details for PubMedCentralID PMC4972316
Generalized benign cutaneous reaction to cytarabine
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
2015; 73 (5): 821-828
Cytarabine-induced toxicity manifests as various cutaneous morphologies. A generalized papular purpuric eruption has not been well described.We aimed to characterize a distinct cytarabine-related eruption.We reviewed all cases of cytarabine-related toxicity with papular purpuric eruptions or violaceous erythema at the University of California, San Francisco between 2006 and 2011.Sixteen cases were identified. The eruption began as erythematous papules that evolved into coalescing purpuric papules and plaques. It had affinity for intertriginous areas, neck, ears, and scalp. Pruritus was common, but no systemic complications were documented. Thirteen patients (81.3%) developed the eruption after completion of chemotherapy. Differential diagnosis often included viral exanthem (62.5%), drug eruption (50%), and vasculitis (37.5%). Histopathology was nonspecific but commonly demonstrated sparse lymphocytic infiltrates, spongiosis, and/or red cell extravasation. Importantly, the eruption was neither predicted by past cytarabine exposure nor predictive of future recurrence.This is a review of cases from a single institution. Observation was limited to acute hospitalization, however, charts were reviewed for subsequent reactions on rechallenge.The eruption described herein represents a specific skin-limited reaction to cytarabine. Awareness of its characteristic morphology, distribution, and timeline will aid in clinical diagnosis. Reassurance concerning its benign nature will prevent unnecessary intervention or cessation of chemotherapy.
View details for DOI 10.1016/j.jaad.2015.07.010
View details for Web of Science ID 000363271400024
View details for PubMedID 26321388
RNA Sequencing for Identification of Differentially Expressed Noncoding Transcripts during Adipogenic Differentiation of Adipose-Derived Stromal Cells.
Plastic and reconstructive surgery
2015; 136 (4): 752-763
Adipose-derived stromal cells represent a relatively abundant source of multipotent cells, with many potential applications in regenerative medicine. The present study sought to demonstrate the use of RNA sequencing in identifying differentially expressed transcripts, particularly long noncoding RNAs, associated with adipogenic differentiation to gain a clearer picture of the mechanisms responsible for directing adipose-derived stromal cell fate toward the adipogenic lineage.Human adipose-derived stromal cells were cultured in adipogenic differentiation media, and RNA was harvested at days 0, 1, 3, 5, and 7. Directional RNA sequencing libraries were prepared and sequenced. Paired-end reads were mapped to the human genome reference sequence hg19. Transcriptome assembly was performed and significantly differentially expressed transcripts were identified. Gene ontology term analysis was then performed to identify coding and noncoding transcripts of interest. Differential expression was verified by quantitative real-time polymerase chain reaction.Of 2868 significantly differentially expressed transcripts identified, 207 were noncoding. Enriched gene ontology terms among up-regulated coding transcripts notably reflected differentiation toward the adipogenic lineage. Enriched gene ontology terms among down-regulated coding transcripts reflected growth arrest. Guilt-by-association analysis revealed noncoding RNA candidates with potential roles in the process of adipogenic differentiation.The precise mechanisms that guide lineage-specific differentiation in multipotent cells are not yet fully understood. Defining long noncoding RNAs associated with adipogenic differentiation allows for potential manipulation of regulatory pathways in novel ways. The authors present RNA sequencing as a powerful tool for expanding the understanding of adipose-derived stromal cells and developing novel applications within regenerative medicine.
View details for DOI 10.1097/PRS.0000000000001582
View details for PubMedID 26090763
A fibrous papule with abundant CD34-immunoreactive ganglion-like multinucleated giant cells: a case report and review of the literature.
Dermatology online journal
2015; 21 (7)
Fibrous papules present clinically as benign, asymptomatic, dome-shaped, flesh colored papules on the face. Histologically, fibrous papules are characterized by fibrous stroma with fibroblasts and dilated blood vessels. Multiple variants of fibrous papules have been reported. Although scattered multinucleated cells in fibrous papules have been well described, we report a fibrous papule with abundant multinucleated ganglion-like giant cells that were immunoreactive with CD34. Recognition of such fibrous papule variants is important to avoid misdiagnosis as potentially more worrisome and/or aggressive melanocytic, soft tissue, or neural lesions that may require more aggressive treatment. Indeed, fibrous papules do not commonly appear on the differential diagnosis for lesions with multinucleated giant cells or ganglion-like cells and consideration should be given to their inclusion in the appropriate clinical setting.
View details for PubMedID 26436978
Long noncoding RNA: significance and potential in skin biology.
Cold Spring Harbor perspectives in medicine
2014; 4 (5)
Over the past few years, advances in genome analyses have identified an emerging class of noncoding RNAs that play critical roles in the regulation of gene expression and epigenetic reprogramming. Given their transcriptional pervasiveness, the potential for these intriguing macromolecules to integrate a myriad of external cellular cues with nuclear responses has become increasingly apparent. Recent studies have implicated noncoding RNAs in epidermal development and keratinocyte differentiation, but the complexity of multilevel regulation of transcriptional programs involved in these processes remains ill defined. In this review, we discuss the relevance of noncoding RNA in normal skin development, their involvement in cutaneous malignancies, and their role in the regulation of adult stem-cell maintenance in stratified epithelial tissues. Furthermore, we provide additional examples highlighting the ubiquity of noncoding RNAs in diverse human diseases.
View details for DOI 10.1101/cshperspect.a015404
View details for PubMedID 24789873
- Abstract 158: Identification of BMP-Responsive Long Noncoding RNAs in Pluripotent Cells. Plastic and reconstructive surgery 2014; 133 (3): 174-?
Essential role of lncRNA binding for WDR5 maintenance of active chromatin and embryonic stem cell pluripotency.
The WDR5 subunit of the MLL complex enforces active chromatin and can bind RNA; the relationship between these two activities is unclear. Here we identify a RNA binding pocket on WDR5, and discover a WDR5 mutant (F266A) that selectively abrogates RNA binding without affecting MLL complex assembly or catalytic activity. Complementation in ESCs shows that WDR5 F266A mutant is unable to accumulate on chromatin, and is defective in gene activation, maintenance of histone H3 lysine 4 trimethylation, and ESC self renewal. We identify a family of ESC messenger and lncRNAs that interact with wild type WDR5 but not F266A mutant, including several lncRNAs known to be important for ESC gene expression. These results suggest that specific RNAs are integral inputs into the WDR5-MLL complex for maintenance of the active chromatin state and embryonic stem cell fates. DOI: http://dx.doi.org/10.7554/eLife.02046.001.
View details for DOI 10.7554/eLife.02046
View details for PubMedID 24521543
- Training the Contemporary Surgeon-Scientist PLASTIC AND RECONSTRUCTIVE SURGERY 2012; 129 (4): 1023-1025
Molecular Mechanisms of Long Noncoding RNAs
2011; 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.
View details for DOI 10.1016/j.molcel.2011.08.018
View details for PubMedID 21925379
Crystal structure of the N-terminal region of human Ash2L shows a winged-helix motif involved in DNA binding
2011; 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 Ash2L(WH) (K131A) breaks the chromatin domain boundary, suggesting that Ash2L also has a role in chromosome demarcation.
View details for DOI 10.1038/embor.2011.101
View details for Web of Science ID 000293326500014
View details for PubMedID 21660059
View details for PubMedCentralID PMC3147254
A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression
2011; 472 (7341): 120-U158
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.
View details for DOI 10.1038/nature09819
View details for PubMedID 21423168
- Neurogenic Rosacea: A Distinct Clinical Subtype Requiring a Modified Approach to Treatment ARCHIVES OF DERMATOLOGY 2011; 147 (1): 123-126
Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis
2010; 464 (7291): 1071-U148
Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumours and metastases, and HOTAIR expression level in primary tumours is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb repressive complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
View details for DOI 10.1038/nature08975
View details for Web of Science ID 000276635000045
View details for PubMedID 20393566
View details for PubMedCentralID PMC3049919
Regeneration, repair and remembering identity: the three Rs of Hox gene expression
TRENDS IN CELL BIOLOGY
2009; 19 (6): 268-275
Hox genes encode transcription factors that specify embryonic positional identity in cells and guide tissue differentiation. Recent advances have greatly increased our understanding of the epigenetic mechanisms that ensure the faithful expression of Hox genes in adult cells and which involve the interplay of histone methylation, demethylation and intergenic transcription of long non-coding RNAs. The transcriptional memory of Hox genes poses both an opportunity and a challenge for regenerative medicine. Matching the positional identity of transplanted stem cells with that of the host environment, as reflected by their respective Hox profiles, is likely to be required to achieve regenerative healing. Strategies to manipulate the plasticity of Hox gene expression will probably become a major focus in regenerative medicine.
View details for DOI 10.1016/j.tcb.2009.03.007
View details for PubMedID 19428253
Recent advances in acne vulgaris research: insights and clinical implications.
Advances in dermatology
2008; 24: 197-209
Understanding of acne vulgaris has taken major steps forward over the past few years. The renewed interest in the effect of dietary interventions on acne, the elucidation of the involvement of TLR and MMPs in acne pathogenesis, and a more detailed functional understanding of various treatment modalities at the molecular level are all promising indications that advances in therapeutics are sure to follow. Health utilities will serve not only as powerful outcome measures of treatment effects but also as clinical decision-making aids in everyday practice. It is hoped that future advances will further uncover additional molecular and cellular details of pathophysiology, leading to rational targeted design of medications, and advance clinical management through improved understanding of the psychosocial impact of acne on patients.
View details for PubMedID 19256310
Images in clinical medicine. Koplik's spots.
New England journal of medicine
2006; 354 (7): 740-?
View details for PubMedID 16481641
PKC mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration
2004; 7 (3): 261-268
Successful axon regeneration in the mammalian central nervous system (CNS) is at least partially compromised due to the inhibitors associated with myelin and glial scar. However, the intracellular signaling mechanisms underlying these inhibitory activities are largely unknown. Here we provide biochemical and functional evidence that conventional isoforms of protein kinase C (PKC) are key components in the signaling pathways that mediate the inhibitory activities of myelin components and chondroitin sulfate proteoglycans (CSPGs), the major class of inhibitors in the glial scar. Both the myelin inhibitors and CSPGs induce PKC activation. Blocking PKC activity pharmacologically and genetically attenuates the ability of CNS myelin and CSPGs to activate Rho and inhibit neurite outgrowth. Intrathecal infusion of a PKC inhibitor, Gö6976, into the site of dorsal hemisection promotes regeneration of dorsal column axons across and beyond the lesion site in adult rats. Thus, perturbing PKC activity could represent a therapeutic approach to stimulating axon regeneration after brain and spinal cord injuries.
View details for DOI 10.1038/nn1193
View details for Web of Science ID 000189197900016
View details for PubMedID 14770187
Structure of the Nogo receptor ectodomain: A recognition module implicated in myelin inhibition
2003; 38 (2): 177-185
Failure of axon regeneration in the adult mammalian central nervous system (CNS) is at least partly due to inhibitory molecules associated with myelin. Recent studies suggest that an axon surface protein, the Nogo receptor (NgR), may play a role in this process through an unprecedented degree of crossreactivity with myelin-associated inhibitory ligands. Here, we report the 1.5 A crystal structure and functional characterization of a soluble extracellular domain of the human Nogo receptor. Nogo receptor adopts a leucine-rich repeat (LRR) module whose concave exterior surface contains a broad region of evolutionarily conserved patches of aromatic residues, possibly suggestive of degenerate ligand binding sites. A deep cleft at the C-terminal base of the LRR may play a role in NgR association with the p75 coreceptor. These results now provide a detailed framework for focused structure-function studies aimed at assessing the physiological relevance of NgR-mediated protein-protein interactions to axon regeneration inhibition.
View details for PubMedID 12718853
p75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp
2002; 420 (6911): 74-78
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.
View details for DOI 10.1038/nature01176
View details for Web of Science ID 000179068100039
View details for PubMedID 12422217
Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth
2002; 417 (6892): 941-944
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.
View details for Web of Science ID 000176441200037
View details for PubMedID 12068310
Knowing how to navigate: mechanisms of semaphorin signaling in the nervous system.
Science's STKE : signal transduction knowledge environment
2002; 2002 (119): re1-?
Neuronal connections are made during embryonic development with astonishing precision to ultimately form the physical basis for the central nervous system's main capacity: information processing. Over the past few decades, much has been learned about the general principles of axon guidance. A key finding to emerge is that extracellular cues play decisive roles in establishing the connections. One family of such cues, the semaphorin proteins, was first identified as repellents for navigating axons during brain wiring. Recent studies have implicated these molecules in many other processes of neuronal development, including axonal fasciculation, target selection, neuronal migration, and dendritic guidance, as well as in the remodeling and repair of the adult nervous system. It appears that responding neuronal processes sense these semaphorin signals by a family of transmembrane molecules, namely the plexins, even though neuropilins were also found to be required for mediating the interaction between plexins and class 3 semaphorins. Our understanding of the intracellular signaling machinery linking the receptors to the cytoskeleton machinery is still incomplete, but several molecules have been implicated in mediating or modulating semaphorin-induced responses. Adding to the complexity of semaphorin biology, new findings implicate semaphorins in functioning not only as signaling ligands, but also as signal-transducing receptors. Thus, semaphorins may serve as important probes for exploring the mechanisms of intercellular communication during the development and function of the nervous system.
View details for PubMedID 11842242
Naked cuticle encodes an inducible antagonist of Wnt signalling
2000; 403 (6771): 789-795
During animal development, cells have to respond appropriately to localized secreted signals. Proper responses to Hedgehog, transforming growth factor-beta, epidermal growth factor and fibroblast growth factor/Ras signals require cognate inducible antagonists such as Patched, Dad, Argos and Sprouty. Wnt signals are crucial in development and neoplasia. Here we show that naked cuticle (nkd), a Drosophila segment-polarity gene, encodes an inducible antagonist for the Wnt signal Wingless (Wg). In fly embryos and imaginal discs nkd transcription is induced by Wg. In embryos, decreased nkd function has an effect similar to excess Wg; at later stages such a decrease appears to have no effect. Conversely, overproduction of Nkd in Drosophila and misexpression of Nkd in the vertebrate Xenopus laevis result in phenotypes resembling those of loss of Wg/Wnt function. nkd encodes a protein with a single EF hand (a calcium-binding motif) that is most similar to the recoverin family of myristoyl switch proteins. Nkd may therefore link ion fluxes to the regulation of the potency, duration or distribution of Wnt signals. Signal-inducible feedback antagonists such as nkd may limit the effects of Wnt proteins in development and disease.
View details for Web of Science ID 000085423100057
View details for PubMedID 10693810