Wendy Wenderski

All Publications

• Author Correction: Rewiring cancer drivers to activate apoptosis. Nature Gourisankar, S., Krokhotin, A., Ji, W., Liu, X., Chang, C. Y., Kim, S. H., Li, Z., Wenderski, W., Simanauskaite, J. M., Yang, H., Vogel, H., Zhang, T., Green, M. R., Gray, N. S., Crabtree, G. R. 2023

  View details for DOI 10.1038/s41586-023-06543-1

  View details for PubMedID 37596490

• Rewiring cancer drivers to activate apoptosis. Nature Gourisankar, S., Krokhotin, A., Ji, W., Liu, X., Chang, C., Kim, S. H., Li, Z., Wenderski, W., Simanauskaite, J. M., Yang, H., Vogel, H., Zhang, T., Green, M. R., Gray, N. S., Crabtree, G. R. 2023

  Abstract

  Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers1-4. Independent studies have identified cell death pathways that eliminate cells for the good of the organism5,6. The coexistence of cell death pathways with driver mutations suggests that the cancer driver could be rewired to activate cell death using chemical inducers of proximity (CIPs). Here we describe a new class of molecules called transcriptional/epigenetic CIPs (TCIPs) that recruit the endogenous cancer driver, or a downstream transcription factor, to the promoters of cell death genes, thereby activating their expression. We focused on diffuse large B cell lymphoma, in which the transcription factor B cell lymphoma 6 (BCL6) is deregulated7. BCL6 binds to the promoters of cell death genes and epigenetically suppresses their expression8. We produced TCIPs by covalently linking small molecules that bind BCL6 to those that bind to transcriptional activators that contribute to the oncogenic program, such as BRD4. The most potent molecule, TCIP1, increases binding of BRD4 by 50% over genomic BCL6-binding sites to produce transcriptional elongation at pro-apoptotic target genes within 15min, while reducing binding of BRD4 over enhancers by only 10%, reflecting a gain-of-function mechanism. TCIP1 kills diffuse large B cell lymphoma cell lines, including chemotherapy-resistant, TP53-mutant lines, at EC50 of 1-10nM in 72h and exhibits cell-specific and tissue-specific effects, capturing the combinatorial specificity inherent to transcription. The TCIP concept also has therapeutic applications in regulating the expression of genes for regenerative medicine and developmental disorders.

  View details for DOI 10.1038/s41586-023-06348-2

  View details for PubMedID 37495688

• Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome. Nature communications Fulton, S. L., Wenderski, W., Lepack, A. E., Eagle, A. L., Fanutza, T., Bastle, R. M., Ramakrishnan, A., Hays, E. C., Neal, A., Bendl, J., Farrelly, L. A., Al-Kachak, A., Lyu, Y., Cetin, B., Chan, J. C., Tran, T. N., Neve, R. L., Roper, R. J., Brennand, K. J., Roussos, P., Schimenti, J. C., Friedman, A. K., Shen, L., Blitzer, R. D., Robison, A. J., Crabtree, G. R., Maze, I. 2022; 13 (1): 6384

  Abstract

  With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.

  View details for DOI 10.1038/s41467-022-34200-0

  View details for PubMedID 36289231

• Systemic enhancement of serotonin signaling reverses social deficits in multiple mouse models for ASD. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Walsh, J. J., Llorach, P., Cardozo Pinto, D. F., Wenderski, W., Christoffel, D. J., Salgado, J. S., Heifets, B. D., Crabtree, G. R., Malenka, R. C. 2021

  Abstract

  Autism spectrum disorder (ASD) is a common set of heterogeneous neurodevelopmental disorders resulting from a variety of genetic and environmental risk factors. A core feature of ASD is impairment in prosocial interactions. Current treatment options for individuals diagnosed with ASD are limited, with no current FDA-approved medications that effectively treat its core symptoms. We recently demonstrated that enhanced serotonin (5-HT) activity in the nucleus accumbens (NAc), via optogenetic activation of 5-HTergic inputs or direct infusion of a specific 5-HT1b receptor agonist, reverses social deficits in a genetic mouse model for ASD based on 16p11.2 copy number variation. Furthermore, the recreational drug MDMA, which is currently being evaluated in clinical trials, promotes sociability in mice due to its 5-HT releasing properties in the NAc. Here, we systematically evaluated the ability of MDMA and a selective 5-HT1b receptor agonist to rescue sociability deficits in multiple different mouse models for ASD. We find that MDMA administration enhances sociability in control mice and reverses sociability deficits in all four ASD mouse models examined, whereas administration of a 5-HT1b receptor agonist selectively rescued the sociability deficits in all six mouse models for ASD. These preclinical findings suggest that pharmacological enhancement of 5-HT release or direct 5-HT1b receptor activation may be therapeutically efficacious in ameliorating some of the core sociability deficits present across etiologically distinct presentations of ASD.

  View details for DOI 10.1038/s41386-021-01091-6

  View details for PubMedID 34239048

• Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism. Proceedings of the National Academy of Sciences of the United States of America Wenderski, W., Wang, L., Krokhotin, A., Walsh, J. J., Li, H., Shoji, H., Ghosh, S., George, R. D., Miller, E. L., Elias, L., Gillespie, M. A., Son, E. Y., Staahl, B. T., Baek, S. T., Stanley, V., Moncada, C., Shipony, Z., Linker, S. B., Marchetto, M. C., Gage, F. H., Chen, D., Sultan, T., Zaki, M. S., Ranish, J. A., Miyakawa, T., Luo, L., Malenka, R. C., Crabtree, G. R., Gleeson, J. G. 2020

  Abstract

  Synaptic activity in neurons leads to the rapid activation of genes involved in mammalian behavior. ATP-dependent chromatin remodelers such as the BAF complex contribute to these responses and are generally thought to activate transcription. However, the mechanisms keeping such "early activation" genes silent have been a mystery. In the course of investigating Mendelian recessive autism, we identified six families with segregating loss-of-function mutations in the neuronal BAF (nBAF) subunit ACTL6B (originally named BAF53b). Accordingly, ACTL6B was the most significantly mutated gene in the Simons Recessive Autism Cohort. At least 14 subunits of the nBAF complex are mutated in autism, collectively making it a major contributor to autism spectrum disorder (ASD). Patient mutations destabilized ACTL6B protein in neurons and rerouted dendrites to the wrong glomerulus in the fly olfactory system. Humans and mice lacking ACTL6B showed corpus callosum hypoplasia, indicating a conserved role for ACTL6B in facilitating neural connectivity. Actl6b knockout mice on two genetic backgrounds exhibited ASD-related behaviors, including social and memory impairments, repetitive behaviors, and hyperactivity. Surprisingly, mutation of Actl6b relieved repression of early response genes including AP1 transcription factors (Fos, Fosl2, Fosb, and Junb), increased chromatin accessibility at AP1 binding sites, and transcriptional changes in late response genes associated with early response transcription factor activity. ACTL6B loss is thus an important cause of recessive ASD, with impaired neuron-specific chromatin repression indicated as a potential mechanism.

  View details for DOI 10.1073/pnas.1908238117

  View details for PubMedID 32312822

• Histone turnover and chromatin accessibility: Critical mediators of neurological development, plasticity, and disease BIOESSAYS Wenderski, W., Maze, I. 2016; 38 (5): 410-419

  Abstract

  In postmitotic neurons, nucleosomal turnover was long considered to be a static process that is inconsequential to transcription. However, our recent studies in human and rodent brain indicate that replication-independent (RI) nucleosomal turnover, which requires the histone variant H3.3, is dynamic throughout life and is necessary for activity-dependent gene expression, synaptic connectivity, and cognition. H3.3 turnover also facilitates cellular lineage specification and plays a role in suppressing the expression of heterochromatic repetitive elements, including mutagenic transposable sequences, in mouse embryonic stem cells. In this essay, we review mechanisms and functions for RI nucleosomal turnover in brain and present the hypothesis that defects in histone dynamics may represent a common mechanism underlying neurological aging and disease.

  View details for DOI 10.1002/bies.201500171

  View details for Web of Science ID 000374715000002

  View details for PubMedID 26990528

  View details for PubMedCentralID PMC4968875

• Engineering of a Histone-Recognition Domain in Dnmt3a Alters the Epigenetic Landscape and Phenotypic Features of Mouse ESCs. Molecular cell Noh, K., Wang, H., Kim, H. R., Wenderski, W., Fang, F., Li, C. H., Dewell, S., Hughes, S. H., Melnick, A. M., Patel, D. J., Li, H., Allis, C. D. 2015; 59 (1): 89-103

  Abstract

  Histone modification and DNA methylation are associated with varying epigenetic "landscapes," but detailed mechanistic and functional links between the two remain unclear. Using the ATRX-DNMT3-DNMT3L (ADD) domain of the DNA methyltransferase Dnmt3a as a paradigm, we apply protein engineering to dissect the molecular interactions underlying the recruitment of this enzyme to specific regions of chromatin in mouse embryonic stem cells (ESCs). By rendering the ADD domain insensitive to histone modification, specifically H3K4 methylation or H3T3 phosphorylation, we demonstrate the consequence of dysregulated Dnmt3a binding and activity. Targeting of a Dnmt3a mutant to H3K4me3 promoters decreases gene expression in a subset of developmental genes and alters ESC differentiation, whereas aberrant binding of another mutant to H3T3ph during mitosis promotes chromosome instability. Our studies support the general view that histone modification "reading" and DNA methylation are closely coupled in mammalian cells, and suggest an avenue for the functional assessment of chromatin-associated proteins.

  View details for DOI 10.1016/j.molcel.2015.05.017

  View details for PubMedID 26073541

  View details for PubMedCentralID PMC4491196

• Critical Role of Histone Turnover in Neuronal Transcription and Plasticity. Neuron Maze, I., Wenderski, W., Noh, K., Bagot, R. C., Tzavaras, N., Purushothaman, I., Elsässer, S. J., Guo, Y., Ionete, C., Hurd, Y. L., Tamminga, C. A., Halene, T., Farrelly, L., Soshnev, A. A., Wen, D., Rafii, S., Birtwistle, M. R., Akbarian, S., Buchholz, B. A., Blitzer, R. D., Nestler, E. J., Yuan, Z., Garcia, B. A., Shen, L., Molina, H., Allis, C. D. 2015; 87 (1): 77-94

  Abstract

  Turnover and exchange of nucleosomal histones and their variants, a process long believed to be static in post-replicative cells, remains largely unexplored in brain. Here, we describe a novel mechanistic role for HIRA (histone cell cycle regulator) and proteasomal degradation-associated histone dynamics in the regulation of activity-dependent transcription, synaptic connectivity, and behavior. We uncover a dramatic developmental profile of nucleosome occupancy across the lifespan of both rodents and humans, with the histone variant H3.3 accumulating to near-saturating levels throughout the neuronal genome by mid-adolescence. Despite such accumulation, H3.3-containing nucleosomes remain highly dynamic-in a modification-independent manner-to control neuronal- and glial-specific gene expression patterns throughout life. Manipulating H3.3 dynamics in both embryonic and adult neurons confirmed its essential role in neuronal plasticity and cognition. Our findings establish histone turnover as a critical and previously undocumented regulator of cell type-specific transcription and plasticity in mammalian brain.

  View details for DOI 10.1016/j.neuron.2015.06.014

  View details for PubMedID 26139371

• ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Noh, K., Maze, I., Zhao, D., Xiang, B., Wenderski, W., Lewis, P. W., Shen, L., Li, H., Allis, C. D. 2015; 112 (22): 6820-6827

  Abstract

  ATRX (the alpha thalassemia/mental retardation syndrome X-linked protein) is a member of the switch2/sucrose nonfermentable2 (SWI2/SNF2) family of chromatin-remodeling proteins and primarily functions at heterochromatic loci via its recognition of "repressive" histone modifications [e.g., histone H3 lysine 9 tri-methylation (H3K9me3)]. Despite significant roles for ATRX during normal neural development, as well as its relationship to human disease, ATRX function in the central nervous system is not well understood. Here, we describe ATRX's ability to recognize an activity-dependent combinatorial histone modification, histone H3 lysine 9 tri-methylation/serine 10 phosphorylation (H3K9me3S10ph), in postmitotic neurons. In neurons, this "methyl/phos" switch occurs exclusively after periods of stimulation and is highly enriched at heterochromatic repeats associated with centromeres. Using a multifaceted approach, we reveal that H3K9me3S10ph-bound Atrx represses noncoding transcription of centromeric minor satellite sequences during instances of heightened activity. Our results indicate an essential interaction between ATRX and a previously uncharacterized histone modification in the central nervous system and suggest a potential role for abnormal repetitive element transcription in pathological states manifested by ATRX dysfunction.

  View details for DOI 10.1073/pnas.1411258112

  View details for Web of Science ID 000355832200036

  View details for PubMedID 25538301

  View details for PubMedCentralID PMC4460490

• Epigenetic Mechanisms of Drug Addiction Vulnerability Epigenetics in Psychiatry Wenderski, W., Maze, I. edited by Peedicayil, J., Grayson, D. R., Avramopoulos, D. Elsevier. 2014; 1: 441–462

  View details for DOI 10.1016/B978-0-12-417114-5.00029-2

• ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Song, R. S., Massenburg, B., Wenderski, W., Jayaraman, V., Thompson, L., Neves, S. R. 2013; 110 (38): 15437-15442

  Abstract

  AMPA-type glutamate receptor (AMPAR) trafficking is essential for modulating synaptic transmission strength. Prior studies that have characterized signaling pathways underlying AMPAR trafficking have identified the cAMP/PKA-mediated phosphorylation of GluA1, an AMPAR subunit, as a key step in the membrane insertion of AMPAR. Inhibition of ERK impairs AMPAR membrane insertion, but the mechanism by which ERK exerts its effect is unknown. Dopamine, an activator of both PKA and ERK, induces AMPAR insertion, but the relationship between the two protein kinases in the process is not understood. We used a combination of computational modeling and live cell imaging to determine the relationship between ERK and PKA in AMPAR insertion. We developed a dynamical model to study the effects of phosphodiesterase 4 (PDE4), a cAMP phosphodiesterase that is phosphorylated and inhibited by ERK, on the membrane insertion of AMPAR. The model predicted that PKA could be a downstream effector of ERK in regulating AMPAR insertion. We experimentally tested the model predictions and found that dopamine-induced ERK phosphorylates and inhibits PDE4. This regulation results in increased cAMP levels and PKA-mediated phosphorylation of DARPP-32 and GluA1, leading to increased GluA1 trafficking to the membrane. These findings provide unique insight into an unanticipated network topology in which ERK uses PDE4 to regulate PKA output during dopamine signaling. The combination of dynamical models and experiments has helped us unravel the complex interactions between two protein kinase pathways in regulating a fundamental molecular process underlying synaptic plasticity.

  View details for DOI 10.1073/pnas.1311783110

  View details for Web of Science ID 000324495300068

  View details for PubMedID 23986500

  View details for PubMedCentralID PMC3780840

• MODELING OF SPATIAL INTRACELLULAR SIGNALING EVENTS IN NEURONS METHODS IN ENZYMOLOGY, VOL 505: IMAGING AND SPECTROSCOPIC ANALYSIS OF LIVING CELLS Wenderski, W. C., Neves, S. R. 2012; 505: 105-124

  Abstract

  A neuron is able to seamlessly respond to a number of signals, in a timely and specific manner. This process, of integrating multiple inputs, relays on the orchestration of intracellular events by signaling networks. The inherent complexity of signaling networks has made computational modeling a useful approach to understand their underlying regulatory principles. Recent advances in imaging techniques have highlighted the nonhomogeneous nature of intracellular signaling and its significant contribution to the maintenance of signal specificity. Computational modeling can provide mechanistic insight into the origins of these inhomogeneous distributions of signaling components and their role in the integrative capabilities of the neuron.

  View details for DOI 10.1016/B978-0-12-388448-0.00014-0

  View details for Web of Science ID 000301550700006

  View details for PubMedID 22289450