Local Sequence Features That Influence AP-1 Cis-Regulatory Activity
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Jmjd2c Facilitates the Assembly of Essential Enhancer-Protein Complexes at the Onset of Embryonic Stem Cell Differentiation Rute A
© 2017. Published by The Company of Biologists Ltd | Development (2017) 144, 567-579 doi:10.1242/dev.142489 STEM CELLS AND REGENERATION RESEARCH ARTICLE Jmjd2c facilitates the assembly of essential enhancer-protein complexes at the onset of embryonic stem cell differentiation Rute A. Tomaz1,JenniferL.Harman2, Donja Karimlou1, Lauren Weavers1, Lauriane Fritsch3, Tony Bou-Kheir1, Emma Bell1, Ignacio del Valle Torres4, Kathy K. Niakan4,CynthiaFisher5, Onkar Joshi6, Hendrik G. Stunnenberg6, Edward Curry1, Slimane Ait-Si-Ali3, Helle F. Jørgensen2 and Véronique Azuara1,* ABSTRACT implantation, a second extra-embryonic lineage, the primitive Jmjd2 H3K9 demethylases cooperate in promoting mouse embryonic endoderm, emerges at the ICM surface. Concurrently, the ICM stem cell (ESC) identity. However, little is known about their maintains its pluripotency as it matures into the epiblast but importance at the exit of ESC pluripotency. Here, we reveal that ultimately goes on to form the three primary germ layers and germ Jmjd2c facilitates this process by stabilising the assembly of cells upon gastrulation (Boroviak and Nichols, 2014; Rossant, mediator-cohesin complexes at lineage-specific enhancers. 2008). Functionally, we show that Jmjd2c is required in ESCs to initiate Pluripotent mouse embryonic stem cells (ESCs) are derived from appropriate gene expression programs upon somatic multi-lineage ICM cells, and can self-renew and faithfully maintain an differentiation. In the absence of Jmjd2c, differentiation is stalled at an undifferentiated state in vitro in the presence of leukaemia inhibitory early post-implantation epiblast-like stage, while Jmjd2c-knockout factor (LIF) and serum components, while preserving their multi- ESCs remain capable of forming extra-embryonic endoderm lineage differentiation capacity (Evans and Kaufman, 1981; Martin, derivatives. -
Id4: an Inhibitory Function in the Control
Id4: an inhibitory function in the control of hair cell formation? Sara Johanna Margarete Weber Thesis submitted to the University College London (UCL) for the degree of Master of Philosophy The work presented in this thesis was conducted at the UCL Ear Institute between September 23rd 2013 and October 19th 2015. 1st Supervisor: Dr Nicolas Daudet UCL Ear Institute, London, UK 2nd Supervisor: Dr Stephen Price UCL Department of Cell and Developmental Biology, London, UK 3rd Supervisor: Prof Guy Richardson School of Life Sciences, University of Sussex, Brighton, UK I, Sara Weber confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Heidelberg, 08.03.2016 ………………………….. Sara Weber 2 Abstract Mechanosensitive hair cells in the sensory epithelia of the vertebrate inner ear are essential for hearing and the sense of balance. Initially formed during embryological development they are constantly replaced in the adult avian inner ear after hair cell damage and loss, while practically no spontaneous regeneration occurs in mammals. The detailed molecular mechanisms that regulate hair cell formation remain elusive despite the identification of a number of signalling pathways and transcription factors involved in this process. In this study I investigated the role of Inhibitor of differentiation 4 (Id4), a member of the inhibitory class V of bHLH transcription factors, in hair cell formation. I found that Id4 is expressed in both hair cells and supporting cells of the chicken and the mouse inner ear at stages that are crucial for hair cell formation. -
Snf2h-Mediated Chromatin Organization and Histone H1 Dynamics Govern Cerebellar Morphogenesis and Neural Maturation
ARTICLE Received 12 Feb 2014 | Accepted 15 May 2014 | Published 20 Jun 2014 DOI: 10.1038/ncomms5181 OPEN Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation Matı´as Alvarez-Saavedra1,2, Yves De Repentigny1, Pamela S. Lagali1, Edupuganti V.S. Raghu Ram3, Keqin Yan1, Emile Hashem1,2, Danton Ivanochko1,4, Michael S. Huh1, Doo Yang4,5, Alan J. Mears6, Matthew A.M. Todd1,4, Chelsea P. Corcoran1, Erin A. Bassett4, Nicholas J.A. Tokarew4, Juraj Kokavec7, Romit Majumder8, Ilya Ioshikhes4,5, Valerie A. Wallace4,6, Rashmi Kothary1,2, Eran Meshorer3, Tomas Stopka7, Arthur I. Skoultchi8 & David J. Picketts1,2,4 Chromatin compaction mediates progenitor to post-mitotic cell transitions and modulates gene expression programs, yet the mechanisms are poorly defined. Snf2h and Snf2l are ATP-dependent chromatin remodelling proteins that assemble, reposition and space nucleosomes, and are robustly expressed in the brain. Here we show that mice conditionally inactivated for Snf2h in neural progenitors have reduced levels of histone H1 and H2A variants that compromise chromatin fluidity and transcriptional programs within the developing cerebellum. Disorganized chromatin limits Purkinje and granule neuron progenitor expansion, resulting in abnormal post-natal foliation, while deregulated transcriptional programs contribute to altered neural maturation, motor dysfunction and death. However, mice survive to young adulthood, in part from Snf2l compensation that restores Engrailed-1 expression. Similarly, Purkinje-specific Snf2h ablation affects chromatin ultrastructure and dendritic arborization, but alters cognitive skills rather than motor control. Our studies reveal that Snf2h controls chromatin organization and histone H1 dynamics for the establishment of gene expression programs underlying cerebellar morphogenesis and neural maturation. -
Essential Role of Retinoblastoma Protein in Mammalian Hair Cell Development and Hearing
Essential role of retinoblastoma protein in mammalian hair cell development and hearing Cyrille Sage*, Mingqian Huang*, Melissa A. Vollrath†, M. Christian Brown‡, Philip W. Hinds§, David P. Corey†, Douglas E. Vetter¶, and Zheng-Yi Chen*ʈ *Neurology Service, Center for Nervous System Repair, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; †Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, MA 02115; ‡Department of Otology and Laryngology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, MA 02114; §Department of Radiation Oncology, Molecular Oncology Research Institute, Tufts–New England Medical Center, Boston, MA 02111; and ¶Departments of Neuroscience and Biomedical Engineering, Tufts University School of Medicine, Boston, MA 02111 Edited by Kathryn V. Anderson, Sloan–Kettering Institute, New York, NY, and approved March 27, 2006 (received for review December 9, 2005) The retinoblastoma protein pRb is required for cell-cycle exit of 10 (E10) causes an overproduction of sensory progenitor cells, embryonic mammalian hair cells but not for their early differenti- which subsequently differentiate into hair cells and supporting cells. ation. However, its role in postnatal hair cells is unknown. To study Remarkably, pRbϪ/Ϫ hair cells and supporting cells also continue the function of pRb in mature animals, we created a new condi- to differentiate and express cellular markers appropriate for their tional mouse model, with the Rb gene deleted primarily in the embryonic stages. Furthermore, pRbϪ/Ϫ hair cells are able to inner ear. Progeny survive up to 6 months. During early postnatal transduce mechanical stimuli and appear capable of forming syn- development, pRb؊/؊ hair cells continue to divide and can trans- apses with ganglion neurons. -
Transcription Factor TFCP2L1 Patterns Cells in the Mouse Kidney Collecting Ducts
RESEARCH ARTICLE Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts Max Werth1†, Kai M Schmidt-Ott1,2,3†, Thomas Leete1, Andong Qiu1,4, Christian Hinze2, Melanie Viltard1,5, Neal Paragas1,6, Carrie J Shawber1, Wenqiang Yu1,7, Peter Lee1, Xia Chen1, Abby Sarkar1, Weiyi Mu1, Alexander Rittenberg1, Chyuan-Sheng Lin1, Jan Kitajewski1,8, Qais Al-Awqati1, Jonathan Barasch1* 1Columbia University, New York, United States; 2Max Delbruck Center for Molecular Medicine, Berlin, Germany; 3Department of Nephrology and Intensive Care Medicine, Charite´ - Universitaetsmedizin Berlin, Berlin, Germany; 4Tongji University, Shanghai, China; 5Institute for European Expertise in Physiology, Paris, France; 6University of Washington, Seattle, United States; 7Fudan University, Shanghai, China; 8University of Illinois at Chicago, Chicago, United States Abstract Although most nephron segments contain one type of epithelial cell, the collecting ducts consists of at least two: intercalated (IC) and principal (PC) cells, which regulate acid-base and salt-water homeostasis, respectively. In adult kidneys, these cells are organized in rosettes suggesting functional interactions. Genetic studies in mouse revealed that transcription factor Tfcp2l1 coordinates IC and PC development. Tfcp2l1 induces the expression of IC specific genes, including specific H+-ATPase subunits and Jag1. Jag1 in turn, initiates Notch signaling in PCs but inhibits Notch signaling in ICs. Tfcp2l1 inactivation deletes ICs, whereas Jag1 inactivation results in the forfeiture of discrete IC and PC identities. Thus, Tfcp2l1 is a critical regulator of IC-PC *For correspondence: jmb4@ patterning, acting cell-autonomously in ICs, and non-cell-autonomously in PCs. As a result, Tfcp2l1 columbia.edu regulates the diversification of cell types which is the central characteristic of ’salt and pepper’ epithelia and distinguishes the collecting duct from all other nephron segments. -
Mechanism of Nucleosome Targeting by Pioneer Transcription Factors
University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2019 Mechanism Of Nucleosome Targeting By Pioneer Transcription Factors Meilin Mary Fernandez Garcia University of Pennsylvania Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biochemistry Commons, and the Biophysics Commons Recommended Citation Fernandez Garcia, Meilin Mary, "Mechanism Of Nucleosome Targeting By Pioneer Transcription Factors" (2019). Publicly Accessible Penn Dissertations. 3624. https://repository.upenn.edu/edissertations/3624 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/3624 For more information, please contact [email protected]. Mechanism Of Nucleosome Targeting By Pioneer Transcription Factors Abstract Transcription factors (TFs) forage the genome to instruct cell plasticity, identity, and differentiation. These developmental processes are elicited through TF engagement with chromatin. Yet, how and which TFs can engage with chromatin and thus, nucleosomes, remains largely unexplored. Pioneer TFs are TF that display a high affinity for nucleosomes. Extensive genetic and biochemical studies on the pioneer TF FOXA, a driver of fibroblast to hepatocyte reprogramming, revealed its nucleosome binding ability and chromatin targeting lead to chromatin accessibility and subsequent cooperative binding of TFs. Similarly, a number of reprogramming TFs have been suggested to have pioneering activity due to their ability to target compact chromatin and increase accessibility and enhancer formation in vivo. But whether these factors directly interact with nucleosomes remains to be assessed. Here we test the nucleosome binding ability of the cell reprogramming TFs, Oct4, Sox2, Klf4 and cMyc, that are required for the generation of induced pluripotent stem cells. In addition, we also test neuronal and macrophage reprogramming TFs. -
Genes Involved in the Development and Physiology of Both the Peripheral and Central Auditory Systems Nicolas Michalski, Christine Petit
Genes Involved in the Development and Physiology of Both the Peripheral and Central Auditory Systems Nicolas Michalski, Christine Petit To cite this version: Nicolas Michalski, Christine Petit. Genes Involved in the Development and Physiology of Both the Peripheral and Central Auditory Systems. Annual Review of Neuroscience, Annual Reviews, 2019, 42, pp.67-86. 10.1146/annurev-neuro-070918-050428. pasteur-02874563 HAL Id: pasteur-02874563 https://hal-pasteur.archives-ouvertes.fr/pasteur-02874563 Submitted on 6 Jul 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution - NonCommercial| 4.0 International License Genes Involved in the Development and Physiology of both the Peripheral and Central Auditory Systems 1,2,3,# 1,2,3,4,5,# Nicolas Michalski & Christine Petit 1 Unité de Génétique et Physiologie de l’Audition, Institut Pasteur, 75015 Paris, France 2 UMRS 1120, Institut National de la Santé et de la Recherche Médicale (INSERM), 75015 Paris, France 3 Sorbonne Universités, UPMC Université Paris 06, Complexité -
Pioneer Activity of an Oncogenic Fusion Transcription Factor at Inaccessible Chromatin
bioRxiv preprint doi: https://doi.org/10.1101/2020.12.11.420232; this version posted June 7, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Title Pioneer activity of an oncogenic fusion transcription factor at inaccessible chromatin Authors Benjamin Sunkel1,6, Meng Wang1,6, Stephanie LaHaye2,6, Benjamin J. Kelly2, James R. Fitch2, FreDeric G. Barr3, Peter White2,4, Benjamin Z. Stanton1,4,5,7,* Author Affiliations 1 Nationwide Children’s Hospital, Center for Childhood Cancer and Blood Diseases, Columbus, OH 43205, USA 2 The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH 43205, USA 3 Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA 4 Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA 5 Department of Biological Chemistry and Pharmacology, The Ohio State University College of Medicine, Columbus, OH 43210, USA 6These authors contributed eQually 7Lead contact *Correspondence: [email protected] (B.Z.S.) Summary Recent characterizations of pioneer transcription factors have leD to new insights into their structures anD patterns of chromatin recognition that are instructive for understanding their role in cell fate commitment and transformation. Intersecting with these basic science concepts, the iDentification of pioneer factors (PFs) fuseD together as Driver translocations in chilDhooD cancers raises questions of whether these fusions retain the funDamental ability to invade repressed chromatin, consistent with their monomeric PF constituents. -
Identification of Regulatory Elements from Nascent Transcription Using Dreg
Downloaded from genome.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Identification of regulatory elements from nascent transcription using dREG Zhong Wang1, Tinyi Chu1,2, Lauren A. Choate1, and Charles G. Danko1,3,* 1 Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853. 2 Graduate field of Computational Biology, Cornell University, Ithaca, NY 14853. 3 Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853. * Address correspondence to: Charles G. Danko, Ph.D. Baker Institute for Animal Health Cornell University Hungerford Hill Rd. Ithaca, NY 14853 Phone: (607) 256-5620 E-mail: [email protected] Abstract: Our genomes encode a wealth of transcription initiation regions (TIRs) that can be identified by their distinctive patterns of actively elongating RNA polymerase. We previously introduced dREG to identify TIRs using PRO-seq data. Here we introduce an efficient new implementation of dREG that uses PRO-seq data to identify both uni- and bidirectionally transcribed TIRs with 70% improvements in accuracy, 3-4-fold higher resolution, and >100-fold increases in computational efficiency. Using a novel strategy to identify TIRs based on their statistical confidence reveals extensive overlap with orthogonal assays, yet also reveals thousands of additional weakly-transcribed TIRs that were not identified by H3K27ac ChIP-seq or DNase-seq. Novel TIRs discovered by dREG were often associated with RNA polymerase III initiation, bound by pioneer transcription factors, or located in broad domains marked by repressive chromatin modifications. Our results suggest that transcription initiation can be a powerful tool for expanding the catalog of functional elements. -
E Proteins Sharpen Neurogenesis by Modulating Proneural Bhlh
RESEARCH ARTICLE E proteins sharpen neurogenesis by modulating proneural bHLH transcription factors’ activity in an E-box-dependent manner Gwenvael Le Dre´ au1†*, Rene´ Escalona1†‡, Raquel Fueyo2, Antonio Herrera1, Juan D Martı´nez1, Susana Usieto1, Anghara Menendez3, Sebastian Pons3, Marian A Martinez-Balbas2, Elisa Marti1 1Department of Developmental Biology, Instituto de Biologı´a Molecular de Barcelona, Barcelona, Spain; 2Department of Molecular Genomics, Instituto de Biologı´a Molecular de Barcelona, Barcelona, Spain; 3Department of Cell Biology, Instituto de Biologı´a Molecular de Barcelona, Barcelona, Spain Abstract Class II HLH proteins heterodimerize with class I HLH/E proteins to regulate transcription. Here, we show that E proteins sharpen neurogenesis by adjusting the neurogenic strength of the distinct proneural proteins. We find that inhibiting BMP signaling or its target ID2 in *For correspondence: the chick embryo spinal cord, impairs the neuronal production from progenitors expressing [email protected] ATOH1/ASCL1, but less severely that from progenitors expressing NEUROG1/2/PTF1a. We show this context-dependent response to result from the differential modulation of proneural proteins’ †These authors contributed activity by E proteins. E proteins synergize with proneural proteins when acting on CAGSTG motifs, equally to this work thereby facilitating the activity of ASCL1/ATOH1 which preferentially bind to such motifs. Present address: Conversely, E proteins restrict the neurogenic strength of NEUROG1/2 by directly inhibiting their ‡ Departamento de Embriologı´a, preferential binding to CADATG motifs. Since we find this mechanism to be conserved in Facultad de Medicina, corticogenesis, we propose this differential co-operation of E proteins with proneural proteins as a Universidad Nacional Auto´noma novel though general feature of their mechanism of action. -
Genetic Determinants and Epigenetic Effects of Pioneer-Factor Occupancy
ARTICLES https://doi.org/10.1038/s41588-017-0034-3 Genetic determinants and epigenetic effects of pioneer-factor occupancy Julie Donaghey1,2, Sudhir Thakurela 1,2, Jocelyn Charlton2,3, Jennifer S. Chen2, Zachary D. Smith1,2, Hongcang Gu1, Ramona Pop2, Kendell Clement1,2, Elena K. Stamenova1, Rahul Karnik1,2, David R. Kelley 2, Casey A. Gifford1,2,5, Davide Cacchiarelli1,2,6, John L. Rinn1,2,7, Andreas Gnirke1, Michael J. Ziller4 and Alexander Meissner 1,2,3* Transcription factors (TFs) direct developmental transitions by binding to target DNA sequences, influencing gene expres- sion and establishing complex gene-regultory networks. To systematically determine the molecular components that enable or constrain TF activity, we investigated the genomic occupancy of FOXA2, GATA4 and OCT4 in several cell types. Despite their classification as pioneer factors, all three TFs exhibit cell-type-specific binding, even when supraphysiologically and ectopically expressed. However, FOXA2 and GATA4 can be distinguished by low enrichment at loci that are highly occupied by these fac- tors in alternative cell types. We find that expression of additional cofactors increases enrichment at a subset of these sites. Finally, FOXA2 occupancy and changes to DNA accessibility can occur in G1-arrested cells, but subsequent loss of DNA meth- ylation requires DNA replication. rganismal development is orchestrated by the selective use the regulatory capabilities of the presumed pioneer TFs FOXA2, and distinctive interpretation of identical genetic material GATA4 and OCT4, which are frequently studied in development Oin each cell. During this process, TFs coordinate protein and used in cellular reprogramming. complexes at associated promoter and distal enhancer elements to modulate gene expression. -
The Expanding World of N-MYC–Driven Tumors
Published OnlineFirst January 22, 2018; DOI: 10.1158/2159-8290.CD-17-0273 REVIEW The Expanding World of N-MYC–Driven Tumors David S. Rickman 1 , 2 , 3 , Johannes H. Schulte 4 , 5 , 6 , and Martin Eilers 7 ABSTRACT Enhanced and deregulated expression of N-MYC, a member of the MYC family of transcription factors, drives the development of multiple tumors, including tumors of the nervous and hematologic systems and neuroendocrine tumors in other organs. This review sum- marizes the cell-of-origin, biological features, associated signaling pathways, and current treatment strategies for N-MYC–driven tumors. We also highlight biological differences within specifi c tumor types that are driven by the different MYC proteins. Signifi cance: N-MYC is a driver of multiple tumor types that are derived through a mechanism that involves direct differentiation within the same lineage (e.g., in the case of neuroblastoma, medulloblas- toma, and acute myeloid leukemia) and is often associated with a poor prognosis. Emerging data suggest that N-MYC also drives other tumor types through a mechanism that promotes a lineage switch and that this switch may be exploited for therapeutic purposes. Cancer Discov; 8(2); 150–63. ©2018 AACR. INTRODUCTION specifi c manner ( 9 ). Each of the MYCBoxes I–IV interacts with different effector proteins (see below). MYC proteins bind The human MYC gene (encoding the C-MYC protein) was very broadly to active promoters and enhancers and can alter fi rst identifi ed as the cellular homolog of an avian retroviral transcription mediated by all three RNA polymerases. Nota- transforming gene, v-myc ( 1 ).