Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development
Hank H. Qi,Hank H. Qi,Madathia Sarkissian,Madathia Sarkissian,Gangqing Hu,Zhibin Wang,Arindam Bhattacharjee,D. Benjamin Gordon,Michelle Gonzales,Fei Lan,Fei Lan,Pat P. Ongusaha,Maite Huarte,Maite Huarte,Nasser K. Yaghi,Nasser K. Yaghi,Hui-Jun Lim,Hui-Jun Lim,Benjamin A. Garcia,Leonardo Brizuela,Keji Zhao,Thomas M. Roberts,Yang Shi,Yang Shi +23 more
TLDR
Genetic and molecular evidence supports a model whereby PHF8 regulates zebrafish neuronal cell survival and jaw development in part by directly regulating the expression of the homeodomain transcription factor MSX1/MSXB, which functions downstream of multiple signalling and developmental pathways.Abstract:
Mutations in the PHF8 gene, which encodes the plant homeo domain (PHD) finger protein 8, are connected to X-linked mental retardation associated with cleft lip and cleft palate. Two groups now report that the PHF8 protein is a histone demethylase with activity against H4K20me1 (histone H4 lysine 20). Qi et al. report a role for PHF8 in regulating gene expression, as well as in neuronal cell survival and craniofacial development in zebrafish. The results suggest there may be a link between histone methylation dynamics and X-linked mental retardation. Liu et al. show that PHF8 is linked to two distinct events during cell-cycle progression. PHF8 is recruited to the promoters of G1/S-phase genes where it removes H4K20me1 and contributes to gene activation, whereas dissociation of PHF8 from chromatin in prophase allows H4K20me1 to accumulate during mitosis. PHF8 is a JmjC domain-containing protein, the gene for which has been linked to X-linked mental retardation (XLMR). These authors demonstrate PHF8 to be a histone demethylase with activity against H4K20me1. It has a role in regulating gene expression as well as in neuronal cell survival and craniofacial development in zebrafish. The results suggest there may be a link between histone methylation dynamics and XLMR. X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability1. Causal mutations have been found in approximately 90 X-linked genes2; however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD (plant homeo domain) finger protein 8) is a JmjC domain-containing protein and its mutations have been found in patients with XLMR and craniofacial deformities. Here we provide multiple lines of evidence establishing PHF8 as the first mono-methyl histone H4 lysine 20 (H4K20me1) demethylase, with additional activities towards histone H3K9me1 and me2. PHF8 is located around the transcription start sites (TSS) of ∼7,000 RefSeq genes and in gene bodies and intergenic regions (non-TSS). PHF8 depletion resulted in upregulation of H4K20me1 and H3K9me1 at the TSS and H3K9me2 in the non-TSS sites, respectively, demonstrating differential substrate specificities at different target locations. PHF8 positively regulates gene expression, which is dependent on its H3K4me3-binding PHD and catalytic domains. Importantly, patient mutations significantly compromised PHF8 catalytic function. PHF8 regulates cell survival in the zebrafish brain and jaw development, thus providing a potentially relevant biological context for understanding the clinical symptoms associated with PHF8 patients. Lastly, genetic and molecular evidence supports a model whereby PHF8 regulates zebrafish neuronal cell survival and jaw development in part by directly regulating the expression of the homeodomain transcription factor MSX1/MSXB, which functions downstream of multiple signalling and developmental pathways3. Our findings indicate that an imbalance of histone methylation dynamics has a critical role in XLMR.read more
Citations
More filters
Journal ArticleDOI
Histone methylation: a dynamic mark in health, disease and inheritance
Eric L. Greer,Yang Shi +1 more
TL;DR: This work provides a broad overview of how histone methylation is regulated and leads to biological outcomes and suggests its links to disease and ageing and possibly to transmission of traits across generations are illustrated.
Journal ArticleDOI
Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders
Phil Lee,Verneri Anttila,Hyejung Won,Yen-Chen Anne Feng,Jacob Rosenthal,Zhaozhong Zhu,Elliot M. Tucker-Drob,Michel G. Nivard,Andrew D. Grotzinger,Danielle Posthuma,Meg M.-J. Wang,Dongmei Yu,Eli A. Stahl,Raymond K. Walters,Richard Anney,Laramie E. Duncan,Tian Ge,Rolf Adolfsson,Tobias Banaschewski,Sintia Iole Belangero,Edwin H. Cook,Giovanni Coppola,Eske M. Derks,Pieter J. Hoekstra,Jaakko Kaprio,Anna Keski-Rahkonen,George Kirov,George Kirov,Henry R. Kranzler,Jurjen J. Luykx,Luis Augusto Rohde,Clement C. Zai,Esben Agerbo,Maria Arranz,Philip Asherson,Marie Bækvad-Hansen,Gisli Baldursson,Mark A. Bellgrove,Richard A. Belliveau,Jan K. Buitelaar,Christie L. Burton,Jonas Bybjerg-Grauholm,Miquel Casas,Felecia Cerrato,Kimberly Chambert,Claire Churchhouse,Bru Cormand,Jennifer Crosbie,Søren Dalsgaard,Ditte Demontis,Alysa E. Doyle,Ashley Dumont,Josephine Elia,Jakob Grove,Olafur O Gudmundsson,Jan Haavik,Hakon Hakonarson,Christine Søholm Hansen,Catharina A. Hartman,Ziarih Hawi,Amaia Hervás,David M. Hougaard,Daniel P. Howrigan,Hailiang Huang,Jonna Kuntsi,Kate Langley,Klaus-Peter Lesch,Patrick W. L. Leung,Sandra K. Loo,Joanna Martin,Alicia R. Martin,James J. McGough,Sarah E. Medland,Jennifer L. Moran,Ole Mors,Preben Bo Mortensen,Robert D. Oades,Duncan S. Palmer,Carsten Bøcker Pedersen,Marianne Giørtz Pedersen,Triinu Peters,Timothy Poterba,Jesper Buchhave Poulsen,Josep Antoni Ramos-Quiroga,Andreas Reif,Marta Ribasés,Aribert Rothenberger,Paula Rovira,Cristina Sánchez-Mora,F. Kyle Satterstrom,Russell Schachar,María Soler Artigas,Stacy Steinberg,Hreinn Stefansson,Patrick Turley,G. Bragi Walters,Thomas Werge,Tetyana Zayats,Dan E. Arking,Francesco Bettella,Joseph D. Buxbaum,Jane H. Christensen,Ryan L. Collins,Hilary Coon,Silvia De Rubeis,Richard Delorme,Dorothy E. Grice,Thomas Hansen,Peter Holmans,Sigrun Hope,Christina M. Hultman,Lambertus Klei,Christine Ladd-Acosta,Páll Magnússon,Terje Nærland,Mette Nyegaard,Dalila Pinto,Per Qvist,Karola Rehnström,Abraham Reichenberg,Jennifer Reichert,Kathryn Roeder,Guy A. Rouleau,Evald Saemundsen,Stephen Sanders,Sven Sandin,Beate St Pourcain,Kari Stefansson,James S. Sutcliffe,Michael E. Talkowski,Lauren A. Weiss,A. Jeremy Willsey,Ingrid Agartz,Huda Akil,Diego Albani,Martin Alda,Thomas Damm Als,Adebayo Anjorin,Lena Backlund,Nicholas Bass,Michael Bauer,Bernhard T. Baune,Frank Bellivier,Sarah E. Bergen,Wade H. Berrettini,Joanna M. Biernacka,Douglas Blackwood,Erlend Bøen,Monika Budde,William E. Bunney,Margit Burmeister,William Byerley,Enda M. Byrne,Sven Cichon,Toni-Kim Clarke,Jonathan R. I. Coleman,Nicholas John Craddock,David Curtis,Piotr M. Czerski,Anders M. Dale,Nina Dalkner,Udo Dannlowski,Franziska Degenhardt,Arianna Di Florio,Torbjørn Elvsåshagen,Bruno Etain,Sascha B. Fischer,Andreas J. Forstner,Liz Forty,Josef Frank,Mark A. Frye,Janice M. Fullerton,Katrin Gade,Helena Gaspar,Elliot S. Gershon,Michael Gill,Fernando S. Goes,Scott D. Gordon,Katherine Gordon-Smith,Melissa J. Green,Tiffany A. Greenwood,Maria Grigoroiu-Serbanescu,Jose Guzman-Parra,Joanna Hauser,Martin Hautzinger,Urs Heilbronner,Stefan Herms,Per Hoffmann,Dominic Holland,Stéphane Jamain,Ian Jones,Lisa Jones,Radhika Kandaswamy,John R. Kelsoe,James L. Kennedy,Oedegaard Ketil Joachim,Sarah Kittel-Schneider,Manolis Kogevinas,Anna C. Koller,Catharina Lavebratt,Cathryn M. Lewis,Qingqin S. Li,Jolanta Lissowska,Loes M. Olde Loohuis,Susanne Lucae,Anna Maaser,Ulrik Fredrik Malt,Nicholas G. Martin,Lina Martinsson,Susan L. McElroy,Francis J. McMahon,Andrew McQuillin,Ingrid Melle,Andres Metspalu,Vincent Millischer,Philip B. Mitchell,Grant W. Montgomery,Gunnar Morken,Derek W. Morris,Bertram Müller-Myhsok,Niamh Mullins,Richard M. Myers,Caroline M. Nievergelt,Merete Nordentoft,Annelie Nordin Adolfsson,Markus M. Nöthen,Roel A. Ophoff,Michael John Owen,Sara A. Paciga,Carlos N. Pato,Michele T. Pato,Roy H. Perlis,Amy Perry,James B. Potash,Céline S. Reinbold,Marcella Rietschel,Margarita Rivera,Mary Roberson,Martin Schalling,Peter R. Schofield,Thomas G. Schulze,Laura J. Scott,Alessandro Serretti,Engilbert Sigurdsson,Olav B. Smeland,Eystein Stordal,Fabian Streit,Jana Strohmaier,Thorgeir E. Thorgeirsson,Jens Treutlein,Gustavo Turecki,Arne E. Vaaler,Eduard Vieta,John B. Vincent,Yunpeng Wang,Stephanie H. Witt,Peter P. Zandi,Roger A.H. Adan,Lars Alfredsson,Tetsuya Ando,Harald N. Aschauer,Jessica H. Baker,Vladimir Bencko,Andrew W. Bergen,Andreas Birgegård,Vesna Boraska Perica,Harry Brandt,Roland Burghardt,Laura Carlberg,Matteo Cassina,Maurizio Clementi,Philippe Courtet,Steven Crawford,Scott J. Crow,James J. Crowley,Unna N. Danner,Oliver S. P. Davis,Daniela Degortes,Janiece E. DeSocio,Danielle M. Dick,Christian Dina,Elisa Docampo,Karin Egberts,Stefan Ehrlich,Thomas Espeseth,Fernando Fernández-Aranda,Manfred M. Fichter,Lenka Foretova,Monica Forzan,Giovanni Gambaro,Ina Giegling,Fragiskos Gonidakis,Philip Gorwood,Monica Gratacos Mayora,Yiran Guo,Katherine A. Halmi,Konstantinos Hatzikotoulas,Johannes Hebebrand,Sietske G. Helder,Beate Herpertz-Dahlmann,Wolfgang Herzog,Anke Hinney,Hartmut Imgart,Susana Jiménez-Murcia,Craig Johnson,Jennifer Jordan,Antonio Julià,Deborah Kaminská,Leila Karhunen,Andreas Karwautz,Martien J H Kas,Walter H. Kaye,Martin A. Kennedy,Youl-Ri Kim,Lars Klareskog,Kelly L. Klump,Gun Peggy Knudsen,Mikael Landén,Stephanie Le Hellard,Robert D. Levitan,Dong Li,Paul Lichtenstein,Mario Maj,Sara Marsal,Sara McDevitt,James R. Mitchell,Palmiero Monteleone,Alessio Maria Monteleone,Melissa A. Munn-Chernoff,Benedetta Nacmias,Marie Navratilova,Julie K. O'Toole,Leonid Padyukov,Jacques Pantel,Hana Papezova,Raquel Rabionet,Anu Raevuori,Nicolas Ramoz,Ted Reichborn-Kjennerud,Valdo Ricca,Marion Roberts,Dan Rujescu,Filip Rybakowski,André Scherag,Ulrike Schmidt,Jochen Seitz,Lenka Slachtova,Margarita C T Slof-Op 't Landt,Agnieszka Słopień,Sandro Sorbi,Lorraine Southam,Michael Strober,Alfonso Tortorella,Federica Tozzi,Janet Treasure,Konstantinos Tziouvas,Annemarie A. van Elburg,Tracey D. Wade,Gudrun Wagner,Esther Walton,Hunna J. Watson,H-Erich Wichmann,D. Blake Woodside,Eleftheria Zeggini,Stephanie Zerwas,Stephan Zipfel,Mark Adams,Till F. M. Andlauer,Klaus Berger,Elisabeth B. Binder,Dorret I. Boomsma,Enrique Castelao,Lucía Colodro-Conde,Nese Direk,Anna R. Docherty,Enrico Domenici,Katharina Domschke,Erin C. Dunn,Jerome C. Foo,E.J.C. de Geus,Hans J. Grabe,Steven P. Hamilton,Carsten Horn,Jouke-Jan Hottenga,David M. Howard,Marcus Ising,Stefan Kloiber,Douglas F. Levinson,Glyn Lewis,Patrik K. E. Magnusson,Hamdi Mbarek,Christel M. Middeldorp,Sara Mostafavi,Dale R. Nyholt,Brenda W.J.H. Penninx,Roseann E. Peterson,Giorgio Pistis,David J. Porteous,Martin Preisig,Jorge A. Quiroz,Catherine Schaefer,Eva C. Schulte,Jianxin Shi,Daniel J. Smith,Pippa A. Thomson,Henning Tiemeier,Rudolf Uher,Sandra Van der Auwera,Myrna M. Weissman,Madeline Alexander,Martin Begemann,Elvira Bramon,Nancy G. Buccola,Murray J. Cairns,Dominique Campion,Vaughan J. Carr,C. Robert Cloninger,David Cohen,David A. Collier,Aiden Corvin,Lynn E. DeLisi,Gary Donohoe,Frank Dudbridge,Jubao Duan,Robert B. Freedman,Pablo V. Gejman,Vera Golimbet,Stephanie Godard,Hannelore Ehrenreich,Annette M. Hartmann,Frans Henskens,Masashi Ikeda,Nakao Iwata,Assen Jablensky,Inge Joa,Erik G. Jönsson,Brian Kelly,Jo Knight,Bettina Konte,Claudine Laurent-Levinson,James Lee,Todd Lencz,Bernard Lerer,Carmel M. Loughland,Anil K. Malhotra,Jacques Mallet,Colm McDonald,Marina Mitjans,Bryan J. Mowry,Kieran C. Murphy,Robin M. Murray,F. Anthony O'Neill,Sang-Yun Oh,Aarno Palotie,Christos Pantelis,Ann E. Pulver,Tracey L. Petryshen,Digby Quested,Brien P. Riley,Alan R. Sanders,Ulrich Schall,Sibylle G. Schwab,Rodney J. Scott,Pak C. Sham,Jeremy M. Silverman,Kang Sim,Agnes A. Steixner,Paul A. Tooney,Jim van Os,Marquis P. Vawter,Dermot Walsh,Mark Weiser,Dieter B. Wildenauer,Nigel Williams,Brandon Wormley,Fuquan Zhang,Christos Androutsos,Paul D. Arnold,Cathy L. Barr,Csaba Barta,Katharina Bey,O. Joseph Bienvenu,Donald W. Black,Lawrence W. Brown,Cathy L. Budman,Danielle C. Cath,Keun-Ah Cheon,Valentina Ciullo,Barbara J. Coffey,Daniele Cusi,Lea K. Davis,Damiaan Denys,Christel Depienne,Andrea Dietrich,Valsamma Eapen,Peter Falkai,Thomas V. Fernandez,Blanca Garcia-Delgar,Daniel A. Geller,Donald L. Gilbert,Marco A. Grados,Erica Greenberg,Edna Grünblatt,Julie Hagstrøm,Gregory L. Hanna,Andreas Hartmann,Tammy Hedderly,Gary A. Heiman,Isobel Heyman,Hyun Ju Hong,Alden Y. Huang,Chaim Huyser,Laura Ibanez-Gomez,Ekaterina A. Khramtsova,Young Key Kim,Young Shin Kim,Robert A. King,Yun-Joo Koh,Anastasios Konstantinidis,Sodahm Kook,Samuel Kuperman,Bennett L. Leventhal,Christine Lochner,Andrea G. Ludolph,Marcos Madruga-Garrido,Irene A. Malaty,Athanasios Maras,James T. McCracken,Inge A. Meijer,Pablo Mir,Astrid Morer,Kirsten R. Müller-Vahl,Alexander Münchau,Tara Murphy,Allan L. Naarden,Peter Nagy,Gerald Nestadt,Paul S. Nestadt,Humberto Nicolini,Erika L. Nurmi,Michael S. Okun,Peristera Paschou,Fabrizio Piras,Federica Piras,Christopher Pittenger,Kerstin J. Plessen,Margaret A. Richter,Renata Rizzo,Mary M. Robertson,Veit Roessner,Stephan Ruhrmann,Jack Samuels,Paul Sandor,Monika Schlögelhofer,Eun-Young Shin,Harvey S. Singer,Dong-Ho Song,Jungeun Song,Gianfranco Spalletta,Dan J. Stein,S. Evelyn Stewart,Eric A. Storch,Barbara E. Stranger,Manfred Stuhrmann,Zsanett Tarnok,Jay A. Tischfield,Jennifer Tübing,Frank Visscher,Nienke Vulink,Michael Wagner,Susanne Walitza,Sina Wanderer,Martin Woods,Yulia Worbe,Gwyneth Zai,Samuel H. Zinner,Patrick F. Sullivan,Barbara Franke,Mark J. Daly,Cynthia M. Bulik,Andrew M. McIntosh,Michael Conlon O'Donovan,Amanda B Zheutlin,Ole A. Andreassen,Anders D. Børglum,Gerome Breen,Howard J. Edenberg,Ayman H. Fanous,Stephen V. Faraone,Joel Gelernter,Carol A. Mathews,Manuel Mattheisen,Karen S. Mitchell,Michael C. Neale,John I. Nurnberger,Stephan Ripke,Susan L. Santangelo,Jeremiah M. Scharf,Murray B. Stein,Laura M. Thornton,James T.R. Walters,Naomi R. Wray,Naomi R. Wray,Daniel H. Geschwind,Benjamin M. Neale,Kenneth S. Kendler,Jordan W. Smoller +606 more
TL;DR: Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes.
Journal ArticleDOI
Molecular mechanisms and potential functions of histone demethylases.
TL;DR: The biochemical activities of these histone demethylases towards specific Lys residues on histones, and in some cases non-histone substrates, have highlighted their importance in developmental control, cell-fate decisions and disease.
Journal ArticleDOI
Writing, erasing and reading histone lysine methylations
TL;DR: A more detailed understanding of histone lysine methylation is necessary for elucidating complex biological processes and, ultimately, for developing and improving disease treatments.
Journal ArticleDOI
ncRNA- and Pc2 Methylation-Dependent Gene Relocation between Nuclear Structures Mediates Gene Activation Programs
Liuqing Yang,Chunru Lin,Wen Liu,Jie Zhang,Kenneth A. Ohgi,Jonathan D. Grinstein,Pieter C. Dorrestein,Michael G. Rosenfeld +7 more
TL;DR: Observations delineate a molecular pathway linking the actions of subnuclear structure-specific ncRNAs and nonhistone protein methylation to relocation of transcription units in the three-dimensional space of the nucleus, thus achieving coordinated gene expression programs.
References
More filters
Journal ArticleDOI
High-resolution profiling of histone methylations in the human genome.
Artem Barski,Suresh Cuddapah,Kairong Cui,Tae-Young Roh,Dustin E. Schones,Zhibin Wang,Gang Wei,Iouri Chepelev,Keji Zhao +8 more
TL;DR: High-resolution maps for the genome-wide distribution of 20 histone lysine and arginine methylations as well as histone variant H2A.Z, RNA polymerase II, and the insulator binding protein CTCF across the human genome using the Solexa 1G sequencing technology are generated.
Journal ArticleDOI
NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins
TL;DR: The National Center for Biotechnology Information Reference Sequence (RefSeq) database provides a non-redundant collection of sequences representing genomic data, transcripts and proteins that pragmatically includes sequence data that are currently publicly available in the archival databases.
Journal ArticleDOI
Combinatorial patterns of histone acetylations and methylations in the human genome
Zhibin Wang,Chongzhi Zang,Jeffrey A. Rosenfeld,Jeffrey A. Rosenfeld,Dustin E. Schones,Artem Barski,Suresh Cuddapah,Kairong Cui,Tae-Young Roh,Weiqun Peng,Michael Q. Zhang,Keji Zhao +11 more
TL;DR: The data suggest that a large number of histone modifications may act cooperatively to prepare chromatin for transcriptional activation and be associated with promoters and enhancers.
Journal ArticleDOI
A Chromatin Landmark and Transcription Initiation at Most Promoters in Human Cells
TL;DR: The results of a genome-wide analysis of human cells suggest that most protein-coding genes, including most genes thought to be transcriptionally inactive, experience transcription initiation, and that transcription initiation at most genes is a general phenomenon in human cells.
Journal ArticleDOI
Identification of Genes Periodically Expressed in the Human Cell Cycle and Their Expression in Tumors
Michael L. Whitfield,Gavin Sherlock,Alok J. Saldanha,John I. Murray,Catherine A. Ball,Karen E. Alexander,John C. Matese,Charles M. Perou,Myra M. Hurt,Patrick O. Brown,David Botstein +10 more
TL;DR: The genome-wide program of gene expression during the cell division cycle in a human cancer cell line (HeLa) was characterized using cDNA microarrays to provide a comprehensive catalog of cell cycle regulated genes that can serve as a starting point for functional discovery.